Impact of IL-21 on Natural Killer cell proliferation and function - a mathematical and functional assessment.

Natural killer (NK) cells are currently in use as immunotherapeutic agents for cancer. Many different cytokines are used to generate NK cells including IL-2, IL-12, IL-15 and IL-18 in solution and membrane bound IL-21. These cytokines drive NK cell activation through the integration of STAT and NF-κB pathways, which overlap and synergize, making it challenging to predict optimal cytokine combinations. We integrated functional assays for NK cells cultured in a variety of cytokine combinations with feature selection and mechanistic regression models. Our regression model successfully predicts NK cell proliferation for different cytokine combinations and indicates synergy between STAT3 and NF-κB transcription factors. Use of IL-21 in solution in the priming, but not post-priming phase of NK cell culture resulted in optimal NK cell proliferation, without compromising cytotoxicity or IFN-γ secretion against hepatocellular carcinoma cell lines. Our work provides a mathematical framework for interrogating NK cell activation for cancer immunotherapy.

Lung Allocation Score Thresholds Prioritize Survival After Lung Transplantation.

BACKGROUND: The lung allocation score (LAS) prioritizes lung transplant (LTx) candidates with poor transplant-free survival and expected survival benefit from LTx. Although patients with the highest LAS have the shortest waiting time, mortality benefit is unclear in this group, raising criticism that the LAS inappropriately prioritizes critically ill candidates. We aim to identify a threshold above which increasing LAS values do not predict increasing survival benefit. METHODS: The United Network for Organ Sharing Registry was queried for first-time adult LTx candidates with LAS ≥ 30 between May 2005 and December 2016. Survival was tracked from the time of listing through the posttransplant period and compared with survival while remaining on the waitlist, using proportional hazards regression. The survival benefit of LTx was modeled as a piecewise-constant time-dependent covariate, moderated by candidate LAS. RESULTS: Of the overall cohort (N = 21,157), LTx was particularly protective for 365 patients with an initial LAS of 70 to 79 (hazard ratio of death after undergoing LTx relative to remaining on the waitlist, 0.2; 95% CI, 0.1-0.3). However, the survival benefit of LTx did not meaningfully increase for 1,042 patients listed with even higher LAS. Among patients with cystic fibrosis, the survival benefit of LTx was constant above an LAS of approximately 50. CONCLUSIONS: Consistent survival benefit of LTx was observed among patients with an initial LAS of 70 and greater. This result supports equalizing priority for donor lung allocation for patients with LAS ≥ 70. A lower LAS threshold for maximum priority is indicated in patients with cystic fibrosis.

Ophthalmic Start-Up Chief Executive Officers' Perceptions of Development Hurdles.

PURPOSE: To identify current challenges facing ophthalmic pharmaceutical start-ups in developing new products. METHODS: Surveys were distributed to the chief executive officer (CEO) or president of ophthalmic start-ups. RESULTS: The survey attracted 24 responses from 78 surveys distributed (31%). The CEOs stated that a lack of financial capital (n = 18, 75%), FDA regulations (n = 6, 25%), and failure to meet clinical endpoints (n = 6, 25%) were their greatest development hurdles. Risk aversion to medicines in early development (n = 18, 75%), mergers and acquisitions reducing corporate choice for licensing agreements (n = 7, 29%), the emergence of large pharmaceutical-based venture capital funding groups (n = 12, 50%), and the failure of many large pharmaceutical companies to develop their own medicines (n = 10, 42%) were noted as recent prominent trends affecting fundraising. CONCLUSION: The study suggests that development funding, regulatory burden, and meeting clinical endpoints are the greatest development challenges faced by ophthalmic start-up CEOs.

What data sources do ophthalmologists trust?

To survey ophthalmologists regarding sources they trust when incorporating new medical knowledge into their practice. The survey was distributed primarily to US-based ophthalmologists. Questions were derived based on the lead author's research experience from congresses and discussions and from mentions in the medical literature. In total, 77 physicians completed the survey of 1886 sent (4% response rate). Regarding study design, physicians preferred a well-controlled, randomised, double-masked trial (99%) with multicentred investigational site across a wide geographical area (80%). Authorship of a research article was most desired from a well-known key opinion leader (KOL) (75%) or any KOL leader at a university (75%). The most selected journal type was a subspecialty publication (86%) and second a multispecialty high impact journal (77%). Study sponsorship was most desired from the NIH or other government agencies (71%) or a university (71%). Doctors preferred clinical opinions from an ophthalmic medical society (75%). For the source of new clinical data, physicians indicated an unsponsored peer-reviewed journal article (77%) or a lecture at a large ophthalmic congress (74%) as the preferred source. Ophthalmologists generally desire sponsors, study designs and opinions that appear free of bias on which to base their clinical practice decisions.

Description of Ophthalmic Pharmaceutical and Device Start-Up Companies.

AIMS: To describe the number, type and location of ophthalmic companies and their associated product areas and indications. METHODS: A retrospective, non-patient-based, observational review of ophthalmic pharmaceutical and device companies with a new product in development. Data was compiled by Internet searches. RESULTS: We identified 190 companies currently developing ophthalmic products: 134 (71%) were privately held and 56 (29%) publicly held, while 136 (72%) were in the United States and 53 (28%) were outside the United States. There were 436 total products of which 338 (78%) were pharmaceuticals and 98 (22%) devices. With pharmaceuticals we identified 46 separate indications with age-related macular degeneration (n = 75), glaucoma (n = 52) and dry eye (n = 46) as most common; anti-vascular endothelial growth factor, hormone therapy and anti-inflammatory products were also common classes. With devices there were 30 indications with glaucoma (n = 26), age-related macular degeneration (n = 19) and dry eye (n = 6) as most common; drug delivery, ocular implants and prostheses were less common classes. CONCLUSIONS: Ophthalmology as a specialty is benefited by a wide effort in new medicine and device development. However, a concentration of effort into relatively few indications suggests a potential lack of market analysis and possible difficulty for many companies in commercializing their product.

Long-term cost and efficacy analysis of latanoprost versus timolol in glaucoma patients in Germany.

AIM: To evaluate 5-year effectiveness and cost between latanoprost or timolol monotherapy in a pilot trial. METHODS: A retrospective, multi-center trial performed at 6 sites in Germany of patients who had a diagnosis of primary open-angle or pigmentary glaucoma, in at least one eye, initiated on monotherapy with latanoprost or timolol maleate. Qualified consecutive charts were reviewed in which 5-year efficacy, safety and cost data was abstracted. RESULTS: Seventy-seoen latanoprost and 49 timolol patients were included, at the final visit no difference existed between the two groups in disc parameters including: rim area, rim area/disc area ratio, cup volume or vertical cup/disc ratio (P>0.05). There was no difference in intraocular pressure (IOP) between the initial latanoprost (17.4±2.6) and timolol (16.3±2.8mmHg) groups. There was less change in medicines over the follow-up period (0.1 vs 0.8) and fewer medications at the final visit (1.2 vs 1.8) with latanoprost compared to timolol. No patient treated with latanoprost discontinued therapy during follow-up, while 12% discontinued timolol mostly due to inadequate IOP control. Cost/year was less with initial timolol ($458±236) as compared to latanoprost ($552±202). CONCLUSION: Patients begun on latanoprost or timolol and followed over 5 years may have similar clinical outcomes. However, timolol patients may require more medicines and medicine changes to control IOP for long-term, but at a lower cost.

Long-term outcomes of prostaglandin analog versus timolol maleate in ocular hypertensive or primary open-angle glaucoma patients in Europe.

PURPOSE: To determine the direct costs of therapy over 5 years of a European monotherapy cohort begun on a prostaglandin (PTG) versus timolol in patients with primary open-angle glaucoma or ocular hypertension. METHODS: A retrospective, multicenter, active-controlled, observational study. Data were abstracted for European patients treated as initial monotherapy in 1996 or afterward, with 5 years of available records. RESULTS: This study included 271 patients (166 on a PTG and 105 on timolol at baseline). The average cost/month/patient over 5 years was $45.47±12.61 for PTG and $31.50±15.47 for timolol (P<0.001, based on German prices). After 5 years, although there was no difference in number of glaucoma medicines prescribed between groups (1.0 PTGs and 1.1 timolol, P=0.41), the timolol group demonstrated a higher intraocular pressure (17.7±2.9 vs. 16.5±3.0 mm Hg, P<0.001), more medication changes (P=0.01), greater incidence of glaucomatous progression (P=0.04), and less patients persistent on original monotherapy (P<0.001) than the PTG cohort. CONCLUSIONS: Patients originally on timolol monotherapy have a lower cost of care over 5 years than those started on a PTG. However, timolol patients during follow-up may demonstrate a higher intraocular pressure, more progression, more medication changes, and lower persistency of the original monotherapy.

Cost-effectiveness of treating ocular hypertension.

PURPOSE: To assess the cost-effectiveness of treating ocular hypertension (OHT) in the United States. DESIGN: A Markov model was constructed to perform a cost-effectiveness analysis. PARTICIPANTS: Patients with OHT. METHODS: The health states considered were stable OHT and glaucoma. Practice patterns for the model were derived from the Ocular Hypertension Treatment Study (OHTS), and transition probabilities were derived from previous literature. Specific unit costs used for medications, patient visits, and diagnostic and therapeutic procedures were obtained from Blue Cross/Blue Shield. The time horizon was 5 years. Costs were discounted at 3% per annum. MAIN OUTCOME MEASURE: Long-term cost effectiveness of treating OHT to prevent the development of glaucoma. RESULTS: The incremental cost-effectiveness ratio (ICER) for all OHT patients to prevent 1 case from progressing to primary open-angle glaucoma was $89,072. However, the minimally cost-effective ICER level after adjustment for risk factors identified by multivariate analysis in the OHTS were: 20 years above the average of 56 years, ICER of $45,155; 4 mmHg above the average pressure of 25 mmHg, ICER of $46,748; 40 microm less than the average central corneal thickness of 573 mum, ICER of $36,683; and a vertical cup-to-disc ratio of 0.2 wider than the average of 0.4, ICER of $35,633. CONCLUSIONS: Based on the results and practice patterns of the OHTS, treating all OHT patients seems not to be cost-effective. However, treating selective OHT patients with risk factors identified in the OHTS, for example, advancing age, higher pressures, thinner central corneal thickness, and wider vertical cup-to-disc ratios, does seem to be cost-effective for preventing the onset of glaucomatous damage.

Comparison of marker types and map assumptions using Markov chain Monte Carlo-based linkage analysis of COGA data.

We performed multipoint linkage analysis of the electrophysiological trait ECB21 on chromosome 4 in the full pedigrees provided by the Collaborative Study on the Genetics of Alcoholism (COGA). Three Markov chain Monte Carlo (MCMC)-based approaches were applied to the provided and re-estimated genetic maps and to five different marker panels consisting of microsatellite (STRP) and/or SNP markers at various densities. We found evidence of linkage near the GABRB1 STRP using all methods, maps, and marker panels. Difficulties encountered with SNP panels included convergence problems and demanding computations.

STAT 5 activators can replace the requirement of FBS in the adipogenesis of 3T3-L1 cells.

The 3T3-L1 cells differentiate into fat cells that have many properties of native adipocytes including: substantial lipid accumulation, insulin sensitivity, and the ability to secrete endocrine hormones. A substantial expense in using these cells is fetal bovine serum (FBS), a critical component of efficient adipogenesis. Our recent studies on STAT 5 proteins have revealed that these transcription factors are phosphorylated and translocate to the nucleus immediately after the initiation of differentiation. Studies by several other laboratories also suggest that STAT 5 proteins can have pro-adipogenic properties. Growth hormone (GH) and prolactin (PRL) are both potent activators of STAT 5A and STAT 5B proteins. Since, FBS has high concentrations of GH; we examined the ability of GH to replace FBS as a component of the differentiation cocktail for 3T3-L1 cells. Our studies revealed that FBS was not required for the adipogenesis of 3T3-L1 cells if GH or PRL was added to the differentiation cocktail. Adipogenesis was judged by Oil Red O staining and expression of adipocyte marker genes. Hence, we have developed a substantially less expensive method for differentiating 3T3-L1 cells without FBS, thiazolidinediones, or expensive cytokines.

A persistency and economic analysis of latanoprost, bimatoprost, or beta-blockers in patients with open-angle glaucoma or ocular hypertension.

PURPOSE: The aim of this study was to evaluate differences in the persistency and treatment costs for latanoprost, bimatoprost, or beta-blockers in open-angle glaucoma or ocular hypertensive patients. METHODS: This study was a retrospective, multicenter, parallel, active-controlled comparison of patients who were prescribed with ocular hypotensive monotherapy between September 1996 and August 2002. RESULTS: 1,182 patients were included. The Kaplan Meier life table analysis showed that latanoprost was continued longest among the groups for the first year of therapy (p=0.02). A significant difference existed between groups in the final intraocular pressure for latanoprost (17.3+/-3.9, N=357), for bimatoprost (18.0+/-3.6, N=146), and for the beta-blockers (17.9+/-3.7, N=335) (p=<0.0001). The average number of visits was statistically higher for beta-blockers (3.3), compared to latanoprost (2.9) and bimatoprost (3.1) (p=0.01). Further, the mean number of medicine changes was greater for bimatoprost (0.45) and beta-blockers (0.47) than for latanoprost (0.27) (p=0.0008). The cost of visits and medications was lowest for beta-blockers ($119.3+/-$78.9) and highest for bimatoprost ($163.8+/-$51.2) (p<0.0001). CONCLUSIONS: Patients were more persistent with latanoprost and demonstrated lower intraocular pressure, fewer visits, and fewer medicine changes when compared to bimatoprost or beta-blocker therapy. In contrast, the beta-blocker group provided lower overall cost.

An economic analysis of switching to latanoprost from a beta-blocker or adding brimonidine or latanoprost to a beta-blocker in open-angle glaucoma or ocular hypertension.

BACKGROUND: In treating patients with ocular hypertension or primary open-angle glaucoma, if a single agent cannot successfully control the pressure, additional medications may be prescribed. The cost of treatment may become expensive, especially with multiple drug therapy. Thus, prescribing techniques that help minimize costs may be beneficial to patients when medically appropriate. OBJECTIVE: To evaluate differences in drug and visit costs after switching to latanoprost 0.005% monotherapy (LM) versus adding latanoprost 0.005% once daily (Lbeta) or brimonidine 0.2% twice daily (Bbeta) in patients uncontrolled on beta-blocker therapy alone. METHODS: This study included 148 consecutive qualified charts of open-angle glaucoma or ocular hypertension patients within the first year of follow-up after switching from beta-blocker monotherapy to latanoprost or adding latanoprost or brimonidine. RESULTS: The Bbeta group demonstrated the highest costs per month, followed by the Lbeta group, then the LM group. A trend existed in the Lbeta group to a lower pressure than the Bbeta or the LM groups. A greater mean change in medication per patient per month was seen in the Bbeta group compared to the latanoprost treatment groups. Additionally, a greater number of visits per month occurred in the Bbeta than in the LM and Lbeta groups. The Bbeta group also reported significantly more tearing and fatigue. CONCLUSIONS: This study suggests that in patients uncontrolled on beta-blocker therapy, switching to latanoprost, when medically appropriate, may provide a further mean reduction in intraocular pressure and save costs compared to adding latanoprost or brimonidine.