First record of Entoleuca mammata in hybrid aspen plantations in hemiboreal Estonia and stand–environmental factors affecting its prevalence

Abstract

Entoleuca mammata [causing Hypoxylon canker (HC)] is one of the most serious pathogens that are colonising Populus species. The area of fast-growing hybrid aspen plantations has remarkably increased in northern Europe because of the high demand for woody biomass, but the prevalence of HC and the stand-related and environmental factors that favour its presence have rarely been monitored in such monocultural plantations. The presence of E. mammata in Estonia was proven by ITS sequence on hybrid aspen. Repeated monitoring after 4 years in 24 hybrid aspen plantations found that the share of visually damaged trees by HC increased from 0.6% (15-year-old trees) to 1.6% (19-year-old trees). The mortality rate of the infected trees during the 4 years was 100%. The probability of HC incidence was favoured by tree vigour and higher soil acidity. The higher susceptibility of more vigorous trees might be related to their trade-off between productivity and defence compounds. The share of trees with clear visual symptoms of HC can be considered marginal, but the aggressive nature of the pathogen suggests the need to extend the monitoring period, especially in recently thinned sites, and to expand the observations to native Populus tremula stands.

http://bit.ly/2CxV3HU

Experimental evolution: its principles and applications in developing stress-tolerant yeasts

Abstract

Stress tolerance and resistance in industrial yeast strains are important attributes for cost-effective bioprocessing. The source of stress-tolerant yeasts ranges from extremophilic environments to laboratory engineered strains. However, industrial stress-tolerant yeasts are very rare in nature as the natural environment forces them to evolve traits that optimize survival and reproduction and not the ability to withstand harsh habitat-irrelevant industrial conditions. Experimental evolution is a frequent method used to uncover the mechanisms of evolution and microbial adaption towards environmental stresses. It optimizes biological systems by means of adaptation to environmental stresses and thus has immense power of development of robust stress-tolerant yeasts. This mini-review briefly outlines the basics and implications of evolution experiments and their applications to industrial biotechnology. This work is meant to serve as an introduction to those new to the field of experimental evolution, and as a guide to biologists working in the field of yeast stress response. Future perspectives of experimental evolution for potential biotechnological applications have also been elucidated.

http://bit.ly/2Mhwnbj

Fiberoptic microindentation technique for early osteoarthritis diagnosis: an in vitro study on human cartilage

Abstract

In this study, the capability of a fiber optic microindenter sensor to discriminate between healthy and slightly degenerated human articular cartilage samples is demonstrated. The purely optical indenter sensor is characterized by extremely reduced dimensions (0.125 mm in diameter and 27 mm in length) in comparison to existing indenter probes offering advantages for endoscopic deployment. The indenter sensor is intended to assist the surgeon in the identification of damaged articular cartilage. From each of seven specimens of human tibia plateau three samples showing different Outerbridge grading were extracted. On each sample stress-relaxation measurements were performed with eight indentation steps, each step being 40 μm and the relaxation of the material was observed for 240 s after each step. A viscoelastic model was used to fit the relaxation and to extract the characteristic parameters according to the model. A highly significant difference in stiffness (p value <0.01) was observed between the native (grade 0) and early diseased (grade 1) human cartilage samples demonstrating the potential of the fiber optic indenter for the diagnosis of cartilage breakdown.

http://bit.ly/2Dj6eGh

Post-partum posterior reversible encephalopathy syndrome requiring decompressive craniectomy: case report and review of the literature

Abstract

Posterior reversible encephalopathy syndrome (PRES) is an uncommon but potentially devastating syndrome if not recognized and treated appropriately. As the name implies, recognition of the condition and proper management may reverse the clinical and radiological findings. However, diagnosis is not always straightforward. We present the case of a 24-year-old female who was 4 days post-partum and presented with headache, neck pain, and new-onset seizures. She had undergone epidural anesthesia during labor, and initial imaging was suggestive of intracranial hypotension versus pachymeningitis. Despite initial conservative therapy including anti-epileptic drugs, magnesium therapy, empiric antibiotics, and Trendelenburg positioning, the patient continued to deteriorate. Follow-up imaging was suggestive of PRES with signs of intracranial hypertension. The patient underwent a decompressive suboccipital craniectomy for refractory and severe PRES and later fully recovered. This case highlights the sometimes difficult diagnosis of PRES, possible association with pregnancy, eclampsia/preeclampsia and/or cerebrospinal fluid drainage, and the rare but life-saving need for decompression in severe cases.

http://bit.ly/2DiKBWt

Exploring the feasibility of a mild and short 4-week combined upper limb and breathing exercise program as a possible home base program to decrease fatigue and improve quality of life in ambulatory and non-ambulatory multiple sclerosis individuals

Abstract

Purpose

To evaluate the feasibility of a combined upper limb and breathing exercise for a home-based program and to explore its effect on primary fatigue and quality of life in ambulatory and non-ambulatory individuals with multiple sclerosis (MS) in a short time.

Method

Nineteen individuals with MS were assigned into semi-controlled pre-post feasibility study based on Expanded Disability Status Scale (EDSS) status and divided into two groups: exercise (five ambulatory, five non-ambulatory; EDSS 1.0–8.0) and related control with no exercise (four ambulatory, five non-ambulatory; EDSS 1.0–7.5). Exercise group performed combined upper limb and breathing exercise in a controlled group (2 days/week, 60 min/session) accompanied by independent home exercise (3 days/week, ≥ 20 min/session). Participants underwent measures of fatigue impact (Modified Fatigue Impact Scale (MFIS) and quality of life (RAND Medical outcomes study 36-item short-form health survey (SF-36)) before and after a 4-week period.

Results

The MFIS (physical, psychosocial, total) showed statistically significant group-by-time interaction in ambulatory (p = 0.033, d = 1.60; p = 0.039, d = 1.59; p = 0.033, d = 1.62) and non-ambulatory individuals (p = 0.009, d = 2.42; p = 0.018, d = 1.96; p = 0.0008, d = 3.92). Physical functioning (SF-36) showed statistically significant group-by-time interaction in ambulatory (p = 0.014, d = 2.14) but no significance in non-ambulatory (p = 0.368, d = 0.68) individuals. Despite the absent statistical significance, there were large intervention effects on MFIS cognitive scores for ambulatory (d = 1.28) and non-ambulatory (d = 1.47), and on other SF-36 scores for ambulatory (general health: d = 1.76 and pain: d = 1.02) and non-ambulatory (physical limitation: d = 1.03 and emotional well-being: d = 0.94) individuals.

Conclusion

Our 4-week program reduced some aspects of fatigue and improved some aspects of quality of life in a small group of ambulatory and non-ambulatory individuals with MS. Good feasibility and significant positive changes from baseline warrant further exploratory work.

Trial registration

Name of the registry: The Impact of Exercise Training on Living Quality in Multiple Sclerosis. Registration: The study was registered at www.clinicaltrial.gov on July 14, 2017. First participant enrollment: August 28, 2017. URL: 602-01/17-01-147; Trial registration ID: NTC03222596.

http://bit.ly/2CwasZi

Esophageal Squamous Cell Carcinoma After Adjustable Gastric Banding

Abstract

The prevalence of morbid obesity has been increasing worldwide. Therefore, multiple laparoscopic adjustable gastric bandings (LAGBs) have been placed in Belgium in the nineties. The procedure was considered as minimal invasive with low morbidity rates. However, some publication cases suggest a possible association between LAGB and the onset of an esophageal cancer. We present a case of a 49-year-old female who consulted for dysphagia, epigastric pain, and anorexia 17 years after LAGB. An esophageal squamous cell carcinoma was diagnosed in the distal esophagus, close to the lap band. The diagnostic value of the performed contrast swallow study seemed limited. We suggest that a routinely gastroscopic evaluation in the long-term follow-up after LAGB should be strived for in patients presenting with late-onset dysphagia.

http://bit.ly/2FHC6pB

Outcomes in Super Obese Patients Undergoing One Anastomosis Gastric Bypass or Laparoscopic Sleeve Gastrectomy

Abstract

Introduction

The data on the role of OAGB in super obese patients and its direct comparison with LSG in super obese patients is scarce.

Objectives

To compare weight loss, impact on comorbidities and nutritional parameters between LSG and OAGB in super obese patients.

Methods

Prospectively collected data of 75 matched patients with BMI > 50, who underwent either laparoscopic sleeve gastrectomy (LSG) or one anastomosis gastric bypass (OAGB), was analyzed retrospectively. Percentage excess weight loss at 1 year and impact on comorbidities were compared in both the groups.

Results

Both the groups were comparable for age, sex, BMI, and presence or absence of diabetes mellitus. Mean TWL% ± 2SD at 1 year was 30.09% ± 19.76 in patients undergoing LSG, while it was 39.9% ± 12.78 in patients undergoing OAGB (p < 0.001). In the LSG group, 85.7% and 66.67% of patients had remission of diabetes mellitus and hypertension, respectively, as compared to 77.77% and 78.5%, respectively, in the OAGB group. All the patients with OSA had a resolution of their symptoms in both the groups. Patients in the OAGB group became more folate deficient despite regular supplementation.

Conclusion

Weight loss following OAGB was found to be better than LSG in the super obese patients in our study. There was a similar resolution of comorbidities and a lesser rate of major complications in the OAGB group.

http://bit.ly/2FyQscn

Probiotic effects of marine Debaryomyces hansenii CBS 8339 on innate immune and antioxidant parameters in newborn goats

Abstract

Several marine Debaryomyces hansenii strains have shown probiotic effects on aquatic animals, and D. hansenii-derived β-glucans have recently provided immunostimulant effects on goat leukocytes. This study assessed the probiotic effects of live yeast D. hansenii CBS 8339 on newborn goats administered orally, and subsequently challenged in vitro with Escherichia coli. D. hansenii CBS 8339 demonstrated the capacity to survive gastrointestinal tract conditions (bile salts and acid pH tolerance) and adhere to goat intestine. Twelve Saanen × Nubian crossbred newborn goats (2.9 ± 0.47 kg) were fed with a controlled diet or D. hansenii (0.7 g/kg body weight per day)–supplemented milk for 30 days. Blood samples of newborn goats were taken at days 15 and 30, and peripheral blood leukocytes were isolated for bacterial challenge, and immunological and antioxidant analyses. Despite cell viability was higher in leukocytes of goat kids fed with the yeast supplement, protection against E. coli challenge was not significantly affected. On the other hand, at day 15, oral administration of D. hansenii enhanced respiratory burst and catalase activity and increased superoxide dismutase activity after challenge. In contrast, at day 30, administration of the yeast supplement increased peroxidase activity and enhanced nitric oxide production and catalase activity after challenge. Finally, the yeast-supplemented diet upregulated the expression of the receptor genes TLR (2, 4, 6), modulator genes Raf.1, Syk, and Myd88, transcription factor gene AP-1, and cytokine genes IL-1β and TNF-α only at day 15 in leukocytes from unchallenged goat kids. These results demonstrated that a short time (15 days) of orally administering the probiotic D. hansenii CBS 8339 to newborn goats stimulated innate immune and antioxidant parameters and the expression of immune-related gene signaling pathways.

http://bit.ly/2SW2csF

Enhanced itaconic acid production in Yarrowia lipolytica via heterologous expression of a mitochondrial transporter MTT

Abstract

Itaconic acid, a promising platform chemical, has been applied in many fields of industrial production. As a potential candidate for itaconic acid production, Yarrowia lipolytica possesses several innate abilities such as the tolerance of low-pH and high-shear stress, fast growth rate, cultivation flexibility, and easy for genetic manipulation. Here, Y. lipolytica Po1f which was tested to show high tolerance to itaconic acid could accumulate itaconic acid (0.363 g/L) by expressing the Aspergillus terreus cis-aconitic acid decarboxylase (CAD). Then, we tried to improve the supply and transport of the immediate precursor cis-aconitic acid by overexpressing a series of genes; these results indicate that overexpression of mitochondrial cis-aconitate transporter MTT is beneficial to the itaconic acid biosynthesis in Y. lipolytica. Further culture optimization enabled 22.03 g/L of itaconic acid to be produced in bioreactors, about 60-fold improvement over the initial titer, which is the highest itaconic acid production achieved at low pH by yeast reported worldwide, to data. This study demonstrates the great potential of Y. lipolytica as an industrial platform for itaconic acid production.

http://bit.ly/2AT5eH1

SAPHO syndrome with pathological fractures of vertebral bodies: a case report

Abstract

Background

It's difficult to diagnose and treat synovitis-acne-pustulosis-hyperostosis-osteomyelitis (SAPHO) syndrome due to its rare and unknown pathogenesis. There is no effective treatment for SAPHO syndrome and the consequences of empirical treatment are unpredictable. This study reports a case of a young female diagnosed as SAPHO syndrome with pathological fractures of vertebral bodies.

Case presentation

A 29-year-old female complained of the right sternoclavicular joint and back pain accompanied limited activities and cutaneous lesions. Laboratory assays revealed abnormal inflammatory factors. Multiple imaging studies illustrated bone lesions and pathological fractures of vertebral bodies. A diagnosis of SAPHO syndrome was made. The patient was treated with Compound Troxerutin and Poreine Cerebroside Injection, non-steroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, corticosteroids and the thoracolumbar brace. The patient was followed up for 6 months and showed improved results.

Conclusions

The case supports that multiple image inspections and laboratory tests contribute to diagnose SAPHO syndrome, and combination therapies of Compound Troxerutin and Poreine Cerebroside Injection, NSAIDs, bisphosphonates, corticosteroids and the thoracolumbar brace in the treatment of SAPHO syndrome with pathological fractures of vertebral bodies are crucial to regain health.

http://bit.ly/2CvPlGw

Disparities in Health Care Coverage Among U.S. Born and Mexican/Central American Born Labor Workers in the U.S.

Abstract

We examined health insurance coverage among U.S. and Mexican/Central American (M/CA) born labor workers living in the U.S. Using data from the 2010–2015 National Health Interview Survey, we employed logistic regression models to examine health insurance coverage and covariates among U.S. and M/CA born labor workers. Prevalence ratios between U.S. and M/CA born workers were also obtained. U.S. born workers had double the prevalence of insurance coverage. Regarding private insurance coverage, U.S. born workers had a higher prevalence of coverage compared to their M/CA born counterparts. Among foreign born workers with U.S. citizenship, the odds of having insurance coverage was greater than that of noncitizens. Additionally, those who had lived in the U.S. for 10 or more years had higher odds of having health insurance coverage. Disparities in health care coverage exist between U.S. born and foreign born labor workers.

http://bit.ly/2FGSZRi

Differences Between U.S.-Born and Non-U.S.-Born Black Adults Reported with Diagnosed HIV Infection: United States, 2008–2014

Abstract

Despite improvements in its treatment, HIV infection continues to affect Blacks disproportionally. Using National HIV Surveillance System data from 50 U.S. states and the District of Columbia, we examined demographic and epidemiologic differences between U.S.-born and non-U.S.-born Black adults. Of 110,452 Black adults reported with diagnosed HIV during 2008–2014 with complete country of birth information, 11.1% were non-U.S.-born. Non-U.S.-born were more likely to be older, female, have HIV infection attributed to heterosexual contact, have been diagnosed late, and live in the northeastern U.S. region. During 2014, the HIV diagnosis rate among African-born Black females was 1.4 times the rate of U.S.-born Black males, 2 times the rate of African-born Black males, and 5.3 times the rate of U.S.-born Black females. We elucidate the differences between U.S.-born and non-U.S.-born Blacks on which to base culturally appropriate HIV-prevention programs and policies.

http://bit.ly/2FBRyV9

Lessons Learned in Clinical Research Recruitment of Immigrants and Minority Group Members with First-Episode Psychosis

Abstract

Recruitment of immigrants and racial and ethnic minorities with first-episode psychosis (FEP) for research studies presents numerous challenges. We describe methods used to recruit 43 U.S. Latinos with FEP and their family caregivers (n = 41) participating in a study to reduce duration of untreated psychosis. A key challenge was that patients were not continuing treatment at an outpatient clinic, as initially expected. To facilitate identification of patients prior to outpatient care, we collaborated with clinic and hospital administrators. Many patients and families were grappling with the aftermath of a hospitalization or adjusting to a diagnosis of a serious mental illness. A considerable amount of time was devoted to addressing participants' concerns and when possible, facilitating needed services. Our experience underscores the importance of establishing long-term relationships through multiple contacts with patients, families, and stakeholders to address recruitment barriers among underserved groups with FEP.

http://bit.ly/2FAUvoA

Stress and Resilience: Key Correlates of Mental Health and Substance Use in the Hispanic Community Health Study of Latino Youth

Abstract

This study examined associations of immigrant generation, acculturation, and sources of stress and resilience with four outcomes—depression symptoms, anxiety symptoms, alcohol susceptibility, and smoking susceptibility. We used data from 1466 youth (ages 8–16) enrolled in the Hispanic Community Health Study of Latino Youth (SOL Youth), a probability sample of Hispanic/Latino youth living in Chicago (IL), Miami (FL), Bronx (NY), and San Diego (CA). We found no evidence of an immigrant paradox. Greater children's acculturative stress was associated with depression/anxiety symptoms; greater parent's acculturative stress was associated with smoking susceptibility. Family functioning and children's ethnic identity were associated with fewer depression/anxiety symptoms and lower alcohol/smoking susceptibility. Although acculturation-related stressors increase youths' risks for poor mental health and substance use, the development of positive ethnic identities and close, well-functioning family support systems can help protect Latino/Hispanic children from the negative behavioral and health-related consequences of stress.

http://bit.ly/2FGWTJH

Refugee Health: A Moral Discussion

http://bit.ly/2FypPV6

Racial Disparities in Type of Heart Failure and Hospitalization

Abstract

Heart failure (HF) is one of the leading causes of hospitalization and readmissions. Our study aimed to examine racial disparities in heart failure patients including onset, mortality, length of stay (LOS), direct costs, and readmission rates. This is a secondary data analysis. We analyzed the risk-adjusted inpatient data of all patients admitted with HF to one health academic center. We compared five health outcomes among three racial groups (white, black, and Hispanic). There were 1006 adult patients making 1605 visits from 10/01/2011 to 09/30/2015. Most black patients were admitted in younger age than other racial groups which indicates the needs for more public health preventions. With risk adjustments, the racial differences in LOS and readmission rates remain. We stratified health outcomes by race/ethnic and type of HF. The findings suggest that further studies to uncover underlying causes of these disparities are necessary. Using risk-adjusted hospitalization data allows for comparisons of quality of care across three racial groups. The study suggests that more prevention and protection services are needed for African American patients with heart failure.

http://bit.ly/2FBiLqO

Neighborhood Racial Diversity and Metabolic Syndrome: 2003–2008 National Health and Nutrition Examination Survey

Abstract

This study investigated the independent association between neighborhood racial/ethnic diversity and metabolic syndrome among US adults, and focused on how this association differed across individual and neighborhood characteristics (i.e., race/ethnicity, sex, age, urbanity, neighborhood poverty). Objectively-measured biomarker data from 2003 to 2008 National Health and Nutrition Examination Survey were linked to census-tract profiles from 2000 decennial census (N = 10,122). Multilevel random intercept logistic regression models were estimated to examine the contextual effects of tract-level racial/ethnic diversity on individual risks of metabolic syndrome. Overall, more than 20% of the study population were identified as having metabolic syndrome, although the prevalence also varied across demographic subgroups and specific biomarkers. Multilevel analyses showed that increased racial/ethnic diversity within a census tract was associated with decreased likelihood of having metabolic syndrome (OR 0.71, 95% CI 0.52–0.96), particularly among female (OR 0.64; 95% CI 0.43–0.96), young adults (OR 0.60; 95% CI 0.39–0.93), and residents living in urban (OR 0.67; 95% CI 0.48–0.93) or poverty neighborhoods (OR 0.54; 95% CI 0.31–0.95). The findings point to the potential benefits of neighborhood racial/ethnic diversity on individual health risks.

http://bit.ly/2FHahO6

The Impact of Acculturation and Racialization on Self-Rated Health Status Among U.S. Latinos

Abstract

We investigate the Hispanic paradox by examining the relationship between acculturation and health status of Latinos to understand nuances among this growing heterogeneous population using a 2011 Latino Decisions survey. We find that acculturation remains an important determinant of Latino health; however, this varies based on whether the sample is restricted to immigrants or includes all Latino adults and on the measures of acculturation employed. We find Latino citizens reported better health than non-citizens; however, other acculturation measures, such as language use and time in the U.S. do not have a marked effect. Furthermore, skin color matters only for U.S.-born Latinos. Racialization is therefore important to consider within the context of the Hispanic paradox. Our findings suggest that some of the disadvantages stemming from minority status in the U.S. are more prominent among Latinos who have greater experience with the racial hierarchy of the U.S. and greater acculturation more broadly.

http://bit.ly/2FFXOKs

Acculturation and Adherence to Physical Activity Recommendations Among Chinese American and Non-Hispanic White Breast Cancer Survivors

Abstract

Chinese American breast cancer survivors' adherence to recommended physical activity (PA) guidelines has been understudied. This study investigated their PA adherence by acculturation level (vs. non-Hispanic White (NHW) survivors). One hundred ninety five Chinese and 202 NHW breast cancer survivors (stage 0–III) responded to a cross-sectional survey including a self-reported PA questionnaire. PA adherence referred to meeting PA recommendations for cancer survivors. Acculturation among Chinese was defined by proxies of U.S. residency, English proficiency, and interview language. Logistic regression was performed to examine factors associated with PA adherence. More-acculturated Chinese survivors' PA adherence rate was 76%. Less-acculturated Chinese survivors' adherence rate (60%) was significantly lower than that of NHWs (80%) (OR 0.38, 95%CI 0.19, 0.75). Less-acculturated Chinese survivors were also less likely to engage in vigorous-intensity PA than NHWs (p < 0.01). Future research on less-acculturated Chinese survivors' motivation for PA to promote their adherence is needed.

http://bit.ly/2FxoUEn

Acculturation and Unmet Health Needs Among Refugees in Omaha, Nebraska

Abstract

This study assessed the association between acculturation and unmet health needs among refugees. Based on data from the Refugee Health Needs Assessment Survey (n = 291) recently conducted in Omaha, Nebraska, Chi square tests and multivariate logistic regressions were estimated to examine how acculturation among refugees was related to their unmet health needs. Relative to refugees who had been in the U.S. for less than 3 years, refugees who had been in the U.S. for 3–5 years were more likely to report lack of health insurance coverage (AOR 2.87, 95% CI 1.19, 6.92) and delaying to see a health care provider due to cost during the 12 months prior to the survey (AOR 4.01, 95% CI 1.18, 13.67). Acculturation among refugees did not necessarily alleviate their unmet health needs. Addressing these needs calls for sustainable medical assistance to refugees that well go beyond the 8-month health insurance coverage currently provided to newly arrived refugees.

http://bit.ly/2FEaDFk

Using the Children with Special Health Care Needs Screener with Immigrant Families: An Analysis of the National Survey of Children’s Health

Abstract

Children in immigrant families are less likely to screen positive with the Children with Special Health Care Needs Screener (CSHCN-S). This may indicate that children in immigrant families are healthier or require fewer health services than non-immigrant peers. Alternatively, the screener may under-identify special healthcare needs in this population. Using the 2011–2012 National Survey of Children's Health, we examined the prevalence of a positive CSHCN-S among children from first, second, and third generation households with an equivalent number of currently diagnosed chronic conditions (0, 1, 2+). Multivariate analyses controlled for sociodemographic factors. Among children with an equivalent number of chronic conditions, fewer children from first and second generation households screened positive with the CSHCN-S relative to children from third generation households. This association remained after adjusting for covariates. The CSHCN Screener may under-identify children from immigrant households, allowing for missed opportunities to allocate health resources.

http://bit.ly/2FH4fNB

Necrotic ulcer on the chin

Necrotic ulcer on the chin of a previously healthy 38-year-old woman.

Simonsen S, Winther C, Zachariae C, Skov L.

Int J Dermatol. 2019 Jan 10. doi: 10.1111/ijd.14378. [Epub ahead of print] No abstract available.

PMID:

 

30632142

Persisting ulcer on the chin

Ned Tijdschr Geneeskd  

Meij V1, Kuijpers KC.

Author information

1

St. Antonius Ziekenhuis, Afd. Heelkunde, Nieuwegein, the Netherlands. v.meij@antoniusziekenhuis.nl

Abstract

A 62-year-old woman presented with an ulcerative lesion on the chin. She had not visited tropical regions, but she had been in Cyprus. A skin biopsy revealed coccoid micro-organisms resembling Leishmania. Subsequently a PCR was performed which showed Leishmania donovani and Leishmania infantum complex and the diagnose 'cutaneous leishmaniasis' was confirmed.

PMID: 22129807

Effect of structural training on surgical outcomes of residents’ first operative laparoscopy: a randomized controlled trial

Abstract

Background

Gynecological surgery and resident education have changed during recent decades, thus impacting surgical training. Training on simulators must begin before operating on patients. The objective of this study was to evaluate the effect of a simple curriculum on the surgical outcome of the participants' first operative laparoscopy.

Methods

This randomized prospective interventional study was carried out in Helsinki University Hospital and Hyvinkää Hospital. We recruited twenty junior residents in Obstetrics and Gynecology, of which half formed a control group and the rest completed the intervention with a theoretical and a practical part. The participants' first laparoscopic salpingectomy was assessed from video recordings by using Objective Structured Assessment of Technical Skills (OSATS) forms and the Numeric Rating Scale (NRS). The surgical outcome and assessed scores were compared between the groups.

Results

We found no differences in operative time, blood loss, or complications, nor in OSATS or NRS scores. In the intervention group, participants with the weakest performances in the simulator, seemed to benefit from the training program more than the participants with the best performances (skill level elevation 29.2–31.6% vs. 21.1–23.3%, respectively). The participants with the best performances in the simulator were scored among the best in the recorded operations as well.

Conclusion

In this study, we found no difference in the surgical outcome between the groups. However, the participants with low starting levels in the simulator could elevate their skill levels more, though they did not reach the skill level of those with a high starting level. Consequently, we found elevation in skills levels in the simulator tasks, but not in the surgical outcome. Likely, our simple training program with a fixed number of repetitions was insufficient to reach a plateau in the learning curve, and thus the training program in such a curriculum should be proficiency based.

http://bit.ly/2VV5QFb

2D versus 3D laparoscopic total mesorectal excision: a developmental multicentre randomised controlled trial

Abstract

Aims

The role of laparoscopy in rectal cancer has been questioned. 3D laparoscopic systems are suggested to aid optimal surgical performance but have not been evaluated in advanced procedures. We hypothesised that stereoscopic imaging could improve the performance of laparoscopic total mesorectal excision (TME).

Methods

A multicentre developmental randomised controlled trial comparing 2D and 3D laparoscopic TME was performed (ISRCTN59485808). Trial surgeons were colorectal consultants that had completed their TME proficiency curve and underwent stereoscopic visual testing. Patients requiring elective laparoscopic TME with curative intent were centrally randomised (1:1) to 2D or 3D using Karl Storz IMAGE1 S D3-Link™ and 10-mm TIPCAM®1S 3D passive polarising laparoscopic systems. Outcomes were enacted adverse events as assessed by the observational clinical human reliability analysis technique, intraoperative data, 30-day patient outcomes, histopathological specimen assessment and surgeon cognitive load.

Results

88 patients were included. There were no differences in patient or tumour demographics, surgeon stereopsis, case difficulty, cognitive load, operative time, blood loss or conversion between the trial arms. 1377 intraoperative adverse events were identified (median 18 per case, IQR 14–21, range 2–49) with no differences seen between the 2D and 3D arms (18 (95% CI 17–21) vs. 17 (95% CI 16–19), p = 0.437). 3D laparoscopy had non-significantly higher mesorectal fascial plane resections (94 vs. 77%, p = 0.059; OR 0.23 (95% CI 0.05–1.16)) but equal lymph node yield and circumferential margin distance and involvement. 30-day morbidity, anastomotic leak, re-operation, length of stay and readmission rates were equal between the 2D and 3D arms.

Conclusion

Feasibility of performing multicentre 3D laparoscopic multicentre trials of specialist performed complex procedures is shown. 3D imaging did not alter the number of intraoperative adverse events; however, a potential improvement in mesorectal specimen quality was observed and should form the focus of future 3D laparoscopic TME trials.

http://bit.ly/2QST6v3

First molecular detection of Rickettsia africae in a tropical bont tick, Amblyomma variegatum , collected in Corsica, France

Abstract

Here we report the first detection of Amblyomma variegatum, a tick species of medical and veterinary importance, and the first molecular evidence of a pathogen, Rickettsia africae, both new to Corsica (France). In August 2018, an ixodid tick with an unusual morphology was removed from the ventral part of a cow's whole skin in a slaughterhouse located in the village of Ponte-Leccia (Haute-Corse). The tick was morphologically identified as an adult male of A. variegatum. This result was confirmed by 16S rDNA sequence analysis with a close relative being a sequence from Senegal showing 99% nucleotide identity. We tested the tick for Ehrlichia and Rickettsia. The tick was positive to Rickettsia and the corresponding sequence matched with R. africae. There is little or no risk of the introduction and establishment of a viable population of A. variegatum in Corsica by migrating birds. However, if it did, it could produce major economic losses for livestock production. Further studies and sustained surveillance are indicated, not only focusing on this species of tick and this rickettsia, but also on other microorganisms of veterinary and medical importance that might be transmitted in Corsica and other Mediterranean islands.

http://bit.ly/2VV4xWN

Alterations in Joint Angular Velocity Following Traumatic Knee Injury in Ovine Models

Abstract

Little effort has been directed towards the consequence of an injury on joint angular velocity. We hypothesized that the magnitude of knee joint angular velocity would be decreased after injury. Four injury groups were investigated in an ovine model: (1) anterior cruciate ligament (ACL) and medial collateral ligament (MCL) transection (ACL/MCL Tx) (n = 5), (2) lateral meniscectomy (Mx) (n = 5), (3) partial ACL transection (p-ACL Tx) (n = 5), and (4) partial-ACL and MCL transection (p-ACL/MCL Tx) (n = 5). The magnitude of the angular velocities decreased in the subjects of all groups at multiple points of the gait cycle. The maximum angular velocities during stance and the maximum extension angular velocities during swing were decreased in 15/20 and 17/20 subjects, respectively. There were strong correlations between morphological osteoarthritis scores and the reduction in the maximum extension angular velocities during swing 40 weeks post-p-ACL Tx and 20 weeks post-ACL/MCL Tx. There was no correlation between the decrease of the angular velocity and morphological osteoarthritis scores in the Mx group and the p-ACL/MCL Tx group. The reduction in angular velocity may be a helpful addition as a surrogate measure of OA risk after ACL injury, and could have clinical significance after further investigation in humans.

http://bit.ly/2RSnUjR

Validated Nuclear-Based Transgene Expression Regulated by the Fea1 Iron-Responsive Promoter in the G reen Alga Chlamydomonas reinhardtii

Abstract

Microalgae are in the focus for the production of recombinant proteins in research and potential commercial application. Inducible promoters represent important tools that potentially allow the expression of recombinant proteins at higher rates. In general, they are used to separate the culture growth phase from the production phase by initiating product formation after high cell densities have been achieved. This potentially offers a higher space–time yield, consequently improving the economics of a process. In the case of the green micro alga Chlamydomonas reinhardtii, a controlled switch between activation and deactivation of gene expression is possible by changes in cultivation parameters. In this work, parameters of induction and deactivation of the iron-responsive Fea1 promoter were analyzed over time in C. reinhardtii. The results presented for the strain CC4351 validate our previous findings presented for strain CC 400. The Fea1 promoter was successfully deactivated upon transferring the cells to medium containing 10 and 20 µM Fe³⁺. Within 120 h, cells showed only 1.7–6% of the initial fluorescence. Activation of the Fea1 promoter occurred promptly and prominently when cells were transferred to iron-deplete medium. In general, both strains showed a pronounced difference between the active and the inactive states of the Fea1 promoter.

http://bit.ly/2RxIl6s

Amyotrophic lateral sclerosis and anesthesia: a case series and review of the literature

Abstract

Purpose

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to death due to respiratory failure. This report describes the perioperative characteristics of ALS patients who underwent procedures with anesthesia at our institution.

Methods

We reviewed perioperative records of ALS patients who underwent procedures with anesthesia from January 1, 2014, through December 31, 2015.

Results

Seventy-eight patients underwent 89 procedures (71 procedures with monitored anesthesia care and 18 with general anesthesia), including 45 gastrostomy tube placements and 18 bone marrow biopsies. Three patients had prolonged duration of postoperative intubation related to preexisting respiratory muscle weakness, and one patient with bilateral pneumothorax required tracheal reintubation for respiratory distress. Four patients had prolonged duration of hospitalization. Three patients were hospitalized for ALS-related complications, and one patient was hospitalized for respiratory distress when pneumoperitoneum developed after gastrostomy tube placement. Three of these patients died of complications attributable to ALS within 30 days of the procedure. Twenty-nine (32.6%) procedures required minimal sedation (e.g., bone marrow biopsy, cataract surgery) and were performed on an ambulatory basis.

Conclusion

When caring for patients with ALS, the perioperative team must be prepared to treat potentially complex medical conditions that may not be directly related to the procedure and anesthetic management. However, minor procedures performed with minimal sedation may be safely performed on an ambulatory basis.

http://bit.ly/2CxpoX4

Managing complexity: the case of nanomaterials

Abstract

The profile management of nanomaterials requires a complicated synergy between component function and shape, material, process, and costs. This study attempts to uncover these relationships by grouping nanomaterial profile components with matching characteristics using cluster analysis. The analysis resulted in the identification of 11 distinct clusters, out of which the physicochemical properties appear to have the higher complexity. We found that this is an efficient method for inspecting the heterogeneity of the nanomaterial profile building blocks and for quantifying nanomaterial characteristics. Using the Cynefin framework, we identified the parameters, which allowed us to comprehend the complexity of the issues, design relative strategies, and overcome difficulties stemming from the application of reductionist approaches on complicated circumstances. It introduces the emergence and implications of "complex" approaches within nanomaterial profile. Cost lies in the disorder domain and the urgency to address the critical issue of asymmetric information calls to understand complex relations. The crux of the issue is the lack of a connected profiling chain that links the nanomaterial development process steps, cost, risk, and toxicity studies, which could reduce opposition from "nano-skeptics" providing sufficient safeguards given the predictive growth of nanomaterials.

Graphical abstract

http://bit.ly/2Hho1RX

Maj. Gen. Prof Khalid Bin Ali Al Khalifa

http://bit.ly/2RVxbIa

Promoter cross-talk affects the inducible expression of intronic shRNAs from the tetracycline response element

Abstract

Background

RNA interference (RNAi), defined as double-stranded, RNA-mediated gene silencing, is a useful tool for functional genomic studies. Along with increasing information about genomic sequences due to the innovative development of genome-sequencing technologies, functional genomic technologies are needed to annotate the genome and determine the processes by which each gene is regulated. Lentiviral vectors have been used to efficiently deliver reagents, such as small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs), into cells and tissues for functional genomic analyses.

Objective

We developed a lentiviral vector that efficiently expresses intronic shRNA from the tetracycline regulatory element (TRE) promoter in a doxycycline-dependent manner.

Methods

We developed a lentiviral vector system that contains reverse tetracycline-controlled transactivator 3 (rtTA3) and the TRE promoter, which are necessary for the doxycycline-inducible expression of shRNAs that are expressed as intronic miR-30a precursors. We then measured the cross-talk between the cytomegalovirus (CMV) and TRE promoters in the vector.

Results

We found that nearby promoters influence each other and that the TRE promoter should be located far from other promoters, such as the CMV promoter, in a vector. The orientation of a promoter with respect to other promoters also influences its transcriptional activity. A head-to-head orientation of the CMV and TRE promoters maintains the lowest level of transcription from TRE in the absence of doxycycline, compared to the tail-to-tail and head-to-tail orientations.

Conclusion

Based on these findings, we were able to construct a lentiviral vector that faithfully expresses intronic miR-30a shRNA precursors in a doxycycline-inducible manner.

http://bit.ly/2HhmJq5

Enhancement of gene knockdown efficiency by CNNC motifs in the intronic shRNA precursor

Abstract

Background

Short hairpin RNAs (shRNAs) expressed from vectors have been used as an effective means of exploiting the RNA interference (RNAi) pathway in mammalian cells. Of several methods to express shRNA, a method of transcribing shRNAs embedded in microRNA precursors has been more widely used than the one that directly expresses shRNA from RNA polymerase III promoters because the microRNA precursor form of shRNA is known to cause lower levels of cytotoxicity and off-target effects than the overexpressed shRNAs from the RNA polymerase III promoters.

Objective

We study the primary sequence features of microRNA precursors, which enhance their processing into mature form, helps design more potent shRNA precursors embedded in microRNA precursors.

Methods

We measure the enhancement of gene knockdown efficiency by adding CNNC motifs in the 3′ flanking region of shRNA precursor embedded in the human miR-30a microRNA precursor.

Results

By systemically adding three CNNC motifs in the 3′ flanking region of shRNA precursor, we found that addition of two CNNC motifs saturates their enhanced knockdown ability of shRNA and that the CNNC motif in the + 17 to + 20 from the drosha cleavage site is most important for the shRNA-mediated target gene knock down. We also did see little knockdown of target gene expression by the shRNA precursor lacking CNNC motif.

Conclusion

Since genetic studies generally require techniques that could reduce gene expression at different degrees, the findings in this study will allow us to use RNAi for genetic studies of reducing gene expression at different degrees.

http://bit.ly/2ROqyaz

Micromotion of implant-abutment interfaces (IAI) after loading: correlation of finite element analysis with in vitro performances

Abstract

Micromotion between IAI affects long-term survival rate of dental implants. The use of practical implants for mechanical test is costly. Finite element analysis (FEA) could test the micron level deformation changes, but whether it reflects the in vitro mechanical performances remains unknown. This study aims to investigate the correlation between IAI micromotion of FEA and in vitro performances. The two-step–two-component FEA method was used to test the relative deformation between IAI for three implant designs (M1, M2, and M3) during torque loading and cyclic oblique loading. The micromotion was divided into directions that perpendicular to (x-axis) and parallel to (y-axis) IAI. In vitro experiments on the micromotion relevant performance of IAI microleakage (tested by toluidine blue releasing with a spectrometer) and IAI locked condition (tested by abutment removal force tests after detaching the central screws) were also conducted for the identical implant systems (G1, G2, and G3). One-way ANOVA and Pearson's correlation tests were performed for data analysis. FEA illustrated that the three implant systems performed different micromotion patterns. Significant differences were found in the IAI microleakage and removal force among the groups. Positive correlations were found between FEA and in vitro outcomes. Therefore, the two-step–two-component FEA method is an appropriate method to evaluate the IAI micromotion after loading.

Graphical abstract

The correspondence of IAI micromotion between FEA analysis and in vitro performances.

http://bit.ly/2AQBvhQ

Different suture anchor fixation techniques affect contact properties in humeral greater tuberosity fracture: a biomechanical study

Abstract

Background

Suture anchor-based fixations of humeral greater tuberosity (GT) fractures have yielded good outcomes in both clinical and biomechanical studies. Be that as it may, the interface contact properties of these fixations have yet to be elaborated. In response, the contact characteristics of two double-row suture anchor fixations for the management of GT fracture were compared.

Methods

Two suture anchor-based fixation techniques, namely the Double-Row Suture Anchor Fixation (DR) and Suture-Bridge Technique (SB), were used to repair humeral GT fractures in 12 fresh-frozen human cadaveric shoulders. A Tekscan pressure sensor placed between the repaired tuberosity and humerus recorded continuous data points directly after repair and for 60 min at set time intervals. The constructs were then cyclically loaded until 100 N, and the shoulders tested at 0°, 30°, and 60° of abduction. Under an applied force, the contact pressure and contact area of the interface were determined.

Results

Although both fixation configurations showed decreased contact pressure and area over time, the SB group had higher contact pressure right after fixation and at all time points thereafter. In contrast, the DR group demonstrated significantly more contact pressure and area at each abduction position with the applied load. Nevertheless, contact pressure and area decreased in response to increasing abduction position for both fixation constructs.

Conclusion

Findings suggest that despite the SB construct having superior interface contact immediately after fixation, the DR construct offered better contact performance at all abduction angles with applied force.

Level of evidence

Basic Science, Biomechanics.

http://bit.ly/2TZZ27v

There is not an increased risk of intraocular hemorrhage associated with the use of novel antiplatelet therapy, but novel anticoagulants may decrease the hazard of bleeding compared with warfarin.

JAMA Ophthalmol. 2018 Feb; 136(2): 122–130.

Published online 2017 Dec 14. doi: 10.1001/jamaophthalmol.2017.5677

PMCID: PMC5838600

PMID: 29242919

Association of Novel Oral Antithrombotics With the Risk of Intraocular Bleeding

Katherine E. Uyhazi, MD, PhD,1 Todd Miano, PharmD, MSCE,2,3 Wei Pan, MS,3 and Brian L. VanderBeek, MD, MPH, MSCE1,2,3,4

Author information Article notes Copyright and License information Disclaimer

See commentary "Novel Antithrombotic Drugs and Intraocular Bleeding: The Importance of Observational Data and Future Perspectives." in JAMA Ophthalmol, doi: 10.1001/jamaophthalmol.2017.4179.

Associated Data

Supplementary Materials

Supplement: eTable 1. Intraocular Bleeding ICD-9 Codes

eTable 2. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Warfarin vs Dabigatran/Rivaroxaban Comparison

eTable 3. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Clopidogrel vs Prasugrel Comparison

jamaophthalmol-136-122-s001.pdf (100K)

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Abstract

Importance

Novel oral anticoagulation and antiplatelet therapies have become a mainstay of treatment for thromboembolic disease. However, the safety profile of these medications has not been completely characterized.

Objective

To determine the risk of developing intraocular hemorrhages with novel oral antithrombotic therapy compared with that of traditional antithrombotic agents.

Design, Setting, and Participants

In this retrospective cohort study, a large national insurance claims database was used to generate 2 parallel analyses. All patients with incident use of dabigatran etexilate or rivaroxaban between January 1, 2010, and September 30, 2015, were compared with patients with incident use of warfarin sodium. Similarly, patients with new use of prasugrel hydrochloride were compared with those with new use of clopidogrel bisulfate. Both analyses required the patient to be in the insurance plan for at least 24 months prior to initiation of therapy and excluded patients with any previous diagnosis of intraocular hemorrhages or any prescription for the comparator medications. Furthermore, the antiplatelet analysis required a diagnosis of acute coronary syndrome or a myocardial infarction within 60 days of initiation of pharmacologic therapy. The anticoagulant analysis excluded patients with end-stage renal disease, renal transplants, and those with heart valve disease.

Main Outcomes and Measures

Incident intraocular hemorrhages at 90 and 365 days. Multivariate Cox proportional hazards regression models were used to compare the hazard ratio (HR) of developing an intraocular hemorrhage in individuals taking novel agents compared with those taking traditional medications.

Results

A total of 146 137 patients taking warfarin (76 714 women and 69 423 men; mean [SD] age, 69.8 [11.8] years) were compared with 64 291 patients taking dabigatran or rivaroxaban (31 576 women and 32 715 men; mean [SD] age, 67.6 [11.7] years). Cox proportional hazards regression revealed a decreased hazard for developing an intraocular hemorrhage with dabigatran or rivaroxaban at 365 days (HR, 0.75; 95% CI, 0.58-0.97; P = .03), but not at 90 days (HR, 0.73; 95% CI, 0.22-2.63; P = .13). A total of 103 796 patients taking clopidogrel (37 578 women and 66 218 men; mean [SD] age, 68.0 [11.3] years) were compared with 8386 patients taking prasugrel (1988 women and 6380 men; mean [SD] age, 61.0 [9.6] years) and no increased hazard for developing an intraocular hemorrhage with prasugrel was seen at 90 days (HR, 0.75; 95% CI, 0.29-1.92; P = .55) or 365 days (HR, 1.19; 95% CI, 0.69-2.04; P = .53).

Conclusions and Relevance

These results suggest a decreased risk of intraocular hemorrhage associated with novel direct thrombin inhibitors and direct factor Xa inhibitors, but no difference for P2Y12 inhibitors compared with traditional vitamin K anticoagulation and antiplatelet therapy, respectively.

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Key Points

Question

Are novel anticoagulant and antiplatelet agents better, the same, or worse than traditional agents with regard to risk of intraocular hemorrhages?

Findings

In a cohort study using a large national insurance claims database, the novel anticoagulant agents dabigatran etexilate and rivaroxaban had a 25% decreased hazard of intraocular hemorrhages compared with warfarin sodium. No difference in the hazard of intraocular hemorrhages was identified for the antiplatelet agent prasugrel hydrochloride compared with clopidogrel bisulfate.

Meaning

These data suggest that novel antithrombotic agents are, at worst, equal in the risk of intraocular hemorrhages and in some instances are safer than their traditional counterparts.

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Introduction

Millions of patients worldwide are treated with oral anticoagulation and antiplatelet therapy to reduce the risk of thromboembolic events. Although traditional anticoagulation therapy has been with the vitamin K antagonist warfarin sodium, several newer agents have become increasingly popular. The direct thrombin inhibitor dabigatran etexilate and the direct factor Xa inhibitors rivaroxaban and apixaban have been shown to be noninferior to warfarin in the prevention of stroke in patients with atrial fibrillation. Unlike warfarin, which requires frequent blood tests and dose titration, these novel anticoagulants do not require routine monitoring. Owing to their predictable pharmacokinetics, shorter half-life, reduced drug-drug interactions, and overall ease of use, more patients are being started on these and similar agents in lieu of traditional vitamin K–based therapies.

Similarly, several novel antiplatelet agents are now available for patients who have had acute coronary syndrome or percutaneous coronary intervention. In lieu of traditional dual antiplatelet therapy with aspirin and clopidogrel bisulfate, the newer oral P2Y12 inhibitors prasugrel hydrochloride and ticagrelor are increasingly prescribed owing to improved efficacy, bioavailability, and onset of action compared with that of clopidogrel.

However, numerous reports of systemic hemorrhagic complications have brought the safety and adverse effect profiles of novel medications into question. Intraocular hemorrhages are a rare but potentially vision-threatening complication of systemic antithrombotic use. Previous studies have shown an increased risk for all types of intraocular hemorrhages in patients taking aspirin, clopidogrel, or warfarin, raising concerns over the safety of these medications.

An analysis using the World Health Organization's database of adverse events suggests that the odds of having a retinal or vitreous hemorrhage while taking dabigatran or rivaroxaban far exceeds that of warfarin. However, the results of this study are based strictly on voluntary physician report and do not quantify the number of patients using the medication. Contrasting these findings is a meta-analysis that found no increased risk of intraocular bleeding in patients taking novel anticoagulants vs those taking vitamin K antagonists, but this analysis was not geared toward finding eye complications.

Even less is known about the ocular risks of novel antiplatelet agents, as, to our knowledge, no studies have assessed intraocular hemorrhages in patients taking the newer oral P2Y12 inhibitors. Given the increasing number of patients using novel antithrombotics, the safety profile of these medications with regard to eye disease needs to be better understood. The goal of this study was to assess the risk of intraocular bleeding in patients taking novel oral antithrombotic agents compared with that of traditional antithrombotic agents.

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Methods

Data Set

Data were abstracted from the Clinformatics Data Mart Database (OptumInsight, Eden Prairie, MN), which contains the deidentified medical claims of all beneficiaries from a large private insurance network in the United States. The database includes all outpatient medical claims (office visits and associated diagnoses), all outpatient pharmaceutical prescriptions filled, and demographic data for each beneficiary during his or her enrollment in the insurance plan. The subset of data available for this study included all patients in the database from January 1, 2010, to September 30, 2015. The University of Pennsylvania institutional review board deemed this study exempt from review owing to the deidentified nature of the data.

Cohorts

For this study, the risk of intraocular bleeding was tested through comparing multiple cohorts of patients. To best assess the potential incremental risk of the novel medications, we compared them with the older medication that the novel drug intended to replace. Two separate analyses were performed. The index date for all comparison groups was the day the patient first filled a prescription. For all cohorts, patients were required to have been enrolled in the insurance plan for 24 months or more prior to the index date without a previous prescription for any of the study medications. Patients were also excluded if they had any previous diagnosis of intraocular hemorrhages or received a prescription for the comparator study medication prior to the index date.

Antiplatelet Cohort

The first analysis examined patients older than 40 years who had received at least 1 prescription for 1 of 2 P2Y12 receptor antagonists of interest: clopidogrel (older drug) or prasugrel (novel drug) during their time in the insurance plan. In addition, specific to the antiplatelet analysis, patients were required to have a history of acute coronary syndrome or a myocardial infarction within 60 days of initiation of therapy to ensure the medications were used for similar indications. Other novel antiplatelet agents (ie, ticagrelor and cangrelor) were not included owing to their limited use within the database. Patients receiving concomitant anticoagulation were either excluded from the analysis or censored at the initiation of anticoagulation. A sensitivity analysis was also performed with removal of patients with a history of ischemic stroke and transient ischemic attacks (TIAs).

Anticoagulant Cohort

The next analysis compared patients older than 40 years who filled at least 1 prescription for either rivaroxaban or dabigatran with patients who filled at least 1 prescription for warfarin. Other novel anticoagulants (ie, apixaban and edoxaban tosylate) were not tested owing to their limited use within the data set. Patients receiving concomitant P2Y12 receptor antagonists (ie, clopidogrel and prasugrel) were not excluded from the analysis; instead, concomitant exposure to P2Y12 receptor antagonists was measured and controlled for in the analysis. The novel anticoagulants studied (dabigatran and rivaroxaban) are cleared by renal elimination and are contraindicated in patients with end stage renal disease. Accordingly, patients with end stage renal disease or undergoing dialysis were excluded from the anticoagulant cohort. In addition, because the novel anticoagulants are approved only for the treatment of nonvalvular atrial fibrillation, patients with heart valve disease or valve replacement were also excluded. These latter exclusions were not applied to the antiplatelet analysis.

Follow-up

For all study cohorts, follow-up began on the date of filling the first prescription and continued until 1 of the following: occurrence of intraocular bleeding, a prescription was filled for a comparator group (ie, alternate antithrombotic), other bleeding (eg, gastrointestinal bleeding or hemorrhagic stroke), the patient's exit from the insurance plan, the end of the observation period, or a gap of more than 14 days in prescription coverage.

Outcomes of Interest

The primary outcome of interest was evidence of new intraocular hemorrhages, defined as having an incident diagnosis code for a new vitreous hemorrhage, nontraumatic intraocular hemorrhage, hyphema, retinal hemorrhage, or expulsive choroidal hemorrhage made by an eye care professional. Subconjunctival hemorrhages were not included. (See eTable 1 in the Supplement for all International Classification of Diseases, Ninth Revision, codes used in this study.)

Covariates

Confounding by indication is any association between a drug and an outcome that is owing to reasons underlying why the drug is actually prescribed, rather than a direct effect of the drug itself, and can limit these types of studies. Although using older antithrombotics as a comparator group reduces this confounding, additional covariates were evaluated for potential inclusion in multivariate analysis. These covariates included demographic information (age, sex, and race), year of initiation of treatment, indications for treatment (acute venous thrombosis, pulmonary embolism, atrial fibrillation, or atrial flutter), comorbid conditions (hypertension, types 1 and 2 diabetes, stroke, myocardial infarction, congestive heart failure, chronic liver disease, chronic pulmonary disease, peripheral vascular disease, and any malignant neoplasm) and eye disease states that are associated with bleeding (diabetic retinopathy, age-related macular degeneration, sickle cell anemia, or retinal vein occlusions). In addition, other classes of medications are known to potentiate or inhibit the effectiveness of anticoagulants and antiplatelet drugs, including selective serotonin reuptake inhibitors, statins, prescription nonsteroidal anti-inflammatory drugs (NSAIDs), and amiodarone. Other direct modulators were grouped into cytochrome P450 inhibitors (antifungals, antibiotics, fenofibrate, and calcium channel blockers) and cytochrome P450 inducers (corticosteroids, antiepileptics, rifampin, and leukotriene receptor antagonists). To assess the potential interaction between these medications and the study drugs at the time of a possible outcome, patients were considered to be users of these medications only if they had an active prescription at the time of outcome or censoring.

Statistical Analysis

Baseline demographic characteristics were assessed at the index date and were analyzed using descriptive statistics. Means and ranges were used for continuous variables and percentages were used for categorical variables. Cox proportional hazards regression models were used to analyze the time from prescription index date to either an outcome of interest that occurred or when the patient was censored. Hazard ratios (HRs) were estimated for 2 observation periods: days 1 to 90 after the index date and days 1 to 365 after the index date. All covariates were first assessed in a Cox univariate analysis. Each covariate with an association (defined as P < .20) with intraocular hemorrhages was then included for multivariate analysis. Backward variable selection was used for fitting the final multivariate models for each observation window in each analysis. Each of the multivariate models was assessed for multicolinearity; none was found. Furthermore, the proportional hazard assumption was tested for all variables using log-log plots and only prescription NSAIDs violated this assumption, which was not included in the multivariate analysis. All statistical analysis was performed with SAS, version 9.4 (SAS Institute Inc), software was used for all statistical analysis. P < .05 was considered significant.

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Results

A total of 146 137 patients prescribed warfarin and 64 291 patients prescribed dabigatran or rivaroxaban met the inclusion criteria (Figure). Approximately half of the patients were female in each cohort (76 714 [52.5%] in the warfarin cohort and 31 576 [49.1%] in the dabigatran or rivaroxaban cohort) and most patients were white (110 639 [75.7%] in the warfarin cohort and 50 523 [78.6%] in the dabigatran or rivaroxaban cohort) (Table 1). The mean (SD) age was 69.8 (11.8) years in the warfarin cohort and 67.6 (11.7) years in the dabigatran or rivaroxaban cohort. (See Table 1 for complete baseline demographic information.) The mean time to a censoring event (in the 365-day periods) was 124 days in the warfarin cohort and 193 days in the dabigatran or rivaroxaban cohort. The warfarin cohort had 81 incident intraocular hemorrhages at 90 days and 203 incident intraocular hemorrhages at 365 days. The novel therapeutic cohort had 33 incident intraocular hemorrhages at 90 days and 92 incident intraocular hemorrhages at 365 days. The longitudinal prevalence rate of an intraocular hemorrhage was 0.14% (205 of 146 137) among patients treated with traditional anticoagulants and was 0.14% (92 of 64 291) among patients treated with novel anticoagulants.

Figure.

Anticoagulation and Antiplatelet Prescriptions After Exclusion Criteria

aPatients were excluded if they had previous intraocular bleeding, end-stage renal disease, a kidney transplant, mitral valve disease, or a heart valve repair or replacement. ACS indicates acute coronary syndrome; MI, myocardial infarction.

Table 1.

Baseline Characteristics of Cohorts

Characteristic	Patients, No. (%)
	Anticoagulant		Antiplatelet
	Warfarin Sodium (n = 146 137)	Dabigatran Etexilate or Rivaroxaban (n = 64 291)	Clopidogrel Bisulfate (n = 103 796)	Prasugrel Hydrochloride (n = 8386)
Age, mean (SD), y	69.8 (11.8)	67.6 (11.7)	68.0 (11.3)	61.0 (9.6)
Female sex	76 714 (52.5)	31 576 (49.1)	37 578 (36.2)	1988 (23.7)
Race
White	110 639 (75.7)	50 523 (78.6)	76 842 (74.0)	6398 (76.3)
Black	13 680 (9.4)	4893 (7.6)	11 407 (11.0)	742 (8.8)
Other	21 818 (14.9)	8875 (13.8)	15 547 (15.0)	1246 (14.9)
Diagnosis
Types 1 and 2 diabetes	47 004 (32.2)	19 874 (30.9)	48 987 (47.2)	3354 (40.0)
Age-related macular degeneration	17 269 (11.8)	7612 (11.8)	12 248 (11.8)	543 (6.5)
Vein occlusions	2111 (1.4)	800 (1.2)	2046 (2.0)	73 (0.9)
Diabetic retinopathy	3203 (2.2)	1524 (2.4)	3150 (3.0)	203 (2.4)
Atrial fibrillation or flutter	44 395 (30.4)	27 714 (43.1)	12 659 (12.2)	607 (7.2)
Hypertension	109 758 (75.1)	49 849 (77.5)	96 481 (93.0)	7276 (86.8)
Chronic kidney disease	25 998 (17.8)	8665 (13.5)	21 809 (21.0)	948 (11.3)
Prior ischemic stroke or TIA	20 936 (14.3)	7194 (11.2)	22 271 (21.5)	609 (7.3)
Prior myocardial infarction	20 610 (14.1)	7232 (11.2)	103 796 (100)	8386 (100)
Congestive heart failure	37 439 (25.6)	13 856 (21.6)	41 159 (39.7)	2154 (25.7)
Any malignant neoplasm	30 343 (20.8)	11 618 (18.1)	16 911 (16.3)	921 (11.0)
Chronic pulmonary disease	55 311 (37.8)	23 513 (36.6)	46 044 (44.4)	2767 (33.0)
Peripheral vascular disease	36 592 (25.0)	13 738 (21.4)	41 344 (39.8)	1926 (23.0)
Acute venous thrombosis	34 825 (23.8)	7993 (12.4)	2704 (2.6)	138 (1.6)
Pulmonary embolism	19 414 (13.3)	3844 (6.0)	1027 (1.0)	45 (0.5)
Medications
Prescription NSAIDs	67 359 (46.1)	34 985 (54.4)	42 321 (40.8)	3918 (46.7)
Statins	78 965 (54.0)	34 338 (53.4)	96 228 (92.7)	8103 (96.6)
SSRIs	33 700 (23.1)	14 865 (23.1)	24 441 (23.5)	1681 (20.0)
Other metabolic inhibitors	110 699 (75.8)	50 838 (79.1)	80 352 (77.4)	6387 (76.2)
Other metabolic inducers	79 921 (54.7)	38 479 (59.9)	54142 (52.2)	4522 (53.9)
Amiodarone or dronedarone	12 284 (8.4)	7429 (11.6)	5590 (5.4)	234 (2.8)
Concurrent antiplatelet use	1032 (0.7)	0	NA	NA
Index year
2010	32 938 (22.5)	205 (0.3)	45 638 (44.0)	0
2011	28 000 (19.2)	5085 (7.9)	9767 (9.4)	0
2012	27 099 (18.5)	10 977 (17.1)	9057 (8.7)	3418 (40.8)
2013	26 223 (17.9)	19 124 (29.7)	23 681 (22.8)	2518 (30.0)
2014	17 721 (12.1)	15 808 (24.6)	8537 (8.2)	1489 (17.8)
2015	14 156 (9.7)	13 092 (20.4)	7116 (6.9)	961 (11.5)

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Abbreviations: NA, not applicable; NSAIDS, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors; TIA, transient ischemic attack.

A total of 103 796 patients prescribed clopidogrel and 8386 patients prescribed prasugrel met the inclusion criteria (Figure). A minority of patients in both cohorts were female (37 578 [36.2%] in the clopidogrel cohort and 1988 [23.7%] in the prasugrel cohort) and most were white (76 842 [74.0%] in the clopidogrel cohort and 6398 [76.3%] in the prasugrel cohort) (Table 1). The mean (SD) age was 68.0 (11.7) years in the clopidogrel cohort and 61.0 (9.6) years in the prasugrel cohort. The mean time to a censoring event was 115 days in the clopidogrel cohort and 180 days in the prasugrel cohort. There were 68 new bleeding events in the traditional clopidogrel cohort at 90 days and 134 new bleeding events at 365 days. The novel antiplatelet cohort had 5 new bleeding events at 90 days and 16 new bleeding events at 365 days. The longitudinal prevalence rate for an intraocular hemorrhage was 0.13% (134 of 103 796) in patients treated with traditional agents and was 0.19% (16 of 8386) in patients treated with novel antiplatelet agents.

Cox univariate analysis revealed that, at 90 days, dabigatran and rivaroxaban were not associated with intraocular hemorrhages compared with warfarin (HR, 0.69; 95% CI, 0.46-1.04; P = .07). However, at 365 days, dabigatran and rivaroxaban were associated with a 32% decreased hazard (HR, 0.68; 95% CI, 0.53-0.87; P = .002). Univariate analysis of prasugrel at both 90 and 365 days showed no association with intraocular hemorrhages compared with clopidogrel (90-day HR, 0.72; 95% CI, 0.29-1.78; P = .47; 365-day HR, 0.98; 95% CI, 0.59-1.65; P = .95). (See eTables 2 and 3 in the Supplement for full univariate analysis results.)

Multivariate analysis again revealed no association for warfarin or dabigatran or rivaroxaban and intraocular hemorrhages in the 90-day period (HR, 0.73; 95% CI, 0.22-2.63; P = .13), but a 25% decreased hazard was seen at 365 days (HR, 0.75; 95% CI, 0.58-0.97; P = .03) (Table 2). No association was also found for developing an intraocular hemorrhage while taking clopidogrel compared with prasugrel in either of the observation windows (90-day HR, 0.75; 95% CI, 0.29-1.92; P = .55; 365-day HR, 1.19; 95% CI, 0.69-2.04; P = .53) (Table 3). A sensitivity analysis that removed all patients with a previous TIA or ischemic stroke from the antiplatelet cohorts found no difference in prasugrel's hazard for intraocular hemorrhages at either time point (90-day HR, 0.60; 95% CI, 0.19-1.93; P = .39; 365-day HR, 1.13; 95% CI, 0.63-2.02; P = .69). With the exception of retinal vein occlusions in the 90-day antiplatelet comparison, the ocular diseases most associated with bleeding (age-related macular degeneration HRs, 2.48-3.15; P < .001 for all comparisons; retinal vein occlusion HRs, 2.32-5.04; P < .009; and diabetic retinopathy HRs, 1.84-2.96; P < .04) were all found to have increased HRs for intraocular hemorrhages (Tables 2 and and33).

Table 2.

Multivariate Results for Significant Associations for Intraocular Hemorrhages in Warfarin vs Dabigatran or Rivaroxaban Comparison

Characteristic	No. (%)		HR (95% CI)	P Value
	Patients (n = 210 428)	Intraocular Hemorrhagesa
90-d Analysisb
Warfarin sodium	146 137 (69.4)	81 (0.06)	1 [Reference]	NA
Dabigatran etexilate or rivaroxaban	64 291 (30.6)	33 (0.05)	0.73 (0.22-2.63)	.13
Peripheral vascular disease	50 330 (23.9)	46 (0.09)	1.60 (1.09-2.36)	.02
Hypertension	159 607 (75.8)	103 (0.06)	2.13 (1.13-4.04)	.02
Metabolic inhibitors	161 537 (76.8)	83 (0.05)	0.62 (0.41-0.95)	.03
Retinal vein occlusion	2911 (1.4)	14 (0.48)	5.04 (2.78-9.12)	<.001
Age-related macular degeneration	24 881 (11.8)	39 (0.16)	2.48 (1.64-3.75)	<.001
Diabetic retinopathy	4727 (2.2)	14 (0.30)	2.96 (1.64-5.35)	<.001
365-d Analysis
Warfarin	146 137 (69.4)	203 (0.14)	1 [Reference]	NA
Dabigatran or rivaroxaban	64 291 (30.6)	92 (0.14)	0.75 (0.58-0.97)	.03
Statins	114 361 (54.3)	197 (0.17)	1.37 (1.07-1.75)	.01
Previous myocardial infarction	27 842 (13.2)	63 (0.23)	1.52 (1.14-2.02)	.004
Diabetic retinopathy	4796 (2.3)	25 (0.52)	1.98 (1.29-3.04)	.002
Retinal vein occlusion	2953 (1.4)	27 (0.91)	3.73 (2.46-5.64)	<.001
Age-related macular degeneration	25 176 (12.0)	106 (0.42)	3.16 (2.46-4.05)	<.001
Index year
2010	33 143 (15.8)	19 (0.06)	1 [Reference]	<.001
2011	33 085 (15.7)	21 (0.06)	1.14 (0.61-2.13)
2012	38 076 (18.1)	38 (0.10)	1.78 (1.03-3.10)
2013	45 347 (21.5)	77 (0.17)	1.12 (0.67-1.86)
2014	33 529 (15.9)	102 (0.30)	1.24 (0.75-2.05)
2015	27 248 (12.9)	38 (0.14)	0.54 (0.31-0.95)

Abbreviations: HR, hazard ratio; NA, not applicable.

aThere is a 1 to 1 correlation between number of patients and number of intraocular hemorrhages.

bTo prevent overfitting a model with a limited number of outcomes, a backward variable selection was used for fitting each of the final models with 1 variable per every additional 10 outcomes allowed to be included in the final model.

Table 3.

Multivariate Results for Significant Associations for Intraocular Hemorrhages in Clopidogrel vs Prasugrel Comparison

Characteristic	No. (%)		HR (95% CI)	P Value
	Patients (n = 112 182)	Intraocular Hemorrhagesa
90-d Analysisb
Clopidogrel bisulfate	103 796 (92.5)	68 (0.07)	1 [Reference]	NA
Prasugrel hydrochloride	8386 (7.5)	5 (0.06)	0.75 (0.29-1.92)	.55
Chronic kidney disease	22 757 (20.3)	26 (0.11)	1.88 (1.15-3.06)	.01
Age-related macular degeneration	12 791 (11.4)	23 (0.18)	2.87 (1.72-4.80)	<.001
diabetic retinopathy	3353 (3.0)	7 (0.21)	2.28 (1.03-5.08)	.04
Index year
2010	45 638 (40.6)	15 (0.03)	1 [Reference]	.05
2011	9767 (8.7)	8 (0.08)	3.15 (1.33-7.43)
2012	12 475 (11.1)	7 (0.06)	2.28 (0.91-5.72)
2013	26 199 (23.4)	25 (0.10)	2.15 (1.13-4.11)
2014	10 026 (8.9)	10 (0.10)	1.26 (0.56-2.82)
2015	8077 (7.2)	8 (0.10)	1.18 (0.50-2.81)
365-d Analysis
Clopidogrel	103 796 (92.5)	134 (0.13)	1 [Reference]	NA
Prasugrel	8386 (7.5)	16 (0.19)	1.19 (0.69-2.04)	.53
Types 1 or 2 diabetes	52 341 (46.7)	95 (0.18)	1.81 (1.29-2.54)	<.001
Congestive heart failure	43 313 (38.6)	73 (0.17)	1.43 (1.03-1.98)	.03
Retinal vein occlusions	2146 (1.9)	11 (0.51)	2.32 (1.23-4.39)	.009
Age-related macular degeneration	12 929 (11.5)	51 (0.39)	3.15 (1.23-4.39)	<.001
Diabetic retinopathy	3405 (3.0)	14 (0.41)	1.84 (1.04-3.26)	.04
Index year
2010	45 638 (40.6)	30 (0.07)	1 [Reference]	.03
2011	9767 (8.7)	10 (0.10)	1.93 (0.94-3.95)
2012	12 475 (11.1)	10 (0.08)	1.45 (0.70-3.04)
2013	26 199 (23.4)	55 (0.21)	1.57 (0.99-2.47)
2014	10 026 (8.9)	30 (0.30)	1.16 (0.69-1.95)
2015	8077 (7.2)	15 (0.19)	0.66 (0.35-1.24)

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Abbreviations: HR, hazard ratio; NA, not applicable.

aThere is a 1 to 1 correlation between number of patients and number of intraocular hemorrhages.

bTo prevent overfitting a model with a limited number of outcomes, a backward variable selection was used for fitting each of the final models with 1 variable per every additional 10 outcomes allowed to be included in the final model.

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Discussion

Novel antithrombotic agents are established as safe and effective alternatives to traditional medications for the treatment of atrial fibrillation, thromboembolic disease, and acute coronary syndrome. The direct thrombin inhibitor dabigatran and the direct factor Xa inhibitor rivaroxaban are increasingly being prescribed owing to their ease of use and improved adverse effect profiles. Likewise, the oral P2Y12inhibitors prasugrel and ticagrelor are approved for use in patients with acute coronary syndrome and have demonstrated superior efficacy compared with clopidogrel.

To our knowledge, this study represents the first evaluation of the risk of intraocular bleeding with a novel antiplatelet agent. Our data suggest that prasugrel carries no additional ocular risk compared with its traditional counterpart, clopidogrel. Further inquiry will be needed on ocular safety profiles as more data become available for even newer antiplatelet and anticoagulation agents such as ticagrelor, cangrelor, apixaban, and edoxaban.

This study found a decreased hazard of intraocular hemorrhages at 365 days for dabigatran and rivaroxaban compared with warfarin. Our results, along with the recent meta-analysis of clinical trial data by Sun et alcontradict the concerns for intraocular bleeding raised by case reports and the World Health Organization adverse events database analysis. Information in the World Health Organization adverse events database results is based solely on voluntary reporting. This type of information can be misleading because it is susceptible to reporting bias and lacks the ability to control for confounding factors or to properly quantitate risk since the total number of prescriptions represented is unknown.

Although our results are similar to those reported in the meta-analysis by Sun et al, it is important to differentiate how each study arrived at its conclusions. Our study focuses on real-world use of anticoagulants, whereas the meta-analysis focused on results from clinical trial populations that may differ from our study in terms of baseline bleeding risk and how the drugs are dosed and monitored. We excluded people with a previous history of intraocular hemorrhages (to limit recurrences in those predisposed to intraocular hemorrhages) and controlled for eye diseases most frequently associated with bleeding. Unless they are specifically focused on ocular outcomes, clinical trials (and by extension, the meta-analysis by Sun et al) are unlikely to exclude patients with previous ocular bleeding or emphasize a history of diabetic retinopathy, retinal vein occlusions, or age-related macular degeneration during randomization. The importance of these risk factors is further highlighted in each of our final models, which show the significant hazard they represent for intraocular bleeding.

Furthermore, the a priori removal of patients predisposed to bleeding from our study also likely explains our lower rate of bleeding (0.14%) in the anticoagulant cohorts compared with that reported by Caldeira et al (0.21%-0.33%). Removal of these patients was needed to best equate the cohorts at baseline and allow for a direct assessment of the association of the medications with intraocular hemorrhages, independent of the underlying disease. Although this limits the generalizability of our results, our exceptionally low rate of intraocular hemorrhages throughout the study supports the safety of antithrombotics with regards to the eye in this population.

Strengths and Limitations

Other strengths of our study should be noted, including our ability to assess many other nonophthalmic factors that could mitigate or potentiate the effects of anticoagulants that may have been an issue in previous studies. In addition, the cohort design of the study minimizes the potential bias of convenience sampling that frequently occurs in case reports (and, by extension, the World Health Organization report) when rare outcomes spur publications that do not reflect the true rate seen in a larger population. Last, pharmacy records, not patient reports, determined medication use; thus, recall bias was eliminated.

Owing to the nature of our data and the inability to know if patients temporarily stopped their medication at or around the time of eye surgery, we are unable to comment on the safety profile of these drugs perioperatively. Although recent studies have shown no increased risk of perioperative vitreous hemorrhage with antithrombotic use, balancing the potentially life-threatening risk of stopping these medications and the low risk of hemorrhagic ocular complications is a difficult decision that should be made between the surgeon, the prescribing clinician, and the patient. Further work should be performed to better inform this decision.

Several limitations need to be considered when reviewing the results of our study. First, the rate of intraocular hemorrhages was exceedingly low, and the power of our study to detect subtle differences between antiplatelet cohorts was limited despite the large number of patients. In another context, however, this is reassuring, given the widespread use of antithrombotic agents. It could even be argued that since the incidence of an intraocular hemorrhage occurring while taking these medications is less than 0.2%, small differences between medication classes may not be clinically significant. Second, not all patients underwent an eye examination while taking the medications studied. Although patients with visually significant bleeding would have presumably been referred for care, it is possible that patients with clinically insignificant intraocular hemorrhages went undiagnosed, suggesting that our incidence rates may be an underestimate. Third, this study used administrative billing data that were unable to be verified with medical record–level data, nor have all the International Classification of Diseases, Ninth Revision codes used been specifically validated. Next, the database consists of claims from 1 insurance network and may not be generalizable to other patient populations.

Last, the database only includes data on prescription NSAIDs. We are unable to account for any over-the-counter use of NSAIDs or other factors that could influence the potency of the antithrombotic medications (ie, the effect of grapefruit juice on warfarin levels). Although this limitation certainly exists, the commonness of use of over-the-counter NSAIDs combined with the extremely low occurrence rate of bleeding found in this study suggest that the overall effect of this issue is likely low.

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Conclusions

Owing to the increasing use of novel antithrombotic medications for the treatment of coronary artery disease and atrial fibrillation, the ocular safety profile of these medications must be understood. Our study suggests that there is not an increased risk of intraocular hemorrhage associated with the use of novel antiplatelet therapy, but novel anticoagulants may decrease the hazard of bleeding compared with warfarin.

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Notes

Supplement.

eTable 1. Intraocular Bleeding ICD-9 Codes

eTable 2. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Warfarin vs Dabigatran/Rivaroxaban Comparison

eTable 3. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Clopidogrel vs Prasugrel Comparison

Click here for additional data file.(100K, pdf)

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