"Window of Opportunity" in Ocular Graft-Versus-Host Disease Treatment: Results of a Longitudinal Study and Case Reports.

OBJECTIVE: To perform a longitudinal study for determining the development of ocular graft-versus-host disease (oGVHD) after allogeneic hematopoietic stem cell transplant (HSCT) and report cases that illustrate the "window of opportunity" concept in oGVHD treatment. METHODS: Patients (n=61) were examined at prescheduled clinic visits before HSCT and three-month intervals after HSCT for 2 years. The presence or absence of oGVHD was determined using the international chronic oGVHD consensus group diagnostic criteria. Ocular surface washings (OSW) were obtained at each visit and analyzed for cytokine levels. RESULTS: In the longitudinal study, 26.2% (n=16; progressed group) developed either probable (11.5%, n=7) or definite oGVHD (14.8%, n=9). In the progressed group, clinically significant changes in signs (corneal staining and Schirmer I test) and symptoms at the post-HSCT visit as compared with the pre-HSCT visit occurred at 9 months. Significant differences in clinical signs and symptoms (whether average post-HSCT values or changes in values over pre-HSCT levels) between the progressed and nonprogressed groups occurred at a 9-month visit or later. In the progressed group, 55.6% of eyes that had negative matrix metalloproteinase 9 (MMP-9) test at pre-HSCT turned MMP-9 positive at 3 to 6 months post-HSCT. In the progressed group, interleukin 8 levels in OSW were significantly increased at 6 months post-HSCT. In the case reports, the "window of opportunity" was detected by MMP-9 turning positive, early corneal staining, interleukin 8 increase in OSW, and peripheral corneal epithelial thinning, which resolved with treatment initiation. CONCLUSIONS: A "window of opportunity" exists before patients developing symptomatic tear-deficient dry eye after HSCT for initiating treatment that may preempt oGVHD development; however, larger-scale longitudinal studies are needed for definitive recommendations.

Recombinant Deoxyribonuclease I Eye Drops for Ocular Graft Versus Host Disease: Results of a Randomized Clinical Trial.

OBJECTIVE: We have previously shown that neutrophil extracellular traps (NETs) are present on the ocular surface of patients with ocular graft versus host disease (oGVHD), contributing to inflammation and surface disease. Therefore, we performed a clinical trial using deoxyribonuclease I (DNAase) eye drops to test the hypothesis that reducing the abundance of NETs from the ocular surface will reduce signs and symptoms of oGVHD. METHODS: A prospective, phase I or II, randomized, placebo-controlled, double-masked clinical trial was performed to determine the safety and preliminary efficacy of DNAase (0.1%) eye drops four times daily for 8 weeks in patients with oGVHD (n=58). Intent-to-treat analysis was performed to determine the change in safety outcome measures (drug tolerability and proportion of adverse events) and efficacy outcome measures (ocular surface disease index [OSDI] score and corneal staining) between baseline and week 8. RESULTS: Tolerability and adverse events were similar in the vehicle and DNAase groups. Within the DNAase group (but not the vehicle group), corneal staining showed a statistically significant and clinically meaningful reduction at week 8 (3.50 [2.75; 5.00]) compared with baseline (5.00 [3.00; 7.00]). The OSDI score also showed a statistically significant clinically meaningful reduction of 18.4 (9.16; 33.1) ( P <0.001) at week 8 compared with baseline (45.5 [31.8; 50.0]) within the DNAase group. The proportion of eyes that had improvement in subjective global assessment (SGA) and mucous discharge was significantly greater in the DNAase group (55.6% and 57.7% at weeks 4 and 8, respectively; P <0.0001 at both time points) as compared with the vehicle group (35.7% and 34.0% at weeks 4 and 8, respectively). CONCLUSIONS: Treatment of patients with oGVHD using DNAase eye drops is safe and demonstrates preliminary efficacy. Deoxyribonuclease I eye drops can potentially reduce the severity of signs and symptoms of ocular surface disease in patients with oGVHD.

Pathological consequences of anti-citrullinated protein antibodies in tear fluid and therapeutic potential of pooled human immune globulin-eye drops in dry eye disease.

PURPOSE: To investigate the role of Anti-Citrullinated Protein autoantibodies (ACPAs) in the pathology of dry eye disease (DED) and the therapeutic potential of pooled human immune globulin-eye drops in these patients. METHODS: We investigated the presence of citrullinated proteins and ACPAs in ocular surface wash (OSW) and conjunctival impressions from patients with DED and determined the pathological consequences of OSW with high ACPA using in vitro experiments and in vivo murine models. We performed a randomized, double-masked, pilot clinical trial to determine the safety, tolerability and preliminary efficacy of using pooled human immune globulin-eye drops to treat DED patients with ACPAs in OSW. RESULTS: We found that neutrophils are a source of citrullinated proteins on the ocular surface of DED patients. We detected significantly higher immunoglobulin amount and presence of several species of ACPAs in OSW from DED patients. We also found that OSW with high ACPA contributes to production of NETs, and that ACPAs cause ocular surface disease in murine eyes, both of which are reduced with addition of Immune globulins. As compared to Vehicle treatment, pooled human immune globulin-eye drops (IVIG 4 mg/mL) twice a day for 8 weeks caused significant reduction in signs and symptoms of DED with no difference in tolerability or adverse events. CONCLUSIONS: This is the first report demonstrating ACPAs in OSW of DED patients and their contribution to ocular surface disease. The first-in-human clinical trial suggests that pooled immune globulin-eye drops are a potential new class of biologic therapies for Dry Eye patients.

Tough love or bullying? New nurse transitional experiences.

AIMS AND OBJECTIVES: This qualitative paper reports on the transition experiences of new nurses and preceptors in Singapore, focussing on the construction of a supervisor strategy termed 'tough love'. The authors discuss the concept of tough love, as a metaphorical euphemism for workplace bullying and interrogate rationales from the data that behaviours associated with tough love, prepare nurses for independence and competence in their new responsibilities. BACKGROUND: Successful transition of new nurses to professional practice is dependent on the transition challenges they face at work. When new nurses are well supported in the clinical environment, retention occurs. However, when workplace adversity intensifies, nurse turnover rates increase. DESIGN: This qualitative study was conducted using a constructivist grounded theory approach. METHODS: New nurses (n = 26) and preceptors (n = 5) from five different hospitals participated in the study. Data were collected from semi-structured interviews and reflective journal entries and analysed using the constant comparative method. FINDINGS: Data analysis gave rise to the generation of a definition of tough love, not otherwise identified in the literature, as the negative behaviours of senior nurses towards new nurses, that is rationalised as a well-intentioned but nevertheless abusive strategy, used to condition targets into conforming to expected professional or organisational behaviour. CONCLUSIONS: The authors conclude that tough love behaviour damages the transition experience of new nurses and has the potential to influence decisions on whether to remain in a health organisation and indeed the profession. RELEVANCE TO CLINICAL PRACTICE: Given nursing shortages in Singapore and internationally and that the retention of new nurses appears to be part of the problem, tough love behaviours and cultures clearly need to be addressed if investment into training and recruitment are to be realised.

New nurse transition: success through aligning multiple identities.

PURPOSE: The purpose of this paper is to explore the perceptions of new nurses in Singapore of their experiences of role transition and to examine the implications for managers in terms of employee training, development and retention. DESIGN/METHODOLOGY/APPROACH: This qualitative study was conducted using a constructivist grounded theory approach. In total 26 novice nurses and five preceptors (n=31) from five different hospitals participated in the study. Data were collected from semi-structured interviews and reflective journal entries and analysed using the constant comparative method. FINDINGS: The findings revealed that novice nurses remained emotionally and physically challenged when experiencing role transition. Two major constructs appear to play an important part in the transition process; learning how to Fit in and aligning personal with professional and organisational identities. The findings highlight factors that facilitate or impede Fitting in and aligning these identities. ORIGINALITY/VALUE: Although the concept of Fitting in and its relation to the attrition of novice nurses has been explored in global studies, that relationship has not yet been theorised as the dynamic alignment of multiple identities. Also, whilst most research around Fitting in, identity and retention has been conducted in western countries, little is known about these issues and their interrelationship in the context of Singapore. The study should inform decision making by healthcare organisations, nurse managers and nursing training institutions with respect to improving the transition experience of novice nurses.