bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurovascular anatomy of the protostegid turtle Rhinochelys pulchriceps and comparisons of membranous and endosseous labyrinth shape in an extant turtle
Authors: Evers Serjoscha W , Neenan James M , Ferreira Gabriel S , Werneburg Ingmar , Barrett Paul M , Benson Roger B J
Published: June 2019

Chelonioid turtles are the only surviving group of reptiles that secondarily evolved marine lifestyles during the Mesozoic Early chelonioid evolution is documented by fossils of their stem group, such as protostegids, which yield insights into the evolution of marine adaptation. Neuroanatomical features are commonly used to infer palaeoecology owing to the functional adaptation of the senses of an organism to its environment. We investigated the neuroanatomy and carotid circulation of the early Late Cretaceous protostegid Rhinochelys pulchriceps based on micro-computed tomography data. We show that the trigeminal foramen of turtles is not homologous to that of other reptiles. The endosseous labyrinth of R. pulchriceps has thick semicircular canals and a high aspect ratio. Comparisons among turtles and other reptiles show that the endosseous labyrinth aspect ratio is not a reliable predictor of the degree of aquatic adaptation, contradicting previous hypotheses. We provide the first models of neuroanatomical soft tissues of an extant turtle. Turtle brain morphology is not reflected by the brain cavity, and the endosseous labyrinth provides an incomplete reflection of membranous semicircular duct morphology. Membranous labyrinth geometry is conserved across gnathostomes, which allows approximate reconstruction of the total membranous labyrinth morphology from the endosseous labyrinth despite their poor reflection of duct morphology.
Improving Distress and Behaviors for Parents of Adolescents With Chronic Pain Enrolled in an Intensive Interdisciplinary Pain Program
Authors: Weiss Karen E. , Junghans-Rutelonis Ashley N. , Aaron Rachel V. , Harbeck-Weber Cynthia , McTate Emily , Luedtke Connie , Bruce Barbara K.
Published: June 2019

Objectives:

Intensive interdisciplinary treatment is emerging as an effective treatment of chronic pain in youth. These programs often include a parental component with the belief that targeting parental distress and responses to a child’s pain will improve outcomes. However, few studies have evaluated the impact of a parental intervention in the interdisciplinary treatment of pediatric chronic pain. The present study consists of a nonrandomized pre-post design to evaluate change in psychological and behavioral functioning of parents who participated in intensive parent programming that utilized cognitive-behavioral therapy and acceptance and commitment therapy, delivered within the context of an interdisciplinary intensive 3-week pain treatment program for youth with chronic pain.

Materials and Methods:

Two hundred twelve parents and their children participated in the study, with 116 participants completing 3-month follow-up measures. Parents completed measures of depressive symptoms, pain catastrophizing, protective responses, and psychological flexibility at admission, discharge, and 3 months after the program. Child functional disability was assessed at the same time points. We examined change in parent factors over time, while controlling for change in child distress.

Results:

Parents reported significant improvements in all areas of functioning from admission to discharge and improvements were maintained at 3-month follow-up.

Discussion:

This study provides evidence suggesting parent interventions can be effective in reducing parent distress and behaviors known to be associated with child outcomes.
The Microsurgical Treatment of Lumbar Disc Herniation
Authors: Burkhardt Benedikt W. , Grimm Marietta , Schwerdtfeger Karsten , Oertel Joachim M.
Published: June 2019

Study Design.

Level 3, cohort study.

Objective.

The aim of this study was to assess long-term clinical outcome, and rate of reoperation following microsurgical subtotal discectomy (MSD).

Summary of Background Data.

Lumbar disc herniation (LDH) is a common cause of discomfort. Studies with >25 years of follow-up are rare and the reported rate of clinical success and reoperation are not well understood.

Methods.

Retrospectively, files with complete documentation of preoperative and postoperative neurological status, process during hospitalization, detailed report of MSD, outpatient visit notes, and full contact information of patients who underwent MSD for the treatment of LDH with a minimum follow-up of 25 years were reviewed. Patients were contacted for personal follow-up assessment which included Oswestry Disability Index (ODI), EQ-5D, and MacNab criteria, usage of pain medication for leg and back pain, limitations in daily life, and repeated procedures at the lumbar spine.

Results.

A total of 355 patients were randomly selected and contacted for final follow-up and 158 patients with a mean follow-up 32 years participated in the study. Clinical success rate was 86.0%, mean ODI was 9% (0–58%), 69.6% of the patients were pain free, 13.9% of patients reported the daily intake of pain medication for back and leg pain. Reoperations were performed in 47 of the patients (29.7%), whereas the rate for recurrent disc herniation at the same level was 8.2%. Reoperation within the first 2 years after initial MSD had negative influence on clinical success. The preoperative physical working status and sex and working status had no influence on the clinical success.

Conclusion.

The MSD is an effective technique to achieve a high rate of patient satisfaction, and high rate of functional recovery. The overall reoperation rate is 30% within 30 years but only 8.2% of the patients underwent reoperation because of recurrent disc herniation at the same level.

Level of Evidence: 3
Eating Behavior Traits, Weight Loss Attempts, and Vertebral Dimensions Among the General Northern Finnish Population
Authors: Oura Petteri , Niinimäki Jaakko , Karppinen Jaro , Nurkkala Marjukka
Published: June 2019

Study Design.

A population-based birth cohort study.

Objective.

To evaluate the associations of eating behavior traits and weight loss attempts with vertebral size among the general Northern Finnish population.

Summary of Background Data.

Vertebral fragility fractures are a typical manifestation of osteoporosis, and small vertebral dimensions are a well-established risk factor for vertebral fracturing. Previous studies have associated cognitive eating restraint and diet-induced weight loss with deteriorated bone quality at various skeletal sites, but data on vertebral geometry are lacking.

Methods.

This study of 1338 middle-aged Northern Finns evaluated the associations of eating behavior traits (flexible and rigid cognitive restraint of eating, uncontrolled eating, emotional eating; assessed by the Three-Factor Eating Questionnaire-18) and weight loss attempts (assessed by a separate questionnaire item) with magnetic resonance imaging-derived vertebral cross-sectional area (CSA). Sex-stratified linear regression models were used to analyze the data, taking body mass index, leisure-time physical activity, general diet, smoking, and socioeconomic status as potential confounders.

Results.

Women with rigid or rigid-and-flexible cognitive eating restraints had 3.2% to 3.4% smaller vertebral CSA than those with no cognitive restraint (P ≤ 0.05). Similarly, the women who reported multiple weight loss attempts in adulthood and midlife had 3.5% smaller vertebral size than those who did not (P = 0.03). Other consistent findings were not obtained from either sex.

Conclusion.

Rigid cognitive eating restraint and multiple weight loss attempts predict small vertebral size and thus decreased spinal health among middle-aged women, but not among men. Future longitudinal studies should confirm these findings.

Level of Evidence: 3
Treatment of Mild Cervical Myelopathy
Authors: Bond Michael , McIntosh Greg , Fisher Charles , Jacobs Bradley , Johnson Michael , Bailey Christopher S. , Christie Sean , Charest-Morin Raphaele , Paquet Jérome , Nataraj Andrew , Cadotte David , Wilson Jeff , Manson Neil , Hall Hamilton , Thomas Kenneth , Rampersaud Yoga Raja , Dea Nicolas
Published: June 2019

Study Design.

Prospective Cohort

Objective.

The aim of this study was to evaluate which demographic, clinical, or radiographic factors are associated with selection for surgical intervention in patients with mild cervical spondylotic myelopathy (CSM).

Summary of Background Data.

Surgery has not been shown superior to best conservative management in mild CSM comparative studies; trials of conservative management represent an acceptable alternative to surgical decompression. It is unknown what patients benefit from surgery.

Methods.

This is a prospective study of patients with mild CSM, defined as modified Japanese Orthopaedic Association Score (mJOA) ≥15. Patients were recruited from seven sites contributing to the Canadian Spine Outcomes Research Network. Demographic, clinical, radiographic and health related quality of life data were collected on all patients at baseline. Multivariate logistic regression modeling was used to identify factors associated with surgical intervention.

Results.

There were 122 patients enrolled, 105 (86.0%) were treated surgically, and 17 (14.0%) were treated nonoperatively. Overall mean age was 54.8 years (SD 12.6) with 80 (65.5%) males. Bivariate analysis revealed no statistically significant differences between surgical and nonoperative groups with respect to age, sex, BMI, smoking status, number of comorbidities and duration of symptoms; mJOA scores were significantly higher in the nonoperative group (16.8 [SD 0.99] vs. 15.9 [SD 0.89], P < 0.001). There was a statistically significant difference in Neck Disability Index, SF12 Physical Component, SF12 Mental Component Score, EQ5D, and PHQ-9 scores between groups; those treated surgically had worse baseline questionnaire scores (P < 0.05). There was no difference in radiographic parameters between groups. Multivariable analysis revealed that lower quality of life scores on EQ5D were associated with selection for surgical management (P < 0.018).

Conclusion.

Patients treated surgically for mild cervical myelopathy did not differ from those treated nonoperatively with respect to baseline demographic or radiographic parameters. Patients with worse EQ5D scores had higher odds of surgical intervention.

Level of Evidence: 3
Regional Differences in the Cost and Utilization of Nonoperative Management Within 3 Months Prior to Lumbar Microdiscectomy
Authors: Davison Mark A. , Lilly Daniel T. , Desai Shyam A. , Vuong Victoria D. , Moreno Jessica , Cheng Joseph , Bagley Carlos , Adogwa Owoicho
Published: June 2019

Study Design.

Retrospective cohort study.

Objective.

The purpose of this investigation was to evaluate the regional variations in the use of nonoperative therapies in patients diagnosed with a lumbar intervertebral disc herniation 3 months prior to undergoing microdiscectomy surgery.

Summary of Background Data.

Regional variations in the management of chronic pain conditions have been previously identified. Patients suffering from a lumbar intervertebral disc herniation are typically treated with a brief course of conservative management prior to attempting microdiscectomy surgery. Whether regional differences exist in the utilization or costs of maximum nonoperative therapy (MNT) remains unknown.

Methods.

Medical records from patients diagnosed with a lumbar intervertebral disc herniation undergoing 1, 2, or 3-level index microdiscectomy operations between 2007 and 2017 were gathered from the HORTHO insurance database consisting of private/commercially insured and Medicare Advantage beneficiaries. Patient regional designation was divided into Midwest, Northeast, South, and West territories and was derived from the insurance claim location. The utilization of MNT within 3 months after initial lumbar herniation diagnosis in adult patients was analyzed.

Results.

Our population consisted of 13,106 patients who underwent primary index microdiscectomy surgery. Significant regional variation was identified in the nonoperative therapy failure rate (P<0.0001), with the highest proportion of Midwest patients failing (2.7%). There were statistical differences in the regional distribution of patients utilizing NSAIDs (P<0.0001), muscle relaxants (P <0.0001), lumbar epidural steroid injections (P <0.0001), physical therapy and occupational therapy sessions (P <0.0001), chiropractor treatments (P <0.0001), and emergency department services (P = 0.0049). The total direct cost associated with all MNT prior to microdiscectomy was $13,205,924, with 59.6% from the South, 31.1% from the Midwest, 8.3% from the West, and 1.1% from the Northeast.

Conclusion.

These findings indicate that regional differences exist in the utilization and costs of MNT of a lumbar intervertebral herniated disc prior to microdiscectomy surgery.

Level of Evidence: 3
Partial response in hairy cell leukemia with vemurafenib despite early discontinuation due to agranulocytosis
Authors: Boilève Alice , Contejean Adrien , Grignano Éric , Dupin Nicolas , Chouchana Laurent , Bouscary Didier , De Witasse-Thezy Thibault
Published: June 2019

Vemurafenib is an oral BRAF kinase inhibitor approved since 2012 for the treatment of patients with unresectable or metastatic melanoma with BRAFV600 mutations. Vemurafenib also demonstrated efficacy for patients with hairy cell leukemia genetically characterized by BRAFV600E mutation. Here, we report the case of a 38-year-old female patient without any previous medical history who experienced agranulocytosis associated with erythrodermia after vemurafenib initiation for the treatment of hairy cell leukemia. Agranulocytosis was confirmed with bone marrow examination. Vemurafenib was considered the most probable drug responsible for this agranulocytosis and was thus stopped. We observed a full neutrophils recovery 10 days after vemurafenib cessation without any haematopoietic growth factors. A bone marrow biopsy performed 1 month after aplasia ending showed a good partial response with less than 5% of hairy cells remaining. To our knowledge, this is the first case ever described by vemurafenib-induced agranulocytosis. Thus, physicians should be warned about this risk given the growing number of patients treated with vemurafenib.
New primary melanoma in a patient under triple therapy with vemurafenib, cobimetinib, and atezolizumab for metastatic melanoma
Authors: Diamantopoulos Panagiotis T. , Lakiotaki Eleftheria , Kyriakakis Georgios , Gogas Helen
Published: June 2019

New primary melanomas (NPMs) in the era of combination treatments for melanoma constitute a challenge for physicians, especially due to the increased incidence of NPMs in patients treated with BRAF inhibitors. We present the unique case of a patient that developed an invasive NPM while under treatment with a combination of vemurafenib, cobimetinib, and atezolizumab. A 39-year-old white male was treated with vemurafenib, cobimetinib, and atezolizumab for a stage IV (T0, N3, M1) BRAF-V600E mutated malignant melanoma in the context of a clinical trial. Eight months from treatment initiation he was diagnosed with an NPM on his back that was found to be BRAF-wild type and neuroblastoma ras mutated, while he was in complete remission. Wide excision of the lesion followed, and the patient was not withdrawn from study treatment. Twenty-two months from treatment initiation, he is still in complete remission. NPMs are a well-known adverse effect of BRAF inhibitors and pose a challenge for the treating physician since these lesions are BRAF-wild type and usually have aggressive biologic behaviour. Invasive NPMs require an aggressive management strategy with clear guidelines to prevent the emergence of advanced or metastatic disease. The emergence of invasive NPMs in patients treated with triple regimens with BRAF/mitogen-activated protein kinase kinase inhibitors and PD1/PDL1 inhibitors is at least unexpected and constitutes a therapeutic stalemate for the physician. Through this case report, we aim to increase awareness about the diagnosis and management of patients with NPM and to express our concerns regarding further management of NPMs in patients under triple combination treatment.
Increased Risk of Opioid Overdose Death Following Cold Weather: A Case–Crossover Study
Authors: Goedel William C. , Marshall Brandon D. L. , Spangler Keith R. , Alexander-Scott Nicole , Green Traci C. , Wellenius Gregory A. , Weinberger Kate R.
Published: June 2019

Background:

The United States is in the midst of an opioid overdose crisis. Little is known about the role of environmental factors in increasing risk of fatal opioid overdose.

Methods:

We conducted a case–crossover analysis of 3,275 opioid overdose deaths recorded in Connecticut and Rhode Island in 2014–2017. We compared the mean ambient temperature on the day of death, as well as average temperature up to 14 days before death, to referent periods matched on year, month, and day of week.

Results:

Low average temperatures over the 3–7 days before death were associated with higher odds of fatal opioid overdose. Relative to 11°C, an average temperature of 0°C over the 7 days before death was associated with a 30% higher odds of death (odds ratio: 1.3; 95% confidence interval, 1.1, 1.5).

Conclusions:

Low average temperature may be associated with higher risk of death due to opioid overdose.
Diagnosed Sleep Apnea and Cardiovascular Disease in Atrial Fibrillation Patients
Authors: Ogilvie Rachel P. , MacLehose Richard F. , Alonso Alvaro , Norby Faye L. , Lakshminarayan Kamakshi , Iber Conrad , Chen Lin Y. , Lutsey Pamela L.
Published: June 2019

Background:

Atrial fibrillation and obstructive sleep apnea are common conditions, but little is known about obstructive sleep apnea and cardiovascular risk among atrial fibrillation patients.

Methods:

Using the Truven Health MarketScan databases, we constructed a prospective cohort of atrial fibrillation patients from 2007 to 2014. Atrial fibrillation, obstructive sleep apnea, stroke, myocardial infarction, and confounders were defined using the International Classification of Disease-9-CM codes. We matched individuals with an obstructive sleep apnea diagnosis with up to five individuals without a diagnosis by age, sex, and enrollment date. Cox proportional hazards models adjusted for confounders and high-dimensional propensity scores. We included migraines as a control outcome. Bias analysis used published sensitivities and specificities to generate rate ratios adjusted for obstructive sleep apnea misclassification.

Results:

We matched 56,969 individuals with an obstructive sleep apnea diagnosis to 323,246 without. During a mean follow-up of 16 months, 3234 incident strokes and 4639 incident myocardial infarctions occurred. After adjustment, obstructive sleep apnea diagnosis was strongly associated with reduced risk of incident stroke (hazard ratio = 0.48, 95% confidence interval = 0.43, 0.53) and myocardial infarction (0.40, [0.37, 0.44]) and a smaller reduced risk of migraines (0.82, [0.68, 0.99]). Bias analysis produced wide-ranging or inestimable rate ratios adjusted for misclassification of obstructive sleep apnea.

Conclusions:

Obstructive sleep apnea diagnosis in atrial fibrillation patients was strongly associated with reduced risk of incident cardiovascular disease. We discuss misclassification, selection bias, and residual confounding as potential explanations.
Nowcasting the Number of New Symptomatic Cases During Infectious Disease Outbreaks Using Constrained P-spline Smoothing
Authors: van de Kassteele Jan , Eilers Paul H. C. , Wallinga Jacco
Published: June 2019

During an infectious disease outbreak, timely information on the number of new symptomatic cases is crucial. However, the reporting of new cases is usually subject to delay due to the incubation period, time to seek care, and diagnosis. This results in a downward bias in the numbers of new cases by the times of symptoms onset towards the current day. The real-time assessment of the current situation while correcting for underreporting is called nowcasting. We present a nowcasting method based on bivariate P-spline smoothing of the number of reported cases by time of symptoms onset and delay. Our objective is to predict the number of symptomatic-but-not-yet-reported cases and combine these with the already reported symptomatic cases into a nowcast. We assume the underlying two-dimensional reporting intensity surface to be smooth. We include prior information on the reporting process as additional constraints: the smooth surface is unimodal in the reporting delay dimension, is (almost) zero at a predefined maximum delay and has a prescribed shape at the beginning of the outbreak. Parameter estimation is done efficiently by penalized iterative weighted least squares. We illustrate our method on a large measles outbreak in the Netherlands. We show that even with very limited information the method is able to accurately predict the number of symptomatic-but-not-yet-reported cases. This results in substantially improved monitoring of new symptomatic cases in real time.
Bayesian Methods for Exposure Misclassification Adjustment in a Mediation Analysis
Authors: Blouin Brittany , Casapia Martin , Kaufman Jay S. , Joseph Lawrence , Larson Charles , Gyorkos Theresa W.
Published: June 2019

Background:

Soil-transmitted helminth infections have been found to be associated with child development. The objective was to investigate hemoglobin levels and malnutrition as mediators of the association between Ascaris infection and intelligence quotient (IQ) scores in children.

Methods:

We conducted a longitudinal cohort study in Iquitos, Peru, between September 2011 and July 2016. A total of 1760 children were recruited at 1 year of age and followed up annually to 5 years. We measured Ascaris infection and malnutrition at each study visit, and hemoglobin levels were measured as of age 3. The exposure was defined as the number of detected Ascaris infections between age 1 and 5. We measured IQ scores at age 5 and used Bayesian models to correct exposure misclassification.

Results:

We included a sample of 781 children in the analysis. In results adjusted for Ascaris misclassification, mean hemoglobin levels mediated the association between Ascaris infection and IQ scores. The natural direct effects (not mediated by hemoglobin) (95% CrI) and natural indirect effects (mediated by hemoglobin) (95% CrI) were compared with no or one infection: −0.9 (−4.6, 2.8) and −4.3 (−6.9, −1.6) for the effect of two infections; −1.4 (−3.8, 1.0) and −1.2 (−2.0, −0.4) for three infections; and −0.4 (−3.2, 2.4) and −2.7 (−4.3, −1.0) for four or five infections.

Conclusion:

Our results are consistent with the hypothesis that hemoglobin levels mediate the association between Ascaris infection and IQ scores. Additional research investigating the effect of including iron supplements in STH control programs is warranted.
The Interaction Continuum
Authors: VanderWeele Tyler J.
Published: June 2019

A common reason given for assessing interaction is to evaluate “whether the effect is larger in one group versus another”. It has long been known that the answer to this question is scale dependent: the “effect” may be larger for one subgroup on the difference scale, but smaller on the ratio scale. In this article, we show that if the relative magnitude of effects across subgroups is of interest then there exists an “interaction continuum” that characterizes the nature of these relations. When both main effects are positive then the placement on the continuum depends on the relative magnitude of the probability of the outcome in the doubly exposed group. For high probabilities of the outcome in the doubly exposed group, the interaction may be positive-multiplicative positive-additive, the strongest form of positive interaction on the “interaction continuum”. As the probability of the outcome in the doubly exposed group goes down, the form of interaction descends through ranks, of what we will refer to as the following: positive-multiplicative positive-additive, no-multiplicative positive-additive, negative-multiplicative positive-additive, negative-multiplicative zero-additive, negative-multiplicative negative-additive, single pure interaction, single qualitative interaction, single-qualitative single-pure interaction, double qualitative interaction, perfect antagonism, inverted interaction. One can thus place a particular set of outcome probabilities into one of these eleven states on the interaction continuum. Analogous results are also given when both exposures are protective, or when one is protective and one causative. The “interaction continuum” can allow for inquiries as to relative effects sizes, while also acknowledging the scale dependence of the notion of interaction itself.
Timing and Amount of Gestational Weight Gain in Association with Adverse Birth Outcomes
Authors: Darling Anne Marie , Werler Martha M. , Cantonwine David E. , Fawzi Wafaie W. , McElrath Thomas F.
Published: June 2019

Background:

Most existing research on gestational weight gain and pregnancy outcomes has not accounted for timing of weight gain. The area under the weight gain curve (AUC) provides a single measure that incorporates both timing of weight gain and total amount gained. This study evaluated predictors and outcomes associated with second- and third-trimester weight gain AUC from the second and third trimester using time-to-event analysis to account for the correlation between gestational weight gain and gestational duration.

Methods:

Our prospective cohort study used data from the LifeCodes study at Brigham and Women’s Hospital. Maternal weights were available from all prenatal and study visits. We used log–Poisson models with empirical variance estimation to identify predictors of total AUC from 14 weeks to delivery and Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between AUC quintile and adverse pregnancy outcomes.

Results:

Compared to the middle quintile, the highest quintile of accumulated pound–days was associated with a decreased hazard of spontaneous preterm birth among multigravid women (HR = 0.44; 95% CI = 0.23, 0.84), a decreased hazard of small-for-gestational-age births (HR = 0.65; 95% CI = 0.45, 0.92) overall and an increased hazard of large-for-gestational-age births among normal and underweight women (HR = 3.21; 95% CI = 1.50, 6.89)

Conclusions:

In our study, a pattern of gestational weight gain characterized by more rapid gains earlier in pregnancy was associated with improved pregnancy outcomes in some subgroups of pregnant women.
MANAGEMENT OF RETINAL HEMANGIOBLASTOMA IN VON HIPPEL–LINDAU DISEASE
Authors: Wiley Henry E. , Krivosic Valerie , Gaudric Alain , Gorin Michael B. , Shields Carol , Shields Jerry , Aronow Mary E. , Chew Emily Y.
Published: June 2019

Purpose:

To review the current state of diagnosis and management of retinal hemangioblastoma and retinal vascular proliferation arising from von Hippel–Lindau (VHL) disease.

Methods:

A review of the literature was performed. Consensus was reached among authors regarding current practice, with reference to published data where possible.

Results:

von Hippel–Lindau disease and its ocular manifestations are relatively rare, and there is limited evidence in the literature on which to base management. There was consensus on core principles, including 1) recognition and diagnosis of von Hippel–Lindau disease when present, with appropriate referral for care of this potentially lethal systemic condition; 2) regular ophthalmic evaluation for individuals with von Hippel–Lindau disease, to identify and offer timely treatment for new or active retinal hemangioblastomas; 3) ablative treatment of retinal hemangioblastomas that can be safely destroyed, to lower risk of vision loss; 4) observation or consideration of nonablative treatments for retinal hemangioblastomas that cannot be safely destroyed; and 5) observation of asymptomatic retinal vascular proliferation, with consideration of vitrectomy for lesions exerting effects on vision.

Conclusion:

Ocular outcomes can be gratifying in many cases with appropriate management. Improved understanding of the molecular basis for the disease creates an opportunity for rational design of better therapies.
EFFICACY AND SAFETY OF A TREAT-AND-EXTEND REGIMEN WITH AFLIBERCEPT IN TREATMENT-NAIVE PATIENTS WITH TYPE 3 NEOVASCULARIZATION
Authors: Arias Luis , Cervera Enrique , Vilimelis Jaume Crespí , Escobar José Juan , Escobar Antonio Gómez , Zapata Miguel Ángel ,   on behalf of the AFLIRAP Trial Investigators
Published: June 2019

Purpose:

To evaluate 52-week efficacy and safety of a treat-and-extend regimen of intravitreal aflibercept 2 mg on treatment-naive Type 3 neovascularization lesions.

Methods:

Phase IV, prospective, open-label, single-arm, multicenter trial including patients with untreated Stage I/II Type 3 neovascularization lesions and baseline best-corrected visual acuity between 78 and 23 Early Treatment Diabetic Retinopathy Study letters. Primary endpoint: mean change in best-corrected visual acuity from baseline at 52 weeks.

Results:

Thirty-two eyes from 32 patients were included (mean ± SD age: 78.2 ± 7.7 years, 68.8% females, baseline best-corrected visual acuity: 57.9 ± 15.4 [Snellen fraction 20/70]). Best-corrected visual acuity increased by 10.5 ± 15.9 Early Treatment Diabetic Retinopathy Study letters at Week 52 (P = 0.0001). The mean foveal and choroidal thickness decreased by 129.1 ± 80.1 µm (P < 0.0001) and 64.3 ± 96.5 (P = 0.0001), respectively. The proportion of patients with intraretinal/subretinal fluid decreased from 28 (87.5%) at baseline to 3 (11.5%) at Week 52 (P < 0.0001). Pigment epithelial detachment and lesion area showed nonsignificant changes over 52 weeks. The mean number of injections was 8.0 ± 2.0. Seven (21.9%) patients experienced treatment-related adverse events and two (6.3%) experienced serious adverse events; one (3.1%) ocular serious adverse event requiring treatment withdrawal, endophthalmitis, and one (3.1%) nonocular spontaneously resolved serious adverse event, palpitations. One (3.1%) patient experienced an APTC ATE: nonfatal stroke not related to trial treatment.

Conclusion:

A treat-and-extend regimen of aflibercept improves visual acuity and retinal edema in eyes with Type 3 neovascularization over 52 weeks with good tolerability.
FAILED LASER RETINOPEXY IN A PATIENT UNDERGOING PAZOPANIB THERAPY
Authors: Lifton Jacob , Chow Audrey , Moshfeghi Andrew A.
Published: June 2019

Purpose:

To report a case of failed endolaser retinopexy in patient taking pazopanib and possible association with impaired retinal remodeling.

Methods:

Case report.

Results:

A 68-year-old man with a history of radiation-induced high-grade metastatic mediastinal leiomyosarcoma, on pazopanib 600 mg daily, presented with a superior retinal tear 2 months after initiating pazopanib. The patient was treated with pars plana vitrectomy and endolaser retinopexy without any immediate complications. One month postoperatively, the patient was found to have a new superior macula-sparing rhegmatogenous retinal detachment extending through the laser barricade nasally. A large proportion of the laser lesions in this area had notably remained chalk-white. The patient underwent pars plana vitrectomy with scleral buckling, and repeat endolaser retinopexy. Pazopanib therapy was stopped 1 week later in consultation with the oncology team and was reinitiated after the retina seemed stable under silicone oil for several weeks. The scars from the patient's repeat endolaser retinopexy remained pale white at his clinic visit 2 months after the procedure, and at that time, his initial laser scars had only just begun to darken with pigment. Four and a half months after the initial vitrectomy and endolaser retinopexy, and three and a half months after his repeat vitrectomy and endolaser retinopexy, all the patient's laser scars have developed increased pigment, and his retina remains completely flat under silicone oil tamponade.

Conclusion:

Pazopanib may have had an adverse effect on retinal wound healing after vitrectomy with endolaser retinopexy, leading to persistence of pale laser lesions many weeks after laser application. It is possible that this may have impaired the typical development of chorioretinal laser scar formation and led to subsequent retinal detachment.
Corneal Densitometry After Secondary Descemet Membrane Endothelial Keratoplasty
Authors: Agha Bishr , Dawson Daniel G. , Kohnen Thomas , Schmack Ingo
Published: June 2019

Purpose:

To evaluate Scheimpflug corneal densitometry (CD) in patients undergoing secondary Descemet membrane endothelial keratoplasty (DMEK) after previous Descemet stripping automated endothelial keratoplasty or DMEK surgery.

Methods:

This was a retrospective institutional case series of 37 eyes of 37 patients. Two secondary DMEK groups, group 1A (n = 12 DMEK after Descemet stripping automated endothelial keratoplasty), group 1B (n = 11 repeat DMEK), and group 2 (n = 14 primary DMEK for Fuchs endothelial dystrophy) were formed. CD was obtained preoperatively, 1, 6, and 12 months postoperatively. In addition, corrected distance visual acuity, central corneal thickness, and endothelial cell density were assessed.

Results:

A significant decrease in grayscale units was observed in the 0- to 2-mm and 2- to 6-mm zones in all groups. For the 0- to 2-mm zone, values decreased from 49.11 ± 17.96 preoperatively to 22.87 ± 5.24 at 12 months (group 1A), from 45.16 ± 9.22 to 24.53 ± 14.21 (group 1B), and from 27.90 ± 8.30 to 16.64 ± 1.51 (group 2) (P < 0.01). Group 2 showed significantly lower grayscale units than groups 1A and 1B preoperatively and 12 months postoperatively in the 0- to 2-mm and 2- to 6-mm zones. Significant correlations of CD and corrected distance visual acuity were found in groups 1A and 1B in the 0- to 2-mm zone at 12 months. There were no significant correlations between CD and central corneal thickness postoperatively.

Conclusions:

A decrease in CD could be demonstrated in secondary DMEK. Nevertheless, CD values remained significantly higher than in controls. This might point out the relevance of secondary corneal structural changes.
Efficacy and Safety of Various Amphotericin B Concentrations on Candida albicans in Cold Storage Conditions
Authors: Tran Khoa D. , Aldrich Benjamin T. , D'Amato Tóthová Jana , Skeie Jessica M. , Kondratick Christine M. , Giurgola Laura , Gatto Claudio , Reed Cynthia R. , Schmidt Gregory A. , Terry Mark A. , Greiner Mark A.
Published: June 2019

Purpose:

To determine the concentration of amphotericin B that would be both effective against Candida albicans contamination and safe for corneal endothelial cells (CECs) in cold storage conditions.

Methods:

Triplicate media cultures were inoculated with 105 colony-forming units (CFUs)/mL of C. albicans (American Type Culture Collection 10231), supplemented with amphotericin B (0–20 μg/mL), stored in cold conditions (2°C–8°C) for 72 hours, and analyzed quantitatively for CFUs. C. albicans concentration in each sample was determined initially and after 6, 24, 48, and 72 hours of storage. CEC mitochondrial function (oxygen consumption rate), apoptosis, and necrosis were examined in donor corneas after 7 days of amphotericin B exposure and compared with untreated controls. CEC viability was also examined by calcein-AM staining and Fiji segmentation after 72 hours or 2 weeks of amphotericin B exposure to mimic potential eye bank practices.

Results:

Amphotericin B concentrations of 1.25, 2.5, and 5.0 μg/mL resulted in 0.47, 1.11, and 1.21 log10 CFU reduction after only 6 hours of cold storage and continued to decrease to 3.50, 3.86, and 4.49 log10 reductions after 72 hours, respectively. By contrast, amphotericin B 0.255 µg/mL showed only 1.01 log10 CFU reduction after 72 hours of incubation. CEC mitochondrial function and viability did not differ in donor corneas exposed to amphotericin B ≤2.59 μg/mL compared with the controls.

Conclusions:

Optimal efficacy of amphotericin B against C. albicans is achieved in cold storage conditions at concentrations ≥1.25 μg/mL, and 2.5 μg/mL reduces Candida contamination by >90% after 6 hours of cold storage without sacrificing CEC health.
Evaluating Dry Eye and Meibomian Gland Dysfunction With Meibography in Patients With Stevens–Johnson Syndrome
Authors: Lekhanont Kaevalin , Jongkhajornpong Passara , Sontichai Vachira , Anothaisintawee Thunyarat , Nijvipakul Sarayut
Published: June 2019

Purpose:

To investigate ocular surface and meibomian gland characteristics using infrared meibography in patients with Stevens–Johnson syndrome (SJS).

Methods:

This is a single-center, prospective, noncontrolled, observational study. Thirty-two Thai patients (64 eyes) with SJS for 1 year or longer (1–44 years) were enrolled in the study. All participants underwent a comprehensive ophthalmic examination including slit-lamp biomicroscopy, tear meniscus height, fluorescein tear breakup time, ocular surface fluorescein staining, eyelid morphology, Schirmer 1 test, meibomian gland expressibility, and upper and lower eyelid meibography using a noncontact infrared meibograph mounted on a slit-lamp biomicroscope.

Results:

The mean age was 42.2 ± 17.7 years (range, 4–68 years). Twenty-nine patients (90.6%) had a history of severe ocular complications in the acute stage of the disease. Medications were the most common cause of SJS (93.8%). Meibum quality could not be assessed in 23 patients (71.9%) due to no glands expressible. Partial or complete loss of the meibomian glands in either the upper or lower eyelid was found in all patients. The degree of meibomian gland dropout significantly correlated with tear breakup time (P < 0.001), meibum quality (P < 0.001), meibum expressibility (P < 0.001), ocular surface staining (P < 0.001), and presence of long-term ocular sequelae including symblepharon (P = 0.027) and limbal stem cell deficiency (P = 0.003).

Conclusions:

SJS is associated with obstructive meibomian gland dysfunction. The severity of meibomian gland dropout has a relationship with abnormal dry eye tests, subjective meibomian gland evaluation, and other ocular sequelae of SJS.
In Vivo Confocal Microscopy of Prominent Conjunctival and Corneal Nerves in Multiple Endocrine Neoplasia Type 2B
Authors: Lam Delphine , Villaret Jeremie , Nguyen Kim Pauline , Gabison Eric , Cochereau Isabelle , Doan Serge
Published: June 2019

Objective:

To report a case of a patient affected by multiple endocrine neoplasia type 2B (MEN 2B) with imaging of conjunctival neuromas by in vivo confocal microscopy (IVCM).

Methods:

Case report.

Results:

A 48-year-old patient affected by MEN2B complained of progressive visual loss in his right eye and severe red, dry and itchy eyes. Best-corrected visual acuity was 20/63 OD and 20/25 OS. Slit lamp exam showed thickened and turned out lid margins, significant blepharitis, conjunctival injection, multiple presumed subconjunctival neuromas at the bulbar conjunctiva and at the limbus, marked prominence of corneal nerves, exposure keratopathy due to incomplete blinking and corneal hypoesthesia, subepithelial corneal neovascularization and scarring in the mid inferior part of both corneas and bilateral iris nodules. We performed IVCM on conjunctival neuromas, revealing large, thick bundles of nerves with disorganization, prominent loops, bifurcations and dilations measuring as much as 1 mm. The IVCM of corneal nerves demonstrated hypertrophic sub basal plexus.

Conclusions:

To date, this is the first report which documents conjunctival neuromas by confocal microscopy in MEN2B.
Schiotz Scleral Intraocular Pressure Readings Predict Goldmann Applanation Readings Better Than Rebound Tonometry
Authors: Senthil Sirisha , Chary Raghava , Ali Mohammed Hasnat , Choudhari Nikhil , Badakere Swathi , Krishnamurthy Rashmi , Dikshit Siddharth , Garudadri Chandrasekhar
Published: June 2019

Purpose:

To study the agreement between scleral intraocular pressure (IOP) measurements using the Schiotz, Icare, and Icare PRO tonometers versus Goldmann applanation tonometer (GAT) in eyes with nonscarred corneas.

Methods:

This cross-sectional study included 83 eyes of 55 subjects. The order of IOP estimation was the corneal GAT, followed by ICare, ICare PRO, and Schiotz on the corneal and temporal sclera. The agreement between different tonometers and the 95% limits of agreement (LoA) were assessed using Bland–Altman plots. The repeated measures correlation coefficient was calculated between GAT IOP and scleral Schiotz IOP, and the 95% confidence intervals were calculated by the bootstrap method. The linear mixed effects model was used (adjusted for both eyes of the subjects) to generate an equation to predict GAT IOP from scleral Schiotz IOP. The prediction model was validated with new data from 60 eyes. Statistical analyses were performed using “R” software (version 3.3.2).

Results:

Comparing the scleral IOP measurements, the mean IOP difference (95% LoA) was the lowest with Schiotz, underestimating by −1.21 mm Hg (7.32, −9.74). Both ICare and ICare PRO significantly overestimated GAT IOP: ICare, 24.6 mm Hg (53.2, −3.97); and ICare PRO, 21.56 mm Hg (52.9, −9.79). The correlation coefficient between scleral Schiotz and GAT IOP was 0.92 (95% bootstrap confidence interval: 0.89, 98). The derived predictive equation was

JOURNAL/corne/04.03/00003226-201909000-00008/inline-formula1/v/2023-09-12T173450Z/r/image-tiff

. The mean difference between the predicted GAT IOP and the actual GAT IOP was 0.96 mm Hg with narrow LoA (+1.79, −3.71), validating the prediction model.

Conclusions:

Among the tonometers tested, the scleral IOP measurements with Schiotz had the best agreement with the GAT although LoA were wide. The predictive equation may have great potential to predict GAT IOP from scleral IOP readings in eyes with scarred/prosthetic corneas.
Why Should We Advocate Maternal Immunization?
Authors: Boonyaratanakornkit Jim , Chu Helen Y.
Published: June 2019

Maternal vaccination provides a method for protecting the pregnant woman, fetus and neonate during a period when there is increased susceptibility to infectious diseases. A dynamic state of immune tolerance during pregnancy and the need to develop adaptive memory to a new foreign antigen-rich environment lead to windows of vulnerability to infection for the mother and neonate, respectively. Passive transfer of humoral immunity through the placenta and breast milk from the mother can bridge the gap in immunity for the neonate. Studies on boosting this natural process of antibody transfer have led to the recommendation for administering inactivated influenza, diphtheria, tetanus toxoid and acellular pertussis vaccines during pregnancy. Several new maternal vaccine candidates are on the horizon.
To LP or not to LP? Identifying the Etiology of Pediatric Meningitis
Authors: Mijovic Hana , Sadarangani Manish
Published: June 2019

Introduction of conjugate vaccines against Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis has led to a substantial reduction in cases of acute bacterial meningitis in countries with high routine childhood immunization coverage. The majority of children hospitalized with meningitis in high-income countries have viral or aseptic meningitis and do not require antibiotic treatment. Cerebrospinal fluid analysis is irreplaceable in appropriately diagnosing and treating bacterial meningitis and avoiding unnecessary antibiotics and prolonged hospitalizations in children with viral meningitis. New diagnostic tests have improved detection of bacterial and viral pathogens in cerebrospinal fluid, underscoring the importance of promptly performing lumbar puncture when meningitis is suspected. This article provides an overview of acute bacterial and viral meningitis in children, focusing on the changing epidemiology, the advantages and limitations of conventional and newer diagnostic methods, and considerations for clinical practice.
Biomarkers for Infection in Children: Current Clinical Practice and Future Perspectives
Authors: Stol Kim , Nijman Ruud G. , van Herk Wendy , van Rossum Annemarie M.C.
Published: June 2019

Biomarkers have become an integral part of the clinical decision-making process of clinicians dealing with febrile children. C-reactive protein, procalcitonin and white blood cell count are probably the most studied ones. Crucial to using biomarkers is the understanding of how a test result will alter post-test probabilities and then impact on clinical decision making. Improved analytical and computational platforms have enabled the next generation of advanced biomarker discovery studies. Promising combinations of candidate biomarkers for a diverse spectrum of febrile illnesses, such as viral and bacterial infections, have been identified using proteomics, RNA gene expression and metabolomics.
Viral Bacterial Interactions in Children: Impact on Clinical Outcomes
Authors: Diaz-Diaz Alejandro , Garcia-Maurino Cristina , Jordan-Villegas Alejandro , Naples Jeffrey , Ramilo Octavio , Mejias Asuncion
Published: June 2019

Respiratory viral infections are associated with significant morbidity and mortality in children < 5 years of age worldwide. Among all respiratory viruses, respiratory syncytial virus (RSV) is the world’s leading cause of bronchiolitis and pneumonia in young children. There are known populations at risk for severe disease but the majority of children who require hospitalization for RSV infection are previously healthy. Viral and host factors have been associated with the pathogenesis of RSV disease; however, the mechanisms that explain the wide variability in the clinical presentation are not completely understood. Recent studies suggest that the complex interaction between the respiratory microbiome, the host’s immune response and the virus may have an impact on the pathogenesis and severity of RSV infection. In this review, we summarize the current evidence regarding the epidemiologic link, the mechanisms of viral–bacterial interactions, and the associations between the upper respiratory tract microbiome and RSV disease severity.
When to Think of Rickettsia
Authors: Galanakis Emmanouil , Bitsori Maria
Published: June 2019

Rickettsiae are globally encountered pathogens with foci of endemicity and epidemic exacerbations under circumstances of crowding and decline of sanitation. Diagnosis is often missed due to misconceptions about epidemiology, confusing terminology and nonspecific clinical presentation. Rickettsioses should be considered in children with febrile illnesses exceeding the usual duration of a viral infection, in particular in children with rash, lymphadenopathy and nearly normal first-line laboratory tests, who reside in or return from endemic areas, recall a compatible contact history, have a constellation of symptoms starting after an arthropod bite, live under troubled social circumstances, or are part of a cluster of similar cases.
What Can We Do About Antimicrobial Resistance?
Authors: Mack Ines , Bielicki Julia
Published: June 2019

Antimicrobial resistance is of global concern, and preserving the ability of many antimicrobials to kill disease-causing bacteria is likely to become more challenging over time. However, we are speeding up this process dramatically by using antibiotics too much or in the wrong way. Respecting simple key principles of optimal antibiotic prescribing together with commitment to further research in this area from the pediatric community is essential to extend the lifeline of antibiotics for the most vulnerable patients without limiting access to antibiotics for those children who require treatment.