Cell-based Therapies for Corneal and Retinal Disorders.

Maintenance of the visual function is the desired outcome of ophthalmologic therapies. The shortcomings of the current treatment options, like partial recovery, post-operation failure, rigorous post-operative care, complications, etc., which are usually encountered with the conventional treatment options has warranted newer treatment options that may eliminate the root cause of diseases and minimize the side effects. Cell therapies, a class of regenerative medicines, have emerged as cutting-edge treatment option. The corneal and retinal dystrophies during the ocular disorders are the major cause of blindness, worldwide. Corneal disorders are mainly categorized mainly into corneal epithelial, stromal, and endothelial disorders. On the other hand, glaucoma, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, Stargardt Disease, choroideremia, Leber congenital amaurosis are then major retinal degenerative disorders. In this manuscript, we have presented a detailed overview of the development of cell-based therapies, using embryonic stem cells, bone marrow stem cells, mesenchymal stem cells, dental pulp stem cells, induced pluripotent stem cells, limbal stem cells, corneal epithelial, stromal and endothelial, embryonic stem cell-derived differentiated cells (like retinal pigment epithelium or RPE), neural progenitor cells, photoreceptor precursors, and bone marrow-derived hematopoietic stem/progenitor cells etc. The manuscript highlights their efficiency, drawbacks and the strategies that have been explored to regain visual function in the preclinical and clinical state associated with them which can be considered for their potential application in the development of treatment.

New Onset Coronary Obstruction in Established Nonischemic Heart Failure: A Late Consequence of Radiation.

The column in this issue is provided by Salil Kumar, MD, and Joe Aoun, MD, chief cardiology fellows in the Houston Methodist Cardiology Department, and Arvind Bhimaraj, MD, associate professor of Clinical Cardiology at the Houston Methodist Academic Institute. Dr. Bhimaraj specializes in cardiovascular disease and advanced heart failure and transplantation.

Long term development of diastolic dysfunction and heart failure with preserved left ventricular ejection fraction in heart transplant recipients.

Heart transplant recipients (HTX) have several risk factors for heart failure which can trigger pro-inflammatory and fibrosis factors and set into motion pathophysiologic changes leading to diastolic dysfunction and HFpEF. The objective of the study was to determine if HTX recipients with dyspnea have diastolic dysfunction and HFpEF. Twenty-five HTX were included. LV systolic and diastolic functions were evaluated using conductance catheters to obtain pressure volume loops. LV function was assessed at rest and during moderate intensity exercise of the upper extremities. A significant increase occurred in LV minimal pressure (3.7 ± 3.3 to 6.5 ± 3.5 mmHg) and end diastolic pressure or EDP (11.5 ± 4 to 18 ± 3.8 mmHg, both P < 0.01) with exercise. With exercise, the time constant of LV relaxation shortened in 2, was unchanged in 3, and increased in the remaining patients (group results: rest 40 ± 11.6 vs 46 ± 9 ms, P < 0.01). LV chamber stiffness constant was abnormally increased in all but 2 patients. Indices of LV systolic properties were normal at rest but failed to augment with exercise. In 15 who agreed to blood draw, inflammation and fibrosis markers were obtained. A significant association was observed between LV EDP and Pro-Col III N-terminal (r = 0.58, P = 0.024) and IL-1-soluble receptor (r = 0.59, P = 0.02) levels. HTX have diastolic dysfunction and can develop HFpEF several years after cardiac transplantation. The abnormally increased LV chamber stiffness and the prolongation or lack of shortening of the time constant of LV relaxation with exercise are the underlying reasons behind the observed changes in LV diastolic pressures with exercise.

State-of-the-art review on management of end-stage heart failure in amyloidosis: transplant and beyond.

Cardiac involvement occurs in light-chain (AL), transthyretin wild-type (wtATTR), and hereditary (hATTR) amyloidosis; other types of amyloidosis account for < 5% of all cardiac amyloidosis (CA). CA can present subclinically on screening, insidiously with symptoms such as exertional dyspnea, or abruptly as cardiogenic shock. Initially, CA patients were thought to be poor candidates for transplant due to short long-term survival; however, there is a marked improvement in heart and multi-organ transplant outcomes over the past 10 years with newer treatments and improvements in support with temporary and durable mechanical circulatory support while awaiting transplant. Patients with AL CA were reported to have worse post-OHT outcomes than patients with ATTR CA, but this gap is quickly closing with improved patient selection, novel chemotherapeutics, and perhaps with selected use of bone marrow transplantation. Waitlist mortality and transplantation rates have markedly improved for CA after the United Network for Organ Sharing (UNOS) policy change in October 2018. In this review, we will evaluate contemporary data from the last 5 years on advances in the field of transplantation and mechanical circulatory support in this patient population.

Full-Time Cardiac Intensive Care Unit Staffing by Heart Failure Specialists and its Association with Mortality Rates.

BACKGROUND: Cardiac intensive care units (CICUs) serve medically complex patients with multiorgan dysfunction. Whether a CICU that is staffed full time by heart failure (HF) specialists is associated with decreased mortality is unclear. METHODS AND RESULTS: A retrospective review of consecutive CICU admissions from January 1, 2012, to December 31, 2016, was performed. In January 2014, the CICU changed from an open unit staffed by any cardiologist to a closed unit managed by HF specialists. Patients' baseline characteristics were determined, and a multivariate regression analysis was performed to ascertain mortality rates in the CICU. Baseline severity of illness was higher in the closed/HF specialist CICU model (P< 0.001). Death occurred in 101 of 1185 patients admitted to the CICU (8.5%) in the open-unit model and in 139 of 2163 patients (6.4%) admitted to the closed/HF specialist model (absolute risk reduction 2.1%, 95% confidence interval [CI] 0.1-4.0%; P = 0.01). The transition from an open to a closed/HF specialist model was associated with a lower overall CICU mortality rate (odds ratio [OR] 0.63; 95% CI 0.43-0.93). Prespecified interaction with a mechanical circulatory support device and unit model showed that treatment with such a device was associated with lower mortality rates in the closed/HF specialist model of a CICU (OR 0.6; 95% CI 0.18-0.78; P for interaction <0.01). CONCLUSION: Transition to a closed unit model staffed by a dedicated HF specialist is associated with lower CICU mortality rates.

A multi-institutional retrospective analysis on impact of RV acute mechanical support timing after LVAD implantation on 1-year mortality and predictors of RV acute mechanical support weaning.

BACKGROUND: There is little insight into which patients can be weaned off right ventricular (RV) acute mechanical circulatory support (AMCS) after left ventricular assist device (LVAD) implantation. We hypothesize that concomitant RV AMCS insertion instead of postoperative implantation will improve 1-year survival and increase the likelihood of RV AMCS weaning. METHODS: A multicenter retrospective database of 826 consecutive patients who received a HeartMate II or HVAD between January 2007 and December 2016 was analyzed. We identified 91 patients who had early RV AMCS on index admission. Cox proportional-hazards model was constructed to identify predictors of 1-year mortality post-RV AMCS implantation and competing risk modeling identified RV AMCS weaning predictors. RESULTS: There were 91 of 826 patients (11%) who required RV AMCS after CF-LVAD implantation with 51 (56%) receiving a concomitant RV AMCS and 40 (44%) implanted with a postoperative RV AMCS during their ICU stay; 48 (53%) patients were weaned from RV AMCS support. Concomitant RV AMCS with CF-LVAD insertion was associated with lower mortality (HR 0.45 [95% CI 0.26-0.80], p = 0.01) in multivariable model (which included age, BMI, angiotensin-converting enzyme inhibitor use, and heart transplantation as a time-varying covariate). In the multivariate competing risk analysis, a TPG < 12 (SHR 2.19 [95% CI 1.02-4.70], p = 0.04) and concomitant RV AMCS insertion (SHR 3.35 [95% CI 1.73-6.48], p < 0.001) were associated with a successful wean. CONCLUSIONS: In patients with RVF after LVAD implantation, concomitant RV AMCS insertion at the time of LVAD was associated with improved 1-year survival and increased chances of RV support weaning compared to postoperative insertion.

Prediction of right heart failure after left ventricular assist implantation: external validation of the EUROMACS right-sided heart failure risk score.

AIMS: Prediction of right heart failure (RHF) after left ventricular assist device (LVAD) implant remains a challenge. The EUROMACS right-sided heart failure (EUROMACS-RHF) risk score was proposed as a prediction tool for post-LVAD RHF but lacks from large external validation. The aim of our study was to externally validate the score. METHODS AND RESULTS: From January 2007 to December 2017, 878 continuous-flow LVADs were implanted at three tertiary centres. We calculated the EUROMACS-RHF score in 662 patients with complete data. We evaluated its predictive performance for early RHF defined as either (i) need for short- or long-term right-sided circulatory support, (ii) continuous inotropic support for ≥14 days, or (iii) nitric oxide for ≥48 h post-operatively. Right heart failure occurred in 211 patients (32%). When compared with non-RHF patients, pre-operatively they had higher creatinine, bilirubin, right atrial pressure, and lower INTERMACS class (P < 0.05); length of stay and in-hospital mortality were higher. Area under the ROC curve for RHF prediction of the EUROMACS-RHF score was 0.64 [95% confidence interval (CI) 0.60-0.68]. Reclassification of patients with RHF was significantly better when applying the EUROMACS-RHF risk score on top of previous published scores. Patients in the high-risk category had significantly higher in-hospital and 2-year mortality [hazard ratio: 1.64 (95% CI 1.16-2.32) P = 0.005]. CONCLUSION: In an external cohort, the EUROMACS-RHF had limited discrimination predicting RHF. The clinical utility of this score remains to be determined.

Evaluation of complications and visual outcome in various nucleus delivery techniques of manual small incision cataract surgery.

Purpose: To evaluate various methods of nucleus delivery in manual small incision cataract surgery, with reference to visual outcome, intraoperative, and postoperative complications. Methods: In this prospective randomized interventional study, five groups of 40 cases each were constituted, with reference to nucleus delivery technique: (a) phacosandwich, (b) fishhook, (c) irrigating vectis, (d) viscoexpression, and (e) anterior chamber maintainer (ACM). Visual outcome, intraoperative, and postoperative complications were evaluated in detail. Follow-up was done on first and seventh postoperative days (PODs) and then at fourth and eighth postoperative weeks. Results: The most common intraoperative complication was intraoperative miosis, followed by intraoperative hyphema, seen more in phacosandwich and irrigating vectis groups. The most common postoperative complication was striate keratopathy followed by transient postoperative corneal edema and AC inflammatory response, seen more in phacosandwich and fishhook groups. With reference to visual acuity, on the first POD 95% cases of ACM group achieved visual acuity >+0.5 logMAR unit. The difference in the visual outcome among groups was statistically significant. On fourth and eighth postoperative weeks, best-corrected visual acuity among various groups was comparable. Conclusion: ACM and viscoexpression are effective techniques for early visual rehabilitation. Fishhook has limited utility in softer nuclear grades and black cataracts. Phacosandwich is more suitable for nuclear sclerosis Grades 3-4. Irrigating vectis, viscoexpression, and ACM technique are effective techniques for all grades of nucleus Postoperative surgical-induced astigmatism was comparable in all techniques.

Efficacy Profile of Intracameral Amphotericin B. The Often Forgotten Step.

PURPOSE: The objectives of this study were to assess visual and structural outcomes in mycotic keratitis after conventional treatment (topical and systemic antifungals) and intracameral amphotericin B (ICAMB), and to evaluate any complications. DESIGN: This was a prospective, nonrandomized, nonblinded interventional study. METHODS: This study was conducted on 104 eyes of 104 patients with fungal corneal ulcers. Patients were categorized into 2 groups: group A, who received conventional topical and systemic antifungal medications, and group B, who received ICAMB in the dose of 5 to 10 µg in 1 mL of 5% dextrose. Response to treatment was evaluated. Results of the 2 groups were compared with appropriate statistical indices. RESULTS: The mean final visual acuity in patients in group B receiving ICAMB was 1.22 ± 0.31 logMAR units. The improvement in mean visual acuity was 1.40 ± 0.2 logMAR units. In group A, mean visual outcome was 1.25 ± 0.73 logMAR units. There was an improvement by 0.55 ± 0.30 logMAR units. Healing with varying degrees of opacification occurred in a significant number of patients (81.48%) treated with ICAMB as compared with conventional treatment (Z = 2.24, P < 0.05). Complications, such as sloughing, occurred in significantly fewer patients treated with ICAMB as compared with conventional treatment (Z = 2.29, P < 0.05). CONCLUSIONS: In cases of keratomycosis where response to local and systemic antifungal treatment is not evident after 7 days, ICAMB can be safely administered to prevent the progression of ulcers and the development of complications.

Production of fortified food for a public supplementary nutrition program: performance and viability of a decentralised production model for the Integrated Child Development Services Program, India.

Integrated Child Development Services in India through its supplementary nutrition programme covers over 100 million children, pregnant and lactating women across the country. Providing a hot cooked meal each day to children aged between 3-6 years and a take-home ration to children aged between 6-36 months, pregnant and lactating women, the Integrated Child Development Services faces a monumental task to deliver this component of services of desired quality and regularity at scale. From intermediaries or contractors who acted as agents for procuring and distributing food to procurement directly from large food manufacturers to using women groups as food producers, different State Governments have adopted a variety of strategies to procure and distribute food, especially the take-home ration. India's Supreme Court, through its directive of 2004, encouraged the Government to engage women's groups for the production of the supplementary food. This study was conducted to determine the operational performance, economic sustainability and social impact of a decentralised production model for India's Supplementary Nutrition Program, in which women groups run smallscale industrialised units. Data were collected through observation, interviews and group discussions with key stakeholders. Operational performance was analysed through standard performance indicators that measured consistency in production, compliance with quality standards and distribution regularity. Assessment of the economic viability included cost structure analysis, five-year projections, and financial ratios. Social impact was assessed using a qualitative approach. The pilot unit has demonstrated its operational performance and cost-efficiency. More data is needed to evaluate the scalability and sustainability of this decentralised model.

Quantitative analysis of microRNAs in tissue microarrays by in situ hybridization.

MicroRNAs (miRNAs) have emerged as key regulators in the pathogenesis of cancers where they can act as either oncogenes or tumor suppressors. Most miRNA measurement methods require total RNA extracts which lack critical spatial information and present challenges for standardization. We have developed and validated a method for the quantitative analysis of miRNA expression by in situ hybridization (ISH) allowing for the direct assessment of tumor epithelial expression of miRNAs. This co-localization based approach (called qISH) utilizes DAPI and cytokeratin immunofluorescence to establish subcellular compartments in the tumor epithelia, then multiplexed with the miRNA ISH, allows for quantitative measurement of miRNA expression within these compartments. We use this approach to assess miR-21, miR-92a, miR-34a, and miR-221 expression in 473 breast cancer specimens on tissue microarrays. We found that miR-221 levels are prognostic in breast cancer illustrating the high-throughput method and confirming that miRNAs can be valuable biomarkers in cancer. Furthermore, in applying this method we found that the inverse relationship between miRNAs and proposed target proteins is difficult to discern in large population cohorts. Our method demonstrates an approach for large cohort, tissue microarray-based assessment of miRNA expression.

Pain relief in laparoscopic cholecystectomy--a review of the current options.

Pain relief after laparoscopic cholecystectomy (LC) is an issue of great practical importance. Pain after LC has several origins: incisional, local visceral, peritoneal, and referred. Several modalities have been employed for achieving effective and safe analgesia: nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors, gabapentinoids, local anesthetics, and transversus abdominis plane (TAP) block. They have their advantages and disadvantages, and multimodal approaches are often followed because of the multiple sources of pain. Among COX-2 inhibitors, parecoxib and valdecoxib are useful, and fears regarding their cardiovascular adverse effects in noncardiac surgery (such as LC) have not been substantiated when used in short term. Gabapentin is useful but more data are needed regarding pregabalin because of inconsistent results. Local anesthetics (LA) can be particularly useful, both port-site infiltration and intraperitoneal instillation in the intra-operative period. Factors enhancing the effectiveness of these agents include early instillation before creating the pneumoperitoneum, larger volume of medium used for instillation, and favorable pharmacological characteristics of the agent. Combination of LA with either NSAID/COX-2 inhibitors or fibrin sealant appears to be effective, although more research is required for determining the exact combinations and efficacy using direct comparisons with single-modality interventions. Finally, newer procedures such as TAP block appear promising if replicated.