High-risk Window Research Articles

Safety and efficacy of early carotid artery stenting in patients with symptomatic stenosis.

Symptomatic carotid artery stenosis is a significant contributor to ischemic strokes. Carotid artery stenting (CAS) is usually indicated for secondary stroke prevention. This study evaluates the safety and efficacy of CAS performed within a short time frame from symptom onset. We conducted a single-center, retrospective study of consecutive patients who underwent CAS for symptomatic carotid stenosis within eight days of symptom onset from July 2019 to January 2022. Data on demographics, medical history, procedural details, and follow-up outcomes were analyzed. The primary outcome measure was the recurrence of the stroke within the first month post-procedure. Secondary outcomes included mortality, the rate of intra-procedural complications, and hyperperfusion syndrome. We included 93 patients with a mean age of 71.7 ± 11.7 years. The median time from symptom onset to CAS was 96 h. The rate of stroke recurrence was 5.4% in the first month, with a significant association between the number of stents used and increased recurrence risk. Mortality within the first month was 3.2%, with an overall mortality rate of 11.8% after a median follow-up of 19 months. Intra-procedural complications were present in five (5.4%) cases and were related to the number of stents used (p = 0.002) and post-procedural angioplasty (p = 0.045). Hyperperfusion syndrome occurred in 3.2% of cases. Early CAS within the high-risk window post-symptom onset is a viable secondary stroke prevention strategy in patients with symptomatic carotid artery stenosis. The procedure rate of complication is acceptable, with a low recurrence of stroke. However, further careful selection of patients for this procedural strategy is crucial to optimize outcomes.

Maintenance Technology and Practice of Mooring Anchor Leg in Deepwater Floating Production Facility

“Nanhai Shengli” is a floating production storage and offloading unit (FPSO) in the Liuhua 11-1 oil field in the South China Sea. During its service, the FPSO suffered severe broken anchor legs due to the hostile impact of several strong typhoons. In order to ensure the safety of its mooring system, emergency maintenance operations were carried out on 10 mooring anchor legs under the condition of non-release and non-production of FPSO, which was the first time in deep water in China. Its construction is difficult, high risk, weather and FPSO draft time window requirements are high, the use of reasonable technology and construction methods is the key to efficient completion of the operation, such as simulation analysis, reasonable selection of machinery and resources, efficient control of site construction, accurate environmental monitoring, etc. Taking the release and tieback of the mooring system of "Nanhai Shengli" FPSO in Liuhua 11-1 oilfield as an example, various technical difficulties and key points in the process of release and tieback construction are introduced, and the rules are summarized and analyzed. The safe and efficient completion of this construction operation is not only the embodiment of management level, but also the result of daring to innovate and face challenges. It has a typical guiding significance for the maintenance of mooring anchor leg of similar deep-water floating production facilities in China.

Increased heat stress risk for maize in arid-based climates as affected by climate change: threats and solutions

Heat stress in combination with drought has become the biggest concern and threat for maize yield production, especially in arid and hot regions. Accordingly, different optimal solutions should be considered in order to maintain maize production and reduce the risk of heat stress under the changing climate. In the current study, the risk of heat stress across Iranian maize agro-ecosystems was analyzed in terms of both intensity and frequency. The study areas comprised 16 provinces and 24 locations classified into five climate categories: arid and hot, arid and temperate, semi-arid and hot, semi-arid and temperate, and semi-arid and cold. The impact of heat stress on maize under a future climate was based on a 5-multi-model ensemble under two optimistic and pessimistic emission scenarios (RCP4.5 and RCP8.5, respectively) for 2040-2070 using the APSIM crop model. Simulation results illustrated that in the period of 2040-2070, intensity and the frequency of heat stress events increased by 2.37°C and 79.7%, respectively, during maize flowering time compared to the baseline. The risk of heat stress would be almost 100% in hot regions in the future climate under current management practices, mostly because of the increasing high-risk window for heat stress which will result in a yield reduction of 0.83 t ha-1. However, under optimal management practices,farmers will economically obtain acceptable yields (6.6 t ha-1). The results also indicated that the high-risk windows in the future will be lengthening from 12 to 33days in different climate types. Rising temperatures in cold regions as a result of global warming would provide better climate situations for maize growth, so that under optimistic emission scenarios and optimal management practices, farmers will be able to boost grain yield up to 9.2 t ha-1. Overall, it is concluded that farmers in hot and temperate regions need to be persuaded to choose optimal sowing dates and new maize cultivars which are well adapted to each climate to reduce heat stress risk and to shift maize production to cold regions.

Lung Transplantation in a Patient With Osteogenesis Imperfecta and Osteoporosis

Background: Osteogenesis imperfecta (OI) and transplantation (TP) are independently associated with fractures. Yet reports regarding the skeletal effects of organ TP in OI are limited. We report the early skeletal outcomes in an OI patient with osteoporosis who underwent lung TP. Clinical Case: A 35-year-old man with moderate/severe OI and severe bronchiectasis was admitted for progressive respiratory failure and expedited lung TP evaluation. OI was diagnosed at age 10 after sustaining a hairline coccyx fracture when falling off a stool; scoliosis was diagnosed at age 14; additional fractures included ankle (18 y), toes (28 y) and rib (34 y). He had dentogenesis imperfecta, but no hearing loss, easy bruising or OI family history. Bronchiectasis also began at age 10 and progressed, with multiple drug resistant infections and glucocorticoid (GC) treatments. At admission, he was on 6L oxygen and bed-bound from dyspnea. Notably, he had been rejected twice for TP because of his bone disease. Admission medications included calcium, D3, famotidine, inhaled fluticasone, tobramycin, and tiotropium bromide. His exam was notable for height 5’5”, BMI 16.5 kg/m2, kyphoscoliosis, blue sclera and joint laxity. Labs were notable for (mg/dl): serum calcium 9.4, magnesium 2.4, phosphate 4.4; albumin 4.2 g/dl, alkaline phosphatase 75 U/L, 25(OH)D 34 ng/ml, sCTX 535 pg/ml, urinary calcium 370 mg/24 hr. DXA showed T-scores of -4.7 (lumbar spine), -3.3 (femoral neck), -3.2 (total hip), -2.6 (1/3 radius). Endocrinology was consulted about the skeletal risk of lung transplantation. Discussion and Follow-up:The patient’s manifestations of OI increased the risk of adverse skeletal outcomes. His high CTX suggested increased bone resorption, often seen with OI; bone formation was not directly measured but in OI is frequently reduced. Notably, his bronchiectasis was likely related to the OI: in addition to restrictive lung disease in OI, the abnormal type 1 collagen likely alters alveolar structure and elasticity. His risk for post-TP fractures was high given that the expected post-TP bone loss would likely be exacerbated by high dose GCs further increasing bone resorption and reducing presumed low bone formation. Nevertheless, because he had never sustained a major fracture even without OI treatment, the decision was made to proceed. He received zoledronate (ZOL) 5 mg IV and underwent an uncomplicated double lung transplant; initial high dose GCs were tapered to prednisone 10 mg/d. Three months later, he has steadily rising lung function, excellent functional status, and is working full time. A current sCTX of 73 pg/ml suggests that bone loss is not increased. Admittedly, the patient remains within the early high-risk fracture window. Yet this case is the first report to our knowledge which suggests that lung TP in an OI patient treated with ZOL did not lead to fracture in the early post-TP period.

Human Mobility Associated With Risk of Schistosoma japonicum Infection in Sichuan, China.

Urbanization increases human mobility in ways that can alter the transmission of classically rural, vector-borne diseases like schistosomiasis. The impact of human mobility on individual-level Schistosoma risk is poorly characterized. Travel outside endemic areas may protect against infection by reducing exposure opportunities, whereas travel to other endemic regions may increase risk. Using detailed monthly travel- and water-contact surveys from 27 rural communities in Sichuan, China, in 2008, we aimed to describe human mobility and to identify mobility-related predictors of S. japonicum infection. Candidate predictors included timing, frequency, distance, duration, and purpose of recent travel as well as water-contact measures. Random forests machine learning was used to detect key predictors of individual infection status. Logistic regression was used to assess the strength and direction of associations. Key mobility-related predictors include frequent travel and travel during July-both associated with decreased probability of infection and less time engaged in risky water-contact behavior, suggesting travel may remove opportunities for schistosome exposure. The importance of July travel and July water contact suggests a high-risk window for cercarial exposure. The frequency and timing of human movement out of endemic areas should be considered when assessing potential drivers of rural infectious diseases.

What Makes Sodium-Glucose Co-Transporter-2 Inhibitors Stand out in Heart Failure?

Purpose of ReviewWe highlight the unique properties of the sodium-glucose cotransporter-2 (SGLT-2 inhibitors) which may lend favorably to their efficient integration in the background of other heart failure (HF) therapies. We also discuss the unique aspects of SGLT-2 inhibitor dosing, lack of titration needs, effects on kidney function and electrolytes, diuretic activity, and safety in the high-risk peri-hospitalization window.Recent FindingsDapagliflozin was recently approved for the treatment of heart failure with reduced ejection fraction (HFrEF), irrespective of the presence or absence of type 2 diabetes mellitus (T2DM) based on the findings of the pivotal DAPA-HF trial. All SGLT-2 inhibitors are once daily medications with minimal drug-drug interactions and do not require titration (for HF treatment) unlike other HF medications. SGLT-2 inhibitors offer modest weight loss and blood pressure reduction without major adverse effects of hyperkalemia, making it ideal for near-simultaneous initiation with other HF medications, and use in high-risk populations (including older adults). Moreover, SGLT-2 inhibitors appear to afford long-term kidney protection in diverse populations.SummarySGLT-2 inhibitors are the latest class of therapies to demonstrate important clinical benefits among patients with HFrEF, and their pharmacological properties favor ease of use and integration in multi-drug disease-modifying regimens.

Association of graft survival with tacrolimus exposure and late intra-patient tacrolimus variability in pediatric and young adult renal transplant recipients-an international CTS registry analysis.

Adolescent and young adult age is a high-risk window with an alarmingly increased likelihood of premature kidney graft loss due to immunological rejection. Using the large database of the Collaborative Transplant Study, we analyzed whether a more intense and less variable exposure to tacrolimus could counteract this young age-related enhanced immunoreactivity. Kidney graft recipients aged 12-23years (n=964) with a 1-year tacrolimus trough level between 4.0 and 10.9ng/ml had a 5-year graft survival rate of 85.1%, significantly better than the poor 66.1% rate in patients with a trough level below 4.0ng/ml who showed a 2.38-fold increased risk of graft loss in the multivariable analysis (P<0.001). This association was not apparent in young children aged 0-11years (n=455) and less pronounced in adults aged 24-34years (n=1466). However, an intra-patient variability of tacrolimus (IPV) trough level ≥1.5 at post-transplant years 1 and 2 was associated with an increased graft loss risk in both 12- to 23-year-old and 0- to 11-year-old recipients (P<0.001 and P=0.045). Patients with high IPV made up as many as 30% of kidney graft recipients, indicating that a more intense and less variable exposure to tacrolimus could improve graft survival strongly in this high-risk group.

Abstract P503: Continuous Diurnal Patterns of Atrial Fibrillation Onset by Chronic Kidney Disease Status: The Atherosclerosis Risk in Communities (aric) Study

Background: Chronic kidney disease (CKD) is associated with atrial fibrillation (AF); however, most studies have looked at its presence or occurrence as a dichotomous outcome, and diurnal patterns of AF by CKD status have not yet been characterized. Methods: Of 2257 adults (71-94 years) who underwent 2 weeks of non-invasive continuous heart rhythm monitoring using the Zio XT Patch, we examined 61 participants with paroxysmal AF and characterized the probability of AF onset over the course of 24 hours using a generalized function-on-scalar regression model. CKD status was defined using eGFR and albuminuria. Results: The median device wear-time was 13.7 (12.6, 13.9) days, and the majority (57%) had CKD. In non-CKD, the probability of AF onset fluctuated over 24 hours with two nadir periods occurring in late morning (~10am) and late evening (~10pm), and somewhat prominent peaks occurring in early morning (~8am) and early evening (~6pm) [figure] . Overall, CKD had a higher probability of AF compared to non-CKD. CKD also demonstrated a less pronounced nadir in late evening, and was significantly more likely to experience AF during this time (OR 2.80; 95% CI 1.05, 11.94) compared to non-CKD. This observation was consistent even after adjusting for various potential confounders such as age, sex, race, diabetes, and a history of cardiovascular disease. Conclusion: Based on 2-week monitoring, AF onset seems to exhibit a diurnal pattern throughout the day with peaks in the early morning and evening, and nadir in late morning and evening. Compared to those without CKD, those with CKD are more likely to experience AF in late evening, suggesting a potential high-risk time window for monitoring. Further studies are needed to evaluate prognostic value of AF diurnal patterns.

Prior Heart Failure Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan Compared With Valsartan in HFpEF

BackgroundThe period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death. ObjectivesThis study sought to determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to hospitalization for HF among patients with HF with preserved ejection fraction (HFpEF). MethodsIn this post hoc analysis of PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF), we assessed the risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (≥45%). The primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed by using a semiparametric proportional rates method, stratified by geographic region. ResultsOf 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31 to 90 days, 435 (9%) within 91 to 180 days, and 694 (14%) after 180 days; 2,490 (52%) were never previously hospitalized. Over a median follow-up of 35 months, risk of total HF hospitalizations and cardiovascular death was inversely and nonlinearly associated with timing from prior HF hospitalization (p < 0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio: 0.73; 95% confidence interval: 0.53 to 0.99) to patients never hospitalized (rate ratio: 1.00; 95% confidence interval: 0.80 to 1.24; trend in relative risk reduction: pinteraction = 0.15). With valsartan alone, the rate of total primary events was 26.7 (≤30 days), 24.2 (31 to 90 days), 20.7 (91 to 180 days), 15.7 (>180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (≤30 days), 4.6% (31 to 90 days), and 3.4% (91 to 180 days), whereas no risk reduction was observed in patients screened >180 days or who were never hospitalized (trend in absolute risk reduction: pinteraction = 0.050). ConclusionsRecent hospitalization for HFpEF identifies patients at high risk for near-term clinical progression. In the PARAGON-HF trial, the relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrant prospective validation. (PARAGON-HF; NCT01920711)

Use of FDA's Sentinel System to Quantify Seizure Risk Immediately Following New Ranolazine Exposure.

Neurological complications including seizures have been reported with ranolazine. We sought to quantify the risk of seizure-related hospitalizations or emergency department events following ranolazine exposure in the Sentinel System (2006-2015). Eligibility criteria were new use of ranolazine after 183days washout period and absence of seizure diagnoses, anti-epileptic drugs, or seizure-related disorders during the baseline period. Among 52,155 ranolazine users, we identified 28 seizures in the 1-32days after new ranolazine dispensing: 12 occurring in days 1-10 (high-risk window), 11 in days 11-20 (moderate-risk window) and 5 in the control window (days 21-32). Assuming an equal likelihood of seizure events across the 32-day observation window, we estimate an attributable risk of 0.9 excess cases per 10,000 exposed users. Using a self-controlled risk interval design with exact logistic regression, seizures were elevated in the high-risk window (relative risk [RR] 2.88 (95% confidence interval [CI] 1.01-8.33) compared with the control window. No significant increased risk was observed in the moderate window. Half of the seizure cases had a diagnosis of renal disease, although seizure risk was not significant (RR 3.20 [CI 0.82-14.01]). A majority of patients in both risk windows were 75years or older. Our study suggests risk among younger ranolazine patients is rare. Given the imprecision of the risk estimates, we interpret the elevated seizure risk following ranolazine exposure with caution. Further analysis in a larger elderly population is warranted.

Non-immunologic allograft loss in pediatric kidney transplant recipients.

Non-immunologic risk factors are a major obstacle to realizing long-term improvements in kidney allograft survival. A standardized approach to assess donor quality has recently been introduced with the new kidney allocation system in the USA. Delayed graft function and surgical complications are important risk factors for both short- and long-term graft loss. Disease recurrence in the allograft remains a major cause of graft loss in those who fail to respond to therapy. Complications of over immunosuppression including opportunistic infections and malignancy continue to limit graft survival. Alternative immunosuppression strategies are under investigation to limit calcineurin inhibitor toxicity. Finally, recent studies have confirmed long-standing observations of the significant negative impact of a high-risk age window in late adolescence and young adulthood on long-term allograft survival.

Adaptation strategies to lessen negative impact of climate change on grain maize under hot climatic conditions: A model-based assessment

Rise in temperature, particularly in warmer areas, could have a negative effect on maize productivity. However, careful management practices could reduce the effects of high temperatures by altering the sowing dates and type of cultivar. The current study applied APSIM (The Agricultural Production Systems sIMulator) crop model to investigate the interaction of sowing date and cultivar when dealing with climate change and high temperatures at nine locations in Khuzestan province, in southwestern Iran. Daily climatic data for the baseline period of 1980–2010 was obtained from the Meteorological Organization of Iran. Projections of the future climate of Khuzestan was done in Miroc5 (Model for Interdisciplinary Research on Climate) GCM (Global Climate Model) for 2040–2070 under two RCPs (Representative Concentration Pathways) (RCP4.5 and RCP8.5) using the methodology developed by AgMIP (The Agricultural Model Intercomparison and Improvement Project). The high risk window for extreme temperature was calculated as the number of days having a maximum temperature of over 36 °C (Tmax > 36 °C) during pre-flowering and flowering. Results indicated that for mid-future (2050), the average maize grain yield in almost all study areas except Masjed Soleyman decreased in comparison to baseline at −13.7% and −22.8% for RCP4.5 and RCP8.5, respectively mainly because the length of the high-risk window for extreme temperature had expanded from 18.8 to 26.3 days for RCP4.5 and RCP8.5, respectively, compared to baseline. Most farmers have not realized that they are currently sowing maize during a high-risk window for extreme temperatures (Tmax > 36 °C) in some seasons. If farmers do not apply adaptive options for their regions (most promising sowing date × cultivar), the probability of economical grain yield will be less than 50% for an average economical grain yield of 8.9 t ha−1. The current findings support the hypothesis that climate change by the middle of the 21st century will not be beneficial for maize agroecosystems in hot areas like Khuzestan province unless the best sowing date × cultivar is applied for both winter and summer sowing dates.

Reported Nonadherence to Immunosuppressive Medication in Young Adults After Heart Transplantation: A Retrospective Analysis of a National Registry.

Young adult heart transplantation (HTx) recipients experience high mortality risk attributed to increased nonadherence to immunosuppressive medication in this age window. This study sought to test whether a high-risk age window in HTx recipients persisted in the absence of reported nonadherence. Heart transplantation recipients aged 2 to 40 years, transplanted between October 1999 and January 2007, were identified in the United Network for Organ Sharing database. Multivariable survival analysis was used to estimate influences of age at transplantation and attained posttransplant age on mortality hazard among patients stratified by center report of nonadherence to immunosuppression that compromised recovery. Three thousand eighty-one HTx recipients were included, with univariate analysis demonstrating peak hazards of mortality and reported nonadherence among 567 patients transplanted between ages 17 and 24 years. Multivariable analysis adjusting for reported nonadherence demonstrated lower mortality among patients transplanted at younger (hazards ratio, 0.813; 95% confidence interval, 0.663-0.997; P = 0.047) or older (hazards ratio, 0.835; 95% confidence interval, 0.701-0.994; P = 0.042) ages. Peak mortality hazard at ages 17 to 24 years was confirmed in the subgroup of patients with no nonadherence reported during follow-up. This result was replicated using attained age after HTx as the time metric, with younger and older ages predicting improved survival in the absence of reported nonadherence. Late adolescence and young adulthood coincide with greater mortality hazard and greater chances of nonadherence to immunosuppressive medication after HTx, but the elevation of mortality hazard in this age range persists in the absence of reported nonadherence. Other causes of the high-risk age window for post-HTx mortality should be demonstrated to identify opportunities for intervention.

A novel lipid prodrug strategy for sustained delivery of hexadecyloxypropyl 9-[2-(phosphonomethoxy)ethyl]guanine (HDP-PMEG) on unwanted ocular proliferation

Proliferative vitreoretinopathy (PVR) is a blinding eye disease and there is no effective pharmacological measure to prevent PVR development. The difficulty comes from lack of potent antiproliferative agent and lack of sustained delivery to cover high-risk time window for PVR to develop. Lipid prodrug of PMEG, hexadecyloxypropyl 9-[(2-phosphonomethoxy)ethyl]guanine (HDP-PMEG), was prepared and was evaluated as a pharmacological adjuvant to surgical management of PVR. A dose-escalation study determined that the highest nontoxic dose for intravitreal use in pigmented rabbits was 3 µg per eye. The genotoxicity of HDP-PMEG was harnessed as a perioperative preventative measure against PVR in a rabbit eye model while the sustained intravitreal pharmacological effect was evaluated on a laser-induced fibrovascular model in rat eye. After intravitreal 3 µg, HDP-PMEG particles in the rabbit vitreous was visible for at least 6 weeks. A single 50-min intravitreal infusion of HDP-PMEG demonstrated significant inhibition of PVR formation when compared with the eyes infused with only BSS (BSS vs. HDP-PMEG: estimate = 1.14, OR = 3.1, p = .027). A single intravitreal 104 ng (equivalent to 3 µg for rabbit eye) of HDP-PMEG significantly inhibit laser-induced fibrovascular proliferation in rat eye by 55% (least square mean pixel, BSS = 4763569.5 vs. HDP-PMEG = 2148129.7, p < .0001, generalized estimating equation [GEE]). Retinal fluorescein angiography showed the odds for BSS intervened eyes to have higher-rated FA leaking grades were 38.5 times compared with HDP-PMEG treated eyes (p < .0001, GEE). Our study results indicate that single intravitreal HDP-PMEG may be a promising ocular drug delivery as a perioperative intervention to prevent PVR reoccurrence following primary surgical management.

Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients.

Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.

Episcleral drug film for better-targeted ocular drug delivery and controlled release using multilayered poly-ε-caprolactone (PCL)

Triamcinolone acetonide (TA) and poly-ε-caprolactone (PCL) were engineered into a micro drug film for episcleral application to better manage chronic vitreoretinal diseases such as proliferative vitreoretinopathy (PVR). Compared to an intravitreal drug injection, this drug film is much safer without breaking into ocular barriers. Compared to a traditional subtenon injection, this drug film demonstrated superior therapeutic duration, better drug bioavailability in the choroid and retina, and better-targeted drug delivery ability. The rabbit eye study demonstrated that using the PCL-TA film led to 5.6 and 3.4 times higher drug AUC in the choroid and the retina respectively than in eyes following a subtenon drug injection. The mean drug residence time in the rabbit choroid was also doubled by using the episcleral TA film (86days versus 43days). Remaining TA in the drug film was consistently higher than that in the subtenon space, indicating controlled release of TA by the PCL-TA film. The pharmacokinetics of triamcinolone in the choroid and retina were optimized from typical first-order kinetics to a more sustained release by use of this film. This episcleral film system worked better on rabbit eyes than on guinea pig eyes, indicating that scleral thickness and eye size may be crucial aspects to consider when choosing an animal model or when designing a transscleral delivery device for human use. This engineered drug film may be very useful in preventing and managing PVR associated with open globe trauma or surgical repair for retinal detachment. Statement of SignificanceThis study demonstrated a novel micro episcleral drug film that is made from the engineering of triamcinolone acetonide (TA) into poly-ε-caprolactone (PCL). The film can be conveniently placed at the injury or disease site during primary surgery and provide controlled release of TA for four months that covers the high-risk time window for developing proliferative vitreoretinopathy (PVR). This engineered drug film may be very useful in preventing and managing PVR associated with open globe trauma or intraocular surgery.

Sexually transmitted infections in pediatric renal transplant recipients: Time to take notice!

We sought to assess the prevalence of STIs, contraception use, and unintentional pregnancy in our pediatric renal transplant recipients. We performed a retrospective chart review. Forty-nine of 65 patients in our program are currently in the high-risk age window of 13 yr or older (34 men, 15 women; mean age 17 yr old, range 13-23 yr old). There was a disproportionate difference in sexual behavior among the men and women, such that while only 15% of the men reported being sexually active, 53% of the women were sexually active. Among high-risk age-group women, 40% were on hormonal contraception. This increased to 75% in sexually active women. There were no cases of unintentional pregnancy. Thirty percent of sexually active recipients had at least one STI. This was higher among sexually active women (37.5%) compared to men (20%). STIs identified included gonococcal and chlamydial urethritis/cervicitis, Trichomonas vaginitis, HSV-2 genital sores, pelvic inflammatory disease, and HIV. In conclusion, STIs are a realistic public health concern in our pediatric renal transplant recipients. Consensus guidelines on STI screening and reproductive health counseling are needed to address this understudied problem.

Loss of Pediatric Kidney Grafts During the “High–Risk Age Window”: Insights From Pediatric Liver and Simultaneous Liver–Kidney Recipients

Pediatric kidney transplant recipients experience a high-risk age window of increased graft loss during late adolescence and early adulthood that has been attributed primarily to sociobehavioral mechanisms such as nonadherence. An examination of how this age window affects recipients of other organs may inform the extent to which sociobehavioral mechanisms are to blame or whether kidney-specific biologic mechanisms may also exist. Graft loss risk across current recipient age was compared between pediatric kidney (n = 17,446), liver (n = 12,161) and simultaneous liver-kidney (n = 224) transplants using piecewise-constant hazard rate models. Kidney graft loss during late adolescence and early adulthood (ages 17-24 years) was significantly greater than during ages <17 (aHR = 1.79, 95%CI = 1.69-1.90, p < 0.001) and ages >24 (aHR = 1.11, 95%CI = 1.03-1.20, p = 0.005). In contrast, liver graft loss during ages 17-24 was no different than during ages <17 (aHR = 1.03, 95%CI = 0.92-1.16, p = 0.6) or ages >24 (aHR = 1.18, 95%CI = 0.98-1.42, p = 0.1). In simultaneous liver-kidney recipients, a trend towards increased kidney compared to liver graft loss was observed during ages 17-24 years. Late adolescence and early adulthood are less detrimental to pediatric liver grafts compared to kidney grafts, suggesting that sociobehavioral mechanisms alone may be insufficient to create the high-risk age window and that additional biologic mechanisms may also be required.

High-risk age window for mortality in children with cystic fibrosis after lung transplantation.

LTx in children with CF remains controversial. The UNOS database was queried from 1987 to 2013 for CF patients <18 yr of age at time of transplant. PCHR model was used to quantify hazard of mortality. 489 recipients were included in the survival analysis. The hazard function of post-transplant mortality was plotted over attained age to identify age window of highest risk, which was 16-20 yr. Unadjusted PCHR model revealed ages immediately after the high-risk window were characterized by lower hazard of mortality (HR = 0.472; 95% CI = 0.302, 0.738; p = 0.001). After adjusting for potential confounders, the decline in mortality hazard immediately after the high-risk window remained statistically significant (HR = 0.394; 95% CI: 0.211, 0.737; p = 0.004). Hazard of mortality in children with CF after LTx was highest between 16 and 20 yr of attained age and declined thereafter.

Sequelae of Early Hospital Readmission After Kidney Transplantation

We recently elucidated risk factors for early hospital readmission (EHR) following kidney transplantation (KT). We now sought to quantify the independent associations between EHR and post-KT outcomes, including late hospital readmission (LHR: 1 year after EHR window), death-censored graft loss and mortality, among Medicare-primary KT recipients (2000-2005). Of 32961 KT recipients, 7.7% had at least one readmission within 3 days of discharge, 14.8% within 7 days, 22.4% within 14 days and 30.5% within 30 days of discharge after the initial KT hospitalization. KT recipients who experienced EHR within 30 days of discharge after the initial KT hospitalization were more likely to have experienced LHR (29.6% vs. 9.0%, p<0.001) and were at 3.02 times higher (95% CI: 2.82-3.23, p<0.001) risk of LHR. Additionally, EHR was associated with death-censored graft loss (deceased donor recipients hazard ratio [HR]: 1.43, 95% CI: 1.36-1.51, p<0.001 and live donor recipients HR: 1.54, 95% CI: 1.40-1.70, p<0.001) and mortality (deceased donor recipients HR: 1.50, 95% CI: 1.43-1.58, p<0.001 and live donor recipients HR: 1.45, 95% CI: 1.32-1.60, p<0.001). Thirty days posttransplant represents a high-risk window for KT recipients and the readmissions during this window are strong predictors of adverse sequelae, particularly LHRs. Efforts should be made to implement and improve systems to reduce LHR and subsequent graft loss and mortality among recipients with EHR.