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Context Many children with advanced cancer are not referred to palliative care despite both professional recommendations to do so and bereaved parental preference for earlier support from sub-specialty palliative care. Objectives To assess the feasibility, acceptability, and impact of an adaptive intervention to address individual and team-level barriers to specialty palliative care referrals. Methods A multiple-method approach assessed feasibility and acceptability among clinicians from pediatric oncology teams at a single institution. Quantitative measures of comfort with palliative care consultations, team cohesion, and team collaboration were conducted before and after the intervention. Number of palliative care consults were examined before, during, and after sessions. Intervention satisfaction surveys and qualitative interviews were conducted after the intervention. Results Twenty-six team members (90% of consented) attended at least one intervention session with 20 (69%) participants completing 75% or more sessions. The intervention was modified in response to participant feedback. After the intervention, participants reported greater team cohesion, comfort discussing palliative care consultation, team collaboration, process satisfaction, and decision satisfaction. Participants agreed that the training was useful, effective, helpful, and worthwhile, that they would use the skills, and that they would recommend the training to other providers. The numbers of palliative care consults increased before intervention sessions were conducted, but did not significantly change during or after the sessions. In the interviews, participants reported overall favorably regarding the intervention with some participants reporting changes in practice. Conclusion An adaptive intervention to reduce barriers to initiating palliative care for pediatric oncology teams is feasible and acceptable.

The instrumentation used in ophthalmic clinics can be a source of epidemics in health care set up. Contact tonometry with Schiotz or Applanation tonometer is associated with nosocomial epidemic keratoconjunctivitis outbreaks. Recently identified SARS-CoV-2 (COVID -19) spreads mainly via the respiratory route and fomites and can transmit through other body fluids, including tear film. Various ophthalmic instruments can become a common source of spreading cross infections. Chemical disinfection is one of the most common methods employed to decontaminate instruments and environmental surfaces and prevent transmission of infectious pathogens to patients through medical and surgical instruments. Various chemical disinfectants are available with a varied spectrum to work on a different group of organisms. In this article, we briefly cover commonly used chemical disinfectants in ophthalmic practice like Alcohol (Ethyl Alcohol, Isopropyl Alcohol), Chlorine-based solution (mainly Sodium Hypochlorite), Glutaraldehyde, Hydrogen Peroxide, Formaldehyde, Iodophors, and Quaternary Ammonium Compounds.

Context Clinicians deciding whether to refer a patient or family to specialty palliative care report facing high levels of uncertainty. Most research on medical uncertainty has focused on prognostic uncertainty. As part of a pediatric palliative referral intervention for oncology teams we explored how uncertainty might influence palliative care referrals. Objectives To describe distinct meanings of the term “uncertainty” that emerged during the qualitative evaluation of the development and implementation of an intervention to help oncologists overcome barriers to palliative care referrals. Methods We conducted a phenomenological qualitative analysis of “uncertainty” as experienced and described by interdisciplinary pediatric oncology team members in discussions, group activities and semistructured interviews regarding the introduction of palliative care. Results We found that clinicians caring for patients with advanced cancer confront seven broad categories of uncertainty: prognostic, informational, individual, communication, relational, collegial, and inter-institutional. Each of these kinds of uncertainty can contribute to delays in referring patients to palliative care. Conclusion Various types of uncertainty arise in the care of pediatric patients with advanced cancer. To manage these forms of uncertainty, providers need to develop strategies and techniques to handle professionally challenging situations, communicate bad news, manage difficult interactions with families and colleagues, and collaborate with other organizations.

BackgroundThe COVID-19 pandemic resulted in a loss of clinical clerkship opportunities for medical students. To address this problem while maintaining patient safety, this pilot study explored the feasibility of using a wearable headset to live stream teaching ward rounds to remotely based medical students.MethodsThree live streamed teaching ward rounds were delivered to three groups of medical students (n=53) using the Microsoft HoloLens 2 device and Microsoft Teams software, and results pooled for analysis. Feedback was gathered from students and instructors using the evaluation of technology-enhanced learning materials (ETELM). Patient feedback was gathered using the Communication Assessment Tool to explore any impact on interpersonal communication.ResultsThe response rate for the ETELM-learner perceptions was 58% (31/53), 100% for the ETELM-instructor perceptions. Students strongly agreed that the overall quality of the teaching session and instructors was excellent. However, 32% experienced issues with audio or video quality and one remote student reported cyber sickness. The statement ‘educational activities encouraged engagement with session materials/content’ returned the most varied response. Instructors reported technological problems with delivery while using the HoloLens 2 device and environmental noise in the ward was a disruptive factor. Preparation and skilled facilitation were key to delivering a high-quality teaching session. Patients reacted generally favourably to the technology and no negative effects on interpersonal communication were identified.ConclusionThe experience of live streamed ward rounds was well received by patients, medical students and teaching faculty. However, there remain limitations to the routine use of HoloLens 2 technology in our setting including steep learning curves, hardware costs and environmental factors such as noise and WiFi connectivity. Live streamed ward rounds have potential postpandemic implications for the judicious use of resources, and the possibility for few educationally minded clinicians to teach at scale in a patient-friendly manner.

Two postmenopausal women with breast cancer developed acute confusion and seizures, less than 24 hours after the first cycle of neoadjuvant chemotherapy with fluorouracil, epirubicin and low-dose cyclophosphamide. They were found to have severe, life-threatening hyponatraemia with sodium levels of 113 and 115 mEq/L, respectively. Both women made a full recovery within 24 hours of admission with slow correction of sodium levels. Following investigational workup, the most likely diagnosis was cyclophosphamide-associated syndrome of inappropriate antidiuretic hormone secretion (SIADH). Aprepitant - a commonly used antiemetic and moderate cytochromeP450 3A4 inhibitor was identified as the precipitating factor. Aprepitant was discontinued and both women were successfully re-challenged with full dose cyclophosphamide in an outpatient setting with no subsequent adverse events. This is a typical case of a rare cause of a common medical problem. A systematic approach to diagnosis and treatment of hyponatraemia in an oncology patient requires awareness of toxicities of systemic anticancer agents.

Context Pediatric palliative care consults for children with cancer often occur late in the course of disease and close to death, when earlier involvement would reduce suffering. The perceptions that pediatric oncology providers hold about the pediatric palliative care service (PPCS) may shape referral patterns. Objectives To explore how pediatric oncology providers at one institution perceived the hospital's PPCS and the way these perceptions may influence the timing of consultation. Methods We conducted semistructured qualitative interviews with pediatric oncology providers at a large children's hospital. Interviews were audio-recorded, transcribed, and analyzed by two coders using a modified grounded theory approach. Results We interviewed 16 providers (10 physicians, one nurse practitioner, two social workers, two psychologists, and one child life specialist). Three core perceptions emerged: 1) the PPCS offers a diverse range of valuable contributions to the care of children with advancing cancer; 2) providers held favorable opinions about the PPCS owing to positive interactions with individual palliative care specialists deemed extraordinarily emotionally skilled; and 3) there is considerable emotional labor involved in calling a PPCS consult that serves as a barrier to early initiation. Conclusion The pediatric oncology providers in our study held a highly favorable opinion about their institution's PPCS and agreed that early consultation is ideal. However, they also described that formally consulting PPCS is extremely difficult because of what the PPCS symbolizes to families and the emotional labor that the provider must manage in introducing them. Interventions to encourage the early initiation of palliative care in this population may benefit from a focus on the emotional experiences of providers.

12026 Background: Immune checkpoint inhibitor (ICI) therapy is now commonly used in a range of tumours and settings. Most data relating to outcomes and rates of immune-related adverse events (irAE) is derived from clinical trial or registry populations and small case series. Limited data exist for patients aged > 75 years. Here we present a multi-centre, real-world analysis of the outcomes and incidence of irAEs in older adults managed within a single comprehensive public health service. We also compare these outcomes to younger patients in the same cohort. Methods: A retrospective analysis of 2049 patients treated with ICIs was undertaken across 12 centres. All patients were managed within the UK National Health Service outside of a trial setting between June 2016 and September 2018. Patients received either ICI monotherapy (MT) or duel combination ICI therapy (CT) for malignant melanoma (MM), non-small cell lung cancer (NSCLC) or renal cell cancer (RCC). Data were collected using a standardised, collection tool. IrAEs ≥ grade 2 or all-grade endocrinopathies were recorded as per the Common Terminology Criteria for Adverse Events (V5) (CTCAE). Statistical analyses were performed using T-tests, Mann-Whitney and Chi-squared. Kaplan-Meier analysis and log-rank test were used for overall survival (OS) analysis. Results: 409 (20%) of patients were aged > 75 years(a), 1413 (69%) aged 50-75(b) and 227 (11.1%) aged < 50(c). There was no difference in sex, ethnicity or PD-L1 status (in the NSCLC cohort) between groups. Older patients were less likely to receive combination therapy (3%(a) v 13%(b) v 34%(c), p < 0.001). There was no difference in median OS across age groups in the cohort as a whole (p = 0.822) or for the individual tumour groups when treated with single agent ICI. Across the total cohort patients aged > 75 had no increased risk of any irAE (35%(a) v 33%(b) v 41%(c),p = 0.074). However there was an increase in irAEs in older patients treated with MT (36%(a) v 26(b) v 25%(c), p = 0.011) However there was no difference in the > 75s with regard to severe (G3/4) toxicity, toxicity type, admission or discontinuation due to toxicity in the aPD-1 group. In the overall cohort younger patients were more likely to develop irAEs and be admitted. Conclusions: Patients aged > 75 years treated with anti-PD1 therapy in the standard of care setting derive similar survival benefit to younger patients. There was no increase in ≥G3 toxicity. Our data support the safety of single agent aPD-1 ICI therapy in older adults and provide reassurance relating to the impact of toxicity.[Table: see text]

Purpose The aim of this study was to investigate the optic disc morphology in primary angle-closure glaucoma (PACG) versus primary open-angle glaucoma (POAG) in South Indians. Methods A total of 60 patients (60 eyes) with PACG and 52 patients (52 eyes) with POAG were included in a cross-sectional observational study. The glaucoma diagnosis was based on a glaucomatous appearance of the optic disc correlating with visual field defects. The glaucoma was graded as early, moderate, or severe, depending upon perimetric loss. All patients underwent an ophthalmic evaluation, including visual field examination and planimetric analysis of 30° stereoscopic color optic disc photographs. Results The POAG and PACG groups did not differ significantly in a disc or rim area, rim width, and frequencies of disc hemorrhages or rim notches. However, early POAG group (n = 15) had a significantly deeper cup depth (P = 0.01), larger beta zone (P = 0.01), and a higher frequency of localized retinal nerve fiber layer (RNFL) defects (P = 0.02) than early PACG (n = 20). Conclusion In the early stage of the disease, POAG compared to PACG may be characterized by deeper disc cupping, a larger beta zone of peripapillary atrophy, and a higher frequency of localized RNFL defects. Such differences in early glaucoma may suggest differences in pathophysiology in POAG and PACG.

7065 Background: Immune-related adverse events (irAE) are a recognised complication of immune checkpoint inhibitor (ICI) therapy. Previous characterisation of irAEs has been limited to clinical trial or registry populations and small case series. Here we present a multi-centre, granular, real-world analysis of the prevalence and outcomes of irAEs experienced by patients managed within a single comprehensive public health service. Methods: A multi-centre retrospective analysis of 2125 consecutive patients treated with ICIs was undertaken across 12 centres. All patients were managed within the UK National Health Service outside of a trial setting between June 2016 and September 2018. Patients received either ICI monotherapy (MT) or combination therapy (CT). Data were collected using a standardised, pre-piloted, collection tool. IrAEs ≥ grade 2 or endocrinopathies of any grade were considered clinically significant and recorded as per the Common Terminology Criteria for Adverse Events (V5) (CTCAE). Descriptive statistics were employed using Stata v15 (College Station, TX). Results: Patients received αPD-1 (1757; 82%), combination αPD-1/αCTLA-4 (285, 13%), αCTLA-4 (51; 2%) and αPD-L1 (31; 1%) immunotherapy for malignant melanoma (961), non-small cell lung cancer (788) or renal cell carcinoma (335). The median age was 66 (MT) and 57 (CT). Clinically significant irAEs occurred in 732 (34%) individuals; 28% (524) on MT and 73% (208) on CT. Colitis (206,10%), thyroiditis (194, 9%), hepatitis (142, 7%) and dermatitis (126, 6%) were most commonly observed. Grade 1 endocrinopathies occurred in 20% (173) of cases. Grade 2 irAEs occurred in 43% (359), grade 3 31% (269) and grade 4 6% (51). The were 3 (0.4%) cases of grade 5 irAE; pneumonitis (2) and hepatitis, all following αPD-1 MT. 93% (680) required corticosteroids with 64% (490) requiring systemic corticosteroids and 11% (80) steroid sparing immunosuppression. 16% (336) of patients had pre-existing autoimmune disease of whom 40% (136) experienced irAEs. IrAEs led to admission in 42% (308) of cases, accounting for 2996 bed days. Length of stay was 7 days (1-67; IQR 4-13). Higher dependency care was required in 0.7% (15) of cases. Colitis (35%, 107) and hepatitis (25%, 77) accounted for the most admissions. Pneumonitis accounted for 3% (66) of irAEs but 12% of admissions. Conclusions: One third of patients experienced a clinically-significant irAE resulting in significant morbidity and admission burden highlighting the need for effective management strategies to optimise patient outcomes.

Diamond Blackfan anemia (DBA) is a congenital disorder with erythroid (Ery) hypoplasia and tissue morphogenic abnormalities. Most DBA cases are caused by heterozygous null mutations in genes encoding ribosomal proteins. Understanding how haploinsufficiency of these ubiquitous proteins causes DBA is hampered by limited availability of tissues from affected patients. We generated induced pluripotent stem cells (iPSCs) from fibroblasts of DBA patients carrying mutations in RPS19 and RPL5. Compared with controls, DBA fibroblasts formed iPSCs inefficiently, although we obtained 1 stable clone from each fibroblast line. RPS19-mutated iPSCs exhibited defects in 40S (small) ribosomal subunit assembly and production of 18S ribosomal RNA (rRNA). Upon induced differentiation, the mutant clone exhibited globally impaired hematopoiesis, with the Ery lineage affected most profoundly. RPL5-mutated iPSCs exhibited defective 60S (large) ribosomal subunit assembly, accumulation of 12S pre-rRNA, and impaired erythropoiesis. In both mutant iPSC lines, genetic correction of ribosomal protein deficiency via complementary DNA transfer into the "safe harbor" AAVS1 locus alleviated abnormalities in ribosome biogenesis and hematopoiesis. Our studies show that pathological features of DBA are recapitulated by iPSCs, provide a renewable source of cells to model various tissue defects, and demonstrate proof of principle for genetic correction strategies in patient stem cells.

We congratulate Jadidi et al1 on their interesting article, “Ablation of Persistent Atrial Fibrillation Targeting Low-Voltage Areas With Selective Activation Characteristics.” They prospectively enrolled 85 patients with persistent atrial fibrillation undergoing ablation with a stepwise approach. No further lesions beyond pulmonary vein isolation (PVI) were delivered in 23 (27%), who were in sinus rhythm at the start or reverted to sinus rhythm during PVI. In the remaining 62 patients, further lesions were delivered within low-voltage areas (LVA) in the left atrium or in their borders. They found that these 62 cases had higher success rates compared with PVI-only controls chosen from a historical population. A couple of observations are …

Role of IOP in the definition, diagnosis and management of glaucoma has been undergoing vast changes over time. IOP has traditionally been one of the most important components in the definition and management of glaucoma. However, various population based studies have emphasized that very high number of patients with glaucoma (at least 50% in various population based studies) shows IOP < 21 mm Hg. Also, the information about the natural history of glaucoma has revealed that despite lowering IOP to early teens, glaucomatous optic neuropathy continues to progress in few patients. This article is an attempt to define the concept of target IOP and how its identification can be of relevance to the glaucoma practitioner.

Aim To report the diagnostic capability of Stratus OCT macular parameters in early glaucoma. Material and methods In a cross-sectional observational study, two groups of subjects (early glaucoma and normals) who satisfied the inclusion and exclusion criteria were recruited. The diagnosis of early glaucoma was based on a glaucomatous appearance of the optic disc correlating with visual-field defects (fulfilling at least two of three Anderson and Patella criteria, with a mean deviation better than or equal to −6 dB. All patients underwent a complete ophthalmic evaluation including visual-field examination (24−2/30−2 SITA standard programme) and imaging with Stratus OCT 3. The macular thickness map in Stratus OCT includes the fovea, inner macula and outer macula, with diameters of 1, 3 and 6 mm, a total of nine sectors. Sensitivity, specificity, area under the receiving operating characteristic curve (AUROC) and likelihood ratio were calculated for volume and thickness parameters in these nine sectors. Results 56 eyes (56 patients) with early glaucoma and 75 eyes (75 normals) were analysed. Only two parameters, the outer inferior average volume (p = 0.003) and the outer inferior average thickness (p = 0.002), were statistically significantly lower in the glaucoma group. Outer inferior average volume had a “best combination” of sensitivity and specificity (56% and 79% respectively). Both outer inferior average volume and thickness parameters yielded the best AUROCs of 0.66. Conclusions Outer inferior macular thickness and volume parameters in early glaucoma are significantly different from normals. The moderate sensitivity and specificity suggest that the role of macular parameters in the diagnosis of early glaucoma is limited.

The glaucomas are not a single disease entity but result from different mechanisms that eventually lead to loss of retinal ganglion cells. The terminal event in the glaucoma continuum is irreversible visual impairment and blindness. All the resources for the management of glaucoma are directed towards arresting further RNFL (retinal nerve fiber layer) loss so as to prevent further visual deterioration and preserve the quality of life for the rest of the patient’s life span. It is a slowly progressive chronic disease and regular follow-up is necessary to monitor the disease stability. It is also important to have regular followup to detect progression in earlier stage that might require escalation of treatment. The objectives of assessment during follow-up visits are: 1. To determine whether glaucoma is stable or progressing 2. If disease is progressing then to identify underlying mechanism for progression and change treatment (management plan) accordingly. Following are the factors we must evaluate during followup visit. However we must remember that every individual is unique and management plan needs to be individualized. Progression in glaucoma is assessed by structure (optic disk and RNFL) and function (visual field testing with white on white perimetry) independently or in association. A higher IOP is a risk factor for progression. Structure, function and IOP should be monitored at regular intervals. The follow-up period depends on the stage of the disease and stability.

In this article we provide an introduction to the use of likelihood ratios in clinical ophthalmology. Likelihood ratios permit the best use of clinical test results to establish diagnoses for the individual patient. Examples and step-by-step calculations demonstrate the estimation of pretest probability, pretest odds, and calculation of posttest odds and posttest probability using likelihood ratios. The benefits and limitations of this approach are discussed.

Cyclodialysis cleft is separation of meridonal ciliary muscle fibers from the scleral spur, thereby creating an additional drainage pathway of aqueous humor into the suprachoroidal space.1-4 This new drainage pathway leads to increase in uveoscleral outflow and may result in chronic ocular hypotony.5 The hypotony may also be due to decreased aqueous production.6 In past, creating an iatrogenic cyclodialysis cleft was used as one of the surgical option for the management of aphakic glaucoma. Cyclodialysis mostly occurs inadvertently during anterior segment surgery or due to blunt ocular trauma.2,7 The magnitude of the hypotony due to cyclodialysis cleft may not be proportional to the size of the cleft.5 As a result of ocular hypotony, patient may develop choroidal effusion, cystoid macular edema, optic nerve edema, engorgement and stasis of retinal veins, retinal folds, shallow anterior chamber, and cataract. Cystoid macular edema is one of the major contributing factor for visual loss due to hypotony caused by cyclodialysis cleft. If hypotony remains undetected and untreated for long time, visual loss may become permanent. Ocular hypotony itself is the most frequent cause of ciliochoroidal detachment following cataract extraction. Therefore, prior to considering cyclodialysis cleft as a cause of hypotony, other causes like wound leak, retinal detachment, chronic inflammation, and anterior segment ischemia should be ruled out. A careful gonioscopic examination of the anterior chamber angle is the key to the diagnosis of iatrogenic or traumatic cyclodialysis cleft. Sometimes it is difficult to see the cleft itself, as it is often small and obscured by a narrowed anterior chamber angle. A shallow chamber generally is caused by diffuse choroidal effusion due to hypotony that leads to forward displacement of the lens iris diaphragm. It has been suggested that anterior chamber deepening by the injection of a viscoelastic agent into the anterior chamber may facilitate visualization of the cleft.8 High-resolution ultrasound biomicroscopy (UBM) is a good tool to diagnose and provide detailed information about the extent and location of a cyclodialysis cleft.9-11 UBM allows imaging of a cyclodialysis cleft along its entire longitudinal and circumferential extent, with an accurate assessment of its location and size, regardless of gonioscopic visibility or patent cleft aperture.10,11 While gonioscopy allows evaluation only from the anterior face of the ciliary cleft, UBM provides cross sectional information of the iridocorneal angle. Once the diagnosis of cyclodialysis is made, medical treatment consisting of topical 1% atropine, 2 to 3 times daily should be attempted at-least for 6-8 weeks. Miotics and corticosteroids should be avoided. If the cleft is small in size (< 1⁄2 clock hour) or no significant structural or functional abnormalities secondary to hypotony is seen, then, wait and watch along with medical treatment may be the best mode of action. In small clefts, Argon laser therapy for repair of cyclodialysis can be tried. Various treatment options to close the cleft with laser has been described.3,12-17 It is assumed that, following laser treatment, edema of the choroid closes the cleft and blocks aqueous flow into the suprachoroidal space or perhaps the inflammation produced by laser treatment plays a role in altering the aqueous humor composition, thereby obstructing the drainage.13 Other surgical options includes external transconjunctival cryotherapy at the presumed location of a cyclodialysis cleft, direct cyclopexy, ciliochoroidal diathermy, anterior scleral buckling, or vitreoretinal procedures.18-24 We usually reserve surgical intervention for those cases that do not respond to medical treatment. We prefer direct surgical cyclopexy (Cleft closure) to other surgical options.

Primary open angle glaucoma (POAG) is usually a chronic, slowly progressive disease. At present, all resources are directed towards reduction of intraocular pressure (IOP), the only known causal and treatable risk factor for glaucoma, and medical management is frequently the first choice in most cases. With the introduction of innovative tools for early diagnosis and newer medications for treatment, decision-making in diagnosis and treatment of glaucoma has become more complex. The philosophy of glaucoma management is to preserve the visual function and quality of life (QOL) of the individual with minimum effects on QOL in terms of cost, side effects, treatment regime, follow-up schedules as well as socioeconomic burden. Our aim should be not to treat just the IOP, optic disc or visual field, but to treat the patient as a whole so as to provide maximum benefit with minimal side effects. In this article, we describe the scientific approach to medical management, mainly of POAG.

To evaluate the diagnostic capability of optical coherence tomography (Stratus OCT 3) for early glaucoma in Asian Indian eyes.Cross-sectional observational study.Two groups of patients (early glaucoma and normal) who satisfied the inclusion and exclusion criteria were included. Early glaucoma was diagnosed in presence of open angles, characteristic glaucomatous optic disc changes correlating with the visual field on automated perimetry (visual field defect fulfilling at least 2 of Anderson and Patella's 3 criteria with mean deviationor = -6 dB). Normals had visual acuityor =20/30, intraocular pressure22 mmHg with normal optic disc and fields and no ocular abnormality.All patients underwent complete ophthalmic evaluation including visual field examination (24-2/30-2 SITA standard program) and imaging with Stratus OCT 3.Sensitivity, specificity, positive and negative predictive values, area under the receiving operating characteristic curve and likelihood ratios were calculated for various Stratus OCT 3 parameters.Seventy-two eyes (72 patients) with early glaucoma and 96 eyes (96 normal subjects) were analyzed. The inferior maximum parameter had the best combination of sensitivity and specificity, 75% (95% confidence interval [CI], 70.2-79.8%) and 89.6% (95% CI, 82.6-96.6%), respectively. The 6-o'clock parameter had a sensitivity of 61.1% (95% CI, 52.3-69.9) and specificity of 99% (95% CI, 95-100); for an assumed prevalence of 5%, the positive and negative predictive values were 75% and 98%, respectively. The positive likelihood ratio for the 6-o'clock parameter (P5%) in early glaucoma was 61.Optical coherence tomography has moderate sensitivity with high specificity for the diagnosis of early glaucoma and may have a potential role in screening.

Purpose To determine the normal age-related loss of retinal nerve fiber layer thickness (RNFLT) as measured on Stratus optical coherence tomography (OCT 3; Carl Zeiss Meditec, Dublin, CA) in an Asian Indian population. Design Prospective, cross-sectional, observational study. Participants One hundred eighty-seven eyes of 187 normal subjects (age range, 5–75 years) who satisfied the inclusion and exclusion criteria were included. The subjects were defined as normal if they had visual acuity of 20/30 or better, intraocular pressure less than 22 mmHg with normal optic disc, and no ocular abnormality. Methods All patients underwent complete ophthalmic evaluation including imaging with Stratus OCT 3. Simple linear regression was performed to study the effect of age on RNFLT, with age as the independent variable and RNFLT as the dependent variable. Spearman's correlation was studied between the age and RNFLT. An analysis of variance was applied to compare RNFLT between the different age groups. The chi-square test also was used to evaluate the relationship between age and RNFLT. Main Outcome Measure Effect of age on RNFLT. Results One hundred eighty-seven eyes of 187 normal subjects were analyzed. Mean age±standard deviation was 33.0±19.7 years (range, 5–75). Average RNFLT and RNFLT by quadrant demonstrated the tendency of RNFLT to decrease with increasing age, especially after age 50 years. Average RNFLT demonstrated a negative slope of 0.16 μm/year (95% confidence interval [CI], −0.1 to −0.24). By quadrant, the superior average (negative slope, –0.23 μm/year; 95% CI, −0.1 to −0.34) showed a maximum tendency to decline with age, whereas in the inferior quadrant (negative slope, −0.08 μm/year; 95% CI, 0.05 to −0.24), the age-related decay was minimal. Six clock-hour RNFLT had a least negative slope of −0.022 μm/year (95% CI, −0.08 to −0.1). Chi-square test results showed a significant inverse relationship between age and average RNFLT ( P = 0.01). Conclusions Age-related retinal nerve fiber layer (RNFL) loss is not uniform in all the quadrants, with maximum loss in the superior quadrant, and seems to reach a maximum after the age of 50 years. Furthermore, it seems that inferior quadrant RNFL is more resistant to loss.

The direct and indirect costs of suspected human rabies exposure were estimated for San Luis Obispo and Santa Barbara counties, California, USA. Clinic, hospital, and county public health records (1998-2002) were examined to determine direct costs for postexposure prophylaxis (PEP), and 55 (41%) former patients were contacted to voluntarily provide estimates of their indirect costs associated with receiving PEP. Additional costs due to public health and animal control personnel responses to rabid animals were collected, including diagnostic testing and wages. The mean total cost of a suspected human rabies exposure was $3,688, the direct costs per case were $2,564, and the indirect costs were $1,124 of that total. About one third of the total cost for suspected human rabies exposure was attributed to indirect costs (e.g., lost wages, transportation, and day-care fees), most of which were not reimbursable to the patient.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow (BM) failure, pancreatic insufficiency, and skeletal abnormalities. Mutations in the SBDS gene on chromosome arm 7q, explain 90% of SDS cases (Boocock et al, 2003). SBDS is essential for the assembly of mature ribosomes. Frequently SDS patients are compound heterozygotes for two common SBDS mutations (the 183_184 TA→CT and 258+2 T→C mutations). The null 183_184 TA→CT mutation results in a stop codon while the 258+2 T→C mutation causes a splicing error with only small amounts of full length protein produced (Austin et al, 2005). Homozygosity for the 183_184 TA→CT mutation has never been found. Here we describe acquired copy number neutral loss of heterozygosity (CN-LOH) for most of 7q in an SDS patient. The clone of BM cells with CN-LOH contained 2 copies of the gene with the 258+2 T→C mutation, which increases the level of SBDS protein providing the likely explanation for clonal expansion of the affected haematopoietic progenitor cell. Neutropenia was found in a neonatal female when a complete blood count was performed due to concerns of neonatal sepsis. In addition to haematological and infectious issues, this patient also developed exocrine pancreatic insufficiency. At four months of age she was diagnosed with SDS, which was confirmed by gene sequencing. A BM aspiration and biopsy were performed on the patient at 13 months of age and a follow-up examination was performed a year later. Karyotypes were prepared, and single nucleotide polymorphism (SNP) analysis of DNA isolated from the BM aspirates was accomplished with the HumanHap610 (first BM) or Omni1-Quad (second BM aspirate) genotyping beadchip (Illumina, San Diego, CA). The patient and her unaffected parents were recruited for a research study at the Children's Hospital of Philadelphia, Pennsylvania, USA. Samples from skin, BM and peripheral blood (PB) from the patient as well as PB from the parents were obtained after written informed consent. The Ethics Committee of the Hospital approved the study in accordance with the declaration of Helsinki. SNP analysis of DNA from the parents PB was performed with the Illumina Human Omni1-Quad gene chip. Data analysis was performed with GenomeStudio Software (Illumina). Plots of two parameters, the log2R ratio and the B allele frequency, provided information regarding copy number and genotype. The comparison between the genotype data of the parents and the CN-LOH region in the patient was performed with GenomeStudio Software. Polymerase chain reaction and Sanger sequencing of BM DNA and DNA from cultured skin fibroblasts and PB was carried out by standard procedures (Boocock et al, 2003, Sanger and Coulson 1975). The BM aspirate and biopsy performed on the patient at 13 months of age, showed normal cellularity, with normal erythropoiesis and megakaryopoiesis, with a decrease in myeloid progenitors. Standard cytogenetic analysis revealed a normal karyotype 46,XX. Genome wide (GW) SNP array analysis revealed CN-LOH in 20% of the cells from a region just below the centromere of chromosome 7 to the end of 7q (Figure 1). A similar percentage of cells with 7q CN-LOH and no other cytogenetic abnormalities were identified on a second BM one year later. Figure 1 B allele frequency results and LOH analysis from BM of CHOP256.01 at chromosome 7 Genotype analysis of the parents showed that the mother was heterozygous for the 183_184 TA→CT mutation and the father was heterozygous for the 258+2 T→C mutation. The patient was heterozygous for both mutations. Analysis of 683 informative markers from 7q showed that the LOH was due to loss of the maternal alleles. The comparison of the 258+2 T→C sequencing peaks between fibroblast and BM samples from the patient showed that the 258+2 C peak was slightly higher than the 258+2 T peak in the BM sample but not in the skin sample (Figure 2). These results indicate that the cells with LOH of 7q detected in the BM of the patient have two copies of the SBDS 258+2 T→C mutation. Figure 2 Chromatograph of the SBSD 258+2 T→C mutation from BM(A) and skin (B) Our results are consistent with clonal expansion of cells, in the BM of an SDS patient, that have undergone a genetic event producing LOH for 7q, including the SBDS gene. Genetic analysis shows that the expanded clone contains 2 copies of the hypomorphic SBDS mutation while the constitutional genotype is compound heterozygous for 258+2 T→C and 183_184 TA→CT. This is the third example of somatic genomic changes leading to clonal expansion in the BM of SDS patients. Clonal cytogenetic abnormalities affecting 7q have been repeatedly observed in the BM of SDS patients (Dror et al, 2002, Shimamura 2006, Smith et al, 2002). The most frequent is an isochromosome 7q (i(7)(q10)), leading to 3 copies of 7q. Interestingly, all of the compound heterozygous SDS patients with i(7)(q10) clones analysed so far have an extra copy of the 258+2 T→C mutated gene (Minelli et al, 2009). In those cases, as in the case described here, there is an increase in the copy number of the gene producing some active protein. Another common cytogenetic event in SDS is an interstitial deletion in 20q removing a region that includes the EIF6 gene (Pressato et al, 2012). It was recently shown that SBDS couples with the GTPase EFL1 to cause the release of EIF6 from the pre-60S ribosome subunit, an essential step in the formation of the mature ribosome (Finch et al, 2011). It was hypothesized that the decreased amount of EIF6 in these cells, in the context of SBDS deficiency, improved ribosome biogenesis. Again the deletion is associated with clonal expansion. Interestingly SDS has an increased likelihood of progression to myelodysplastic syndrome/acute myeloid leukaemia that is frequently associated with numerical and structural chromosome 7 anomalies. To the contrary, both i(7)(q10) and the 20q deletion in patients with SDS are associated with low risk of transformation of the affected cell clone (Minelli et al, 2009, Pressato, et al, 2012), though this relationship has been questioned (Dror et al, 2002). Interestingly this patient is another example of an emerging paradigm whereby, in the context of the aplastic BM, haematopoietic progenitor cells that partially overcome the disease causing genetic lesion due to acquired genomic changes have a survival or growth advantage, leading to clonal expansion. Somatic genomic changes and clonal expansion have been observed in other BM failure syndromes (May 2011). These changes often improve blood cell production and in some cases decrease the risk of leukaemic transformation. Such “natural gene therapy” may be instructive concerning possible drug targets.

Development of drug resistance in HIV infected children with treatment failure is a major impediment to selection of appropriate therapy. HIV genotype resistance assays predict drug resistance on the basis of mutations in the viral genome. However, their clinical utility, especially in a resource limited setting is still a subject of debate. The authors report two cases in which both the children suffered from treatment failure of various antiretroviral therapy regimes. In both the cases, Genotype Resistance Testing (GRT) prompted a radical change from proposed failure therapy as per existing guidelines. GRT was specifically important for the selection of a new dual Nucleoside reverse transcriptase inhibitors (NRTI) component of failure regimen by identifying TAMS and M184V mutations in the HIV genome. These case reports highlight the importance of GRT in children failing multiple antiretroviral regimes; and emphasizes the need to recognize situations where GRT is absolutely essential to guide appropriate therapy, even in a resource limited setting.

“Early Aspirin” or a medium dose of aspirin 6 hours after Coronary Artery Bypass Graft (CABG) Surgery is strongly recommend by international guidelines (EACTS 2007/AHA 2011 guidelines, Level1a evidence) to protect venous graft patency. However, compliance with Early Aspirin prescription at our centre is poor due to long standing hospital cultural practices and lack of awareness. We completed a two-cycled retrospective audit of 53 (September 2015 Baseline), 65 (January 2016 First Cycle) and 58 (June 2016 Second Cycle) consecutive CABG patients. Interval interventions included educational presentations, educational leaflets/posters, pharmacy liaison and modifications to e-prescription order-sets. Medical, nursing and pharmacy staff were involved in the audit strategies. Early aspirin prescription improved from 23% to 48% to 55% while administration of Early Aspirin improved from 17% to 38% and finally to 48% by second improvement cycle. Significantly, the proportion of patients with omission of early aspirin despite a clear clinical indication, decreased by 50% over the audit period. Important practical considerations were the last dose of anti-platelets preoperatively and amount of of bleeding from mediastinal drains post operatively. A multidisciplinary team based approach led to a 139% improvement in prescription and 182% improvement in administration of “Early Aspirin” after CABG surgery.

A 5-year-old girl presented with a 3-month history of left side facial palsy, followed sequentially by purulent ear discharge, complete external ophthalmoplaegia and blurred vision. On clinical examination she was febrile with left-sided conductive hearing loss. She was clinically diagnosed to have chronic suppurative otitis media of the unsafe type with petrous apicitis, middle cranial fossa abscess and cavernous sinus involvement. Preliminary CT scan findings were reported as a large left temporal lobe abscess and left otitis media with cholesteatoma. MRI of the brain obtained later corroborated the abnormalities detected on the CT scan. Ten days after admission, a mass was seen protruding from the external auditory canal. A biopsy of the mass was obtained and sent for histopathological examination. Meanwhile, review of the MRI suggested an aggressive neoplasm such as sarcoma/rhabdomyosarcoma. Histopathology clinched the final diagnosis of an anaplastic type of embryonal rhabdomyosarcoma of the middle ear cleft.

PURPOSE To report the role of choroidal drainage in patient with acute bilateral angle closure secondary to cilio-choroidal effusion with Topiramate. DESIGN Interventional case report. METHODS Two weeks after commencing tablet Topiramate (Sulfamate derivative) for management of epilepsy, a patient developed bilateral acute angle closure secondary to cilio-choroidal effusion with lenticulo-corneal touches for which choroidal drainage was performed in 1 eye. RESULTS After choroidal drainage, anterior chamber deepened, corneal edema resolved, choroidals started resolving, and intraocular pressure was controlled without medication. CONCLUSIONS In patients presenting with acute angle closure secondary to Topiramate toxicity, choroidal drainage if indicated, is a safe and effective interventional procedure.

Describe 3 approaches to enhance collaboration between palliative care and cancer researchers. Successful integration of palliative care with oncologic care requires an understanding of specific challenges, opportunities, and strategies. Among challenges, the taskofmeetingpalliative careneedswhile supportingpatients, families, and clinicians who wish to continue cancer-directed treatment, including experimental therapies, is especially complex. Rapid developments in oncologic therapies with better outcomes for some malignancies may make it harder to establish realistic and appropriate goals of care. Other important issues include the appropriate distribution of responsibilities for palliative care within the healthcare team, so that not only are the contributions of clinicians across disciplines and professions valued, optimized, and coordinated, but also that patients with cancer receive the benefits of both generalists and specialists in palliative care. Effective collaboration between palliative care and cancer researchers is essential to enhance the evidentiary foundation for integrated care and to ensure attention to the palliative needs of patients participating in clinical trials. In addition, the development of innovative strategies is neededaswemakeprogress in educating the clinical workforce, including oncologists, other generalists, andpalliative care specialists toprovidepalliative care together with cancer care. Models of integration of palliative care in oncologymust fit the needs of patients, families, and providers in community settings (inpatient and outpatient), where most cancer care in the US is delivered, as well as in academic referral centers. Finally, in our rapidly changing healthcare environment, palliative caremust be paired with cancer care in ways that are appropriate across different systems for reimbursement, including distinctive systems that apply in some care hospitals. In the proposed workshop, we will bring together individuals with relevant expertise from across the country to provide an interprofessional perspective, help participants think about key topics, and engage them in envisioning the future for palliative care at the forefront of cancer care.

Background: CD4 counts are a standard laboratory measure of disease progression in HIV-infected children. However, CD4 counting is done by flow cytometry and may not always be possible in every centre treating HIV-infected children in resource-limited countries. Absolute Lymphocyte Count (ALC) can be derived easily by performing a routine white blood cell count. The World Health Organization (WHO) in 2006 had recommended ALC to identify HIV-infected children in need of ART in resource-limited settings, when CD4 cell count is not available. Aims: This study aims to assess the reliability of using ALC as a marker for starting antiretroviral therapy (ART) in HIV-infected children in a tertiary hospital setting. Settings and Design: Retrospective analysis of 46 HIV-infected children who presented at a pediatric HIV clinic at a tertiary referral centre from 2002-2005. Materials and Methods: Using WHO 2006 guidelines for cutoff values of ALC and 2008 guidelines for CD4% as a comparative standard, a retrospective analysis was done on ART-naοve HIV-infected children who underwent baseline CD4% and ALC, and sensitivity and specificity of ALC was calculated. Statistical Analysis: Fischer exact two-tailed analysis was used to correlate ALC and CD4 and need for starting ART. Results: Sensitivity of ALC was 27.6% (72.4% were false negatives), specificity was 70.6%, with positive predictive value of 61.5%. On comparison across all clinical stages of disease, only 13/46 children (28.2%) would have been started on ART according to ALC cutoffs versus 29/46 children (63.04%) using CD4 criteria (P value=0.0015). In children with WHO clinical Stage 1 or 2 of disease, only 1/11 (9.1%) children were identified by ALC as requiring ART as opposed to 6/11 (54.5%) children by CD4% (P=0.0635). Conclusions: ALC is an unreliable marker to determine the need for starting ART in HIV-infected children.

Inherited bone marrow failure syndromes (IBMFS) are a diverse set of genetic disorders characterized by the inability of the bone marrow to produce sufficient circulating blood cells. The purpose of this review is to highlight novel findings in recent years and their impact on the understanding of IBMFS.Mutations in over 80 different genes have been associated with the development of bone marrow failure (BMF). The products of the genes mutated in IBMFS frequently participate in housekeeping pathways, which are important for cell growth and division rather than being specific for hematopoiesis. The common theme of these pathways, when disturbed, is the activation of p53, leading to cell cycle arrest, senescence, and cell death. With continued improvement in therapy for IBMFS, late complications, such as development of malignancies, are seen more frequently. This highlights the importance of understanding the affected pathways and their roles in cancer development.The recent advancement of our understanding of IBMFS has come largely through the identification of the genetic lesions responsible for disease and the investigations of their pathways. Applied in clinical practice, these findings make it possible to unambiguously identify mutation carriers even before the development of BMF and exclude or confirm a suspected clinical diagnosis for many of the more common IBMFS. The further characterization of the pathways leading to IBMFS is likely to reveal novel targets for screening tests, prognostic biomarkers, and improved and specific therapeutics.

Purpose To report the prevalence of ocular morbidity in patients with treated multibacillary Hansen's disease (HD) using modern ophthalmic diagnostic techniques in a rural community endemic for HD. Design Cross-sectional, observation study. Participants All patients with multibacillary HD who had completed their multidrug therapy and who resided in 4 defined geographical areas in Vellore, Tamil Nadu, India. Methods All participants underwent a complete eye examination that included slit-lamp examination, esthesiometry, gonioscopy, applanation tonometry, and dilated fundus examination, including a stereobiomicroscopic examination of the fundus at an ophthalmic center set up for that purpose. Glaucoma suspects underwent automated perimetry using a Humphrey Field Analyzer (Humphrey Instruments, San Leandro, CA). Main Outcome Measures The prevalence of various ocular disease parameters were reported as mean value with 95% confidence interval. The difference of disease prevalence between various leprosy groups was compared using an unpaired t test. The association between eye symptoms and potentially sight-threatening complications was analyzed using the chi-square test. Results Three hundred eighty-six of the 446 patients with multibacillary HD residing in the defined areas were evaluated. Four patients (1.04%; 95% confidence interval [CI], 0.0%–2.0%) were bilaterally blind; 33 (8.55%; 95% CI, 5.8%–11.3%) had unilateral blindness. Mean intraocular pressure was 12 mmHg (standard deviation, 4.1 mmHg), and prevalence of glaucoma was 3.6% (95% CI, 1.8%–5.5%). Potentially sight-threatening (PST) pathologic features (corneal anesthesia, lagophthalmos, uveitis, scleritis, and advanced glaucoma) were present in 10.4% (95% CI, 7.4%–13.4%) of patients. Significant cataracts occurred 3 times more frequently in those with polar lepromatous leprosy. The odds ratio for PST pathology in the presence of patient-reported symptoms (pain, redness, inability to close eye, burning, and irritation) was 2.9 (95% CI, 1.34–6.26). Conclusions Patients who have completed treatment for multibacillary HD continue to have significant ocular morbidity. A history of specific eye symptoms can be the basis for referral by field staff. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Purpose To evaluate the diagnostic ability of scanning laser polarimetry (GDx variable corneal compensator [VCC]) for early glaucoma in Asian Indian eyes. Design Cross-sectional observational study. Participants Two groups of patients (early glaucoma and normal) who satisfied the inclusion and exclusion criteria were included. Early glaucoma was diagnosed in presence of open angles, characteristic glaucomatous optic disc changes correlating with the visual field (VF) on automated perimetry (VF defect fulfilling at least 2 of 3 Anderson and Patella's criteria with mean deviation ≥ −6 decibels). Normal subjects had visual acuity ≥ 20/30 and intraocular pressure Methods All patients underwent complete ophthalmic evaluation, including VF examination (24-2/30-2 Swedish interactive threshold algorithm standard program) and imaging with GDx VCC. Main Outcome Measures Sensitivity, specificity, positive predictive value and negative predictive value, area under the receiving operating characteristic curve, and likelihood ratios (LRs) were calculated for various GDx VCC parameters. Results Seventy-four eyes (74 patients) with early glaucoma and 104 eyes (104 normal subjects) were enrolled. TSNIT Std Dev (temporal–superior–nasal–inferior–temporal standard deviation) had the best combination of sensitivity and specificity—61.3 and 95.2, respectively—followed by nerve fiber index score > 50 (sensitivity, 52.7%; specificity, 99%). Nerve fiber index score > 50 had positive and negative predictive values of 74.3% and 97.6%, respectively, for an assumed glaucoma prevalence of 5%. Nerve fiber index score > 50 had a positive LR (+LR) of 54.8 for early glaucoma. Conclusions GDx VCC has moderate sensitivity, with high specificity, in the diagnosis of early glaucoma. The high +LR for the nerve fiber index score can provide valuable diagnostic information for individual patients.

Objectives Identify three unique pharmacologic properties of ketamine. Identify three challenges and three benefits of the use of ketamine in the palliative care setting. Collect three tools to develop a protocol for ketamine use and implementation in one’s own palliative care practice. The N-methyl-D-aspartate (NMDA) receptor is involved in both the sensitization of central neurons and the functioning of the opioid receptor, and there is evidence that one NMDA receptor antagonist, ketamine, has analgesic properties. At subanesthetic doses, ketamine may be used as a brief infusion for treatment of severe refractory pain or as a more prolonged infusion, typically at the end of life. Ketamine has also been delivered orally and intranasally to patients in the palliative care setting. The evidence to support the benefit of ketamine as an adjuvant to opioid therapy is quite limited. Nevertheless, this approach continues to be used by experienced pain and palliative care clinicians, particularly in the setting of otherwise refractory neuropathic pain at the end of life. The goal of this session is to review the literature involving ketamine use in the palliative care setting, review its pharmacokinetics and pharmacodynamics, relay case studies to delineate the challenges and benefits of ketamine use, and enable practitioners to implement the use of ketamine in both pediatric and adult palliative care settings.