Cost analysis of childhood glaucoma surgeries using the US Medicaire allowable costs

AIM: To analyze and calculate the relative cost of various childhood glaucoma surgical interventions per mm Hg intraocular pressure(IOP) reduction($/mm Hg).METHODS: Representative index studies were reviewed to quantitate the reduction of mean IOP and glaucoma medications for each surgical intervention in childhood glaucoma. A US perspective was adopted, using Medicare allowable costs to calculate cost/mm Hg IOP reduction($/mm Hg) at 1y postoperatively.RESULTS: At 1y postoperatively, the cost/mm Hg IOP reduction was $226/mm Hg for microcatheter-assisted circumferential trabeculotomy, $284/mm Hg for cyclophotocoagulation, $288/mm Hg for conventional ab-externo trabeculotomy, $338/mm Hg for Ahmed glaucoma valve, $350/mm Hg for Baerveldt glaucoma implant, $351/mm Hg for goniotomy, and $400/mm Hg for trabeculectomy.CONCLUSION: Microcatheter-assisted circumferential trabeculotomy is the most cost-efficient surgical method to lower IOP in childhood glaucoma, while trabeculectomy is the least cost-efficient surgical method.

The role of monocytes in optic nerve injury

Monocytes,including monocyte-derived macrophages and resident microglia,mediate many phases of optic nerve injury pathogenesis.Resident microglia respond first,followed by infiltrating macrophages which regulate neuronal inflammation,cell proliferation and differentiation,scar formation and tissue remodeling following optic nerve injury.However,microglia and macrophages have distinct functions which can be either beneficial or detrimental to the optic nerve depending on the spatial context and temporal sequence of their activity.These divergent effects are attributed to pro-and anti-inflammatory cytokines expressed by monocytes,crosstalk between monocyte and glial cells and even microglia-macrophage communication.In this review,we describe the dynamics and functions of microglia and macrophages in neuronal inflammation and regeneration following optic nerve injury,and their possible role as therapeutic targets for axonal regeneration.

Electrophysiology and genetic testing in the precision medicine of congenital deafness:A review

Background:Congenital hearing loss is remarkably heterogeneous,with over 130 deafness genes and thousands of variants,making for innumerable genotype/phenotype combinations.Understanding both the pathophysiology of hearing loss and molecular site of lesion along the auditory pathway permits for significantly individualized counseling.Electrophysiologic techniques such as electrocochleography(ECochG)and electrically-evoked compound action potentials(eCAP)are being studied to localize pathology and estimate residual cochlear vs.neural health.This review describes the expanding roles of genetic and electrophysiologic evaluation in the precision medicine of congenital hearing loss.The basics of genetic mutations in hearing loss and electrophysiologic testing(ECochG and eCAP)are reviewed,and how they complement each other in the diagnostics and prognostication of hearing outcomes.Used together,these measures improve the understanding of insults to the auditory system,allowing for individualized counseling for CI candidacy/outcomes or other habilitation strategies.Conclusion:Despite tremendous discovery in deafness genes,the effects of individual genes on neural function remain poorly understood.Bridging the understanding between molecular genotype and neural and functional phenotype is paramount to interpreting genetic results in clinical practice.The future hearing healthcare provider must consolidate an ever-increasing amount of genetic and phenotypic information in the precision medicine of hearing loss.

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

Skeletal stem and progenitor cells(SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

Intraductal papillary neoplasm of the bile ducts: A case report and literature review

Intraductal papillary neoplasm of the bile duct(IPNB) is a rare bile duct neoplasm mostly found in far eastern nations where hepatolithiasis and clonorchiasis infections are endemic. In western countries,it is very rare and the etiology is unknown. In this article,we report the first IPNB patient we encountered in our clinic and a literature review. The patient is a 38-yearold female with a history of choledocholithiasis who presented with obstructive jaundice. She was found to have a papillary mass at the junction of the right hepatic duct and common hepatic duct with six masses in the liver parenchyma. The immunophenotypic and histologic features of the tumor are consistent with IPNB,gastric subtype. The patient had a partial hepatectomy and has been receiving palliative chemotherapy. In a search of Pub Med database,we collected 354 IPNB patients reported in 22 articles. In these patients,52.8% were from Japan and 27.7% were from western countries including the United States(11.0%). The age of the patients ranged from 35 to 80 years old with an average of 64.6. Male/female ratio was 1.5. Macroscopically,57.5% of the tumors were in the left lobe and 29.5% were in the right lobe. The average size of the tumor were 4.2 cm at the time of diagnosis. Histologically,pancreato-biliary subtype accounted for 41.8%,intestinal 28.0%,gastric 13.5% and oncocytic 16%. An invasive component is most often present in the pancreato-biliary and gastric subtypes. Despite recent advanced technologies,diagnosis of IPNB is still challenging,especially in western countries due to its rarity. Defined clinicopathologic features are in demand for the accurate diagnosis and proper treatment.

A growing field: the regulation of axonal regeneration by Wnt signaling

The canonical Wnt/β-catenin pathway is a highly conserved signaling cascade that plays critical roles during embryogenesis. Wnt ligands regulate axonal extension, growth cone guidance and synaptogenesis throughout the developing central nervous system （CNS）. Recently, studies in mammalian and fish model systems have demonstrated that Wnt/β-catenin signaling also promotes axonal regeneration in the adult optic nerve and spinal cord after injury, raising the possibility that Wnt could be developed as a therapeutic strategy. In this review, we summarize experimental evidence that reveals novel roles for Wnt signaling in the injured CNS, and discuss possible mechanisms by which Wnt ligands could overcome molecular barriers inhibiting axonal growth to promote regeneration. A central challenge in the neuroscience field is developing therapeutic strategies that induce robust axonal regeneration. Although adult axons have the capacity to respond to axonal guidance molecules after injury, there are several major obstacles for axonal growth, including extensive neuronal death, glial scars at the injury site, and lack of axonal guidance signals. Research in rodents demonstrated that activation of Wnt/β-catenin signaling in retinal neurons and radial glia induced neuronal survival and axonal growth, but that activation within reactive glia at the injury site promoted proliferation and glial scar formation. Studies in zebrafish spinal cord injury models confirm an axonal regenerative role for Wnt/β-catenin signaling and identified the cell types responsible. Additionally, in vitro and in vivo studies demonstrated that Wnt induces axonal and neurite growth through transcription-dependent effects of its central mediator β-catenin, potentially by inducing regeneration-promoting genes. Canonical Wnt signaling may also function through transcription-independent interactions of β-catenin with cytoskeletal elements, which could stabilize growing axons and control growth cone movement. Therefore, these studies suggest that Wnt-induced pathways responsible for regulating axonal growth during embryogenesis could be repurposed to promote axonal growth after injury.

Molecular mechanisms of the suppression of axon regeneration by KLF transcription factors

Molecular mechanisms of the Kruppel-like family of transcription factors （KLFs） have been studied more in proliferating cells than in post-mitotic cells such as neurons. We recently found that KLFs regulate intrinsic axon growth ability in central nervous system （CNS） neurons in- cluding retinal ganglion cells, and hippocampal and cortical neurons. With at least 15 of 17 KLF family members expressed in neurons and at least 5 structurally unique subfamilies, it is import- ant to determine how this complex family functions in neurons to regulate the intricate genetic programs of axon growth and regeneration. By characterizing the molecular mechanisms of the KLF family in the nervous system, including binding partners and gene targets, and comparing them to defined mechanisms defined outside the nervous system, we may better understand how KLFs regulate neurite growth and axon regeneration.

New approaches for diagnosis of dry eye disease

We reviewed the literature for different diagnostic approaches for dry eye disease(DED) including the most recent advances, contradictions and promising diagnostic tools and technique. We performed a broad literature search for articles discussing different methods for diagnosis of DED including assessment of tear osmolarity, tear film stability, ocular biomarkers and others. Articles indexed in PubMed and google scholar were included. With the growing cosmetic industry, environmental pollution, and booming of digital screens, DED is becoming more prevalent. Its multifactorial etiology renders the diagnosis challenging and invites the emergence of new diagnostic tools and tests. Diagnostic tools can be classified, based on the parameter they measure, into tear film osmolarity, functional visual acuity, tear volume, tear turnover, tear film stability, tear film composition, ocular biomarkers and others. Although numerous methods exist, the most accurate diagnosis can be reached through combining the results of more than one test. Many reported tests have shown potential as diagnostic/screening tools, however, require more research to prove their diagnostic power, alone or in combination. Future research should focus on identifying and measuring parameters that are the most specific to DED diagnosis.

Utility of endoscopic ultrasound and endoscopy in diagnosis and management of hepatocellular carcinoma and its complications: What does endoscopic ultrasonography offer above and beyond conventional cross-sectional imaging?

Hepatocellular carcinoma constitutes over 90% of the primary liver tumors, the rest being cholangiocarcinoma. It has an insidious presentation, which is responsible for the delayed presentation. Hence, the management strategy relies on screening to diagnose it an early stage for curative resection and/or treatment with local ablative techniques or chemotherapy. However, even with different screening programs, more than 60% of tumors are still detected at an advanced stage, leading to an unchanged mortality rate, thereby implying a room for improvement in the screening and diagnostic process. In the last few years, there has been evolution of utility of endoscopy, specifically endoscopic ultrasonography along with Fine needle aspiration, for this purpose, which we comprehensively review in this article.

Economic impact of minimally invasive lumbar surgery

Cost effectiveness has been demonstrated for traditional lumbar discectomy, lumbar laminectomy as well as for instrumented and noninstrumented arthrodesis. While emerging evidence suggests that minimally invasive spine surgery reduces morbidity, duration of hospitalization, and accelerates return to activites of daily living, data regarding cost effectiveness of these novel techniques is limited. The current study analyzes all available data on minimally invasive techniques for lumbar discectomy, decompression, short-segment fusion and deformity surgery. In general, minimallyinvasive spine procedures appear to hold promise in quicker patient recovery times and earlier return to work. Thus, minimally invasive lumbar spine surgery appears to have the potential to be a cost-effective intervention. Moreover, novel less invasive procedures are less destabilizing and may therefore be utilized in certain indications that traditionally required arthrodesis procedures. However, there is a lack of studies analyzing the economic impact of minimally invasive spine surgery. Future studies are necessary to confirm the durability and further define indications for minimally invasive lumbar spine procedures.

Strategies to avoid a missed diagnosis of co-occurring concussion in post-acute patients having a spinal cord injury

Research scientists and clinicians should be aware that missed diagnoses of mild-moderate traumatic brain injuries in post-acute patients having spinal cord injuries may approach 60-74% with certain risk factors, potentially causing clinical consequences for patients, and confounding the results of clinical research studies. Factors leading to a missed diagnosis may include acute trauma-related life-threatening issues, sedation/intubation, subtle neuropathology on neuroimaging, failure to collect Glasgow Coma Scale scores or duration of posttraumatic amnesia, or lack of validity of this information, and overlap in neuro-cognitive symptoms with emotional responses to spinal cord injuries. Strategies for avoiding a missed diagnosis of mild-moderate traumatic brain injuries in patients having a spinal cord injuries are highlighted in this perspective.

Molecular imaging of movement disorders

Positron emission tomography measures the activity of radioactively labeled compounds which distribute and accumulate in central nervous system regions in proportion to their metabolic rate or blood flow. Specific circuits such as the dopaminergic nigrostriatal projection can be studied with ligands that bind to the pre-synaptic dopamine transporter or post-synaptic dopamine receptors(D1 and D2). Single photon emission computerized tomography(SPECT) measures the activity of similar tracers labeled with heavy radioactive species such as technetium and iodine. In essential tremor, there is cerebellar hypermetabolism and abnormal GABAergic function in premotor cortices, dentate nuclei and ventral thalami, without significant abnormalities in dopaminergic transmission. In Huntington's disease, there is hypometabolism in the striatum, frontal and temporal cortices. Disease progression is accompanied by reduction in striatal D1 and D2 binding that correlates with trinucleotide repeat length, disease duration and severity. In dystonia, there is hypermetabolism in the basal ganglia, supplementary motor areas and cerebellum at rest. Thalamic and cerebellar hypermetabolism is seen during dystonic movements, which can be modulated by globus pallidus deep brain stimulation(DBS). Additionally, GABA-A receptor activity is reduced in motor, premotor and somatosensory cortices. In Tourette's syndrome, there is hypermetabolism in premotor and sensorimotor cortices, as well as hypometabolism in the striatum, thalamus and limbic regions at rest. During tics, multiple areas related to cognitive, sensory and motor functions become hypermetabolic. Also, there is abnormal serotoninergic transmission in prefrontal cortices and bilateral thalami, as well as hyperactivity in the striatal dopaminergic system which can be modulated with thalamic DBS. In Parkinson's disease(PD), there is asymmetric progressive decline in striatal dopaminergic tracer accumulation, which follows a caudal-to-rostral direction. Uptake declines prior to symptom presentation and progresses from contralateral to the most symptomatic side to bilateral, correlating with symptom severity. In progressive supranuclear palsy(PSP) and multiple system atrophy(MSA), striatal activity is symmetrically and diffusely decreased. The caudal-to-rostral pattern is lost in PSP, but could be present in MSA. In corticobasal degeneration(CBD), there is asymmetric, diffuse reduction of striatal activity, contralateral to the most symptomatic side. Additionally, there is hypometabolism in contralateral parietooccipital and frontal cortices in PD; bilateral putamen and cerebellum in MSA; caudate, thalamus, midbrain, mesial frontal and prefrontal cortices in PSP; and contralateral cortices in CBD. Finally, cardiac sympathetic SPECT signal is decreased in PD. The capacity of molecular imaging to provide in vivo time courses of gene expression, protein synthesis, receptor and transporter binding, could facilitate the development and evaluation of novel medical, surgical and genetic therapies in movement disorders.

Surgical management of uveitis-glaucoma-hyphema syndrome

AIM:To report outcomes of patients after intraocular lens(IOL)repositioning or exchange for the version of the uveitisglaucoma-hyphema(UGH)syndrome that does not include closed loop anterior chamber IOL(nUGH).METHODS:Chart review of patients with nUGH who underwent IOL repositioning or exchange by one surgeon were reviewed.The main outcome measures were best corrected visual acuity(BCVA)as a decimal fraction preoperatively and postoperatively after IOL repositioning or exchange.Clinical findings evaluated included the presence of uveitis,hyphema,elevated intraocular pressure(IOP),and other complications such as pigment dispersion or vitreous hemorrhage.The number of anti-inflammatory and glaucoma medications were assessed before and after IOL repositioning or exchange.RESULTS:The study included 14 pseudophakic eyes.The median time at the onset of contemporary UGH after cataract extraction and IOL implantation(CE/IOL)was7.5 y.IOL repositioning or exchange was performed at a mean duration of 8.1±4.7 mo(median:4 mo)after onset of UGH.The mean BCVA was improved from 0.45±0.26 preoperatively after onset of UGH syndrome to 0.76±0.22(P=0.016)after IOL repositioning or exchange.Among the14 eyes,uveitis,elevated IOP,and hyphema were present preoperatively in 13,13,and 6 eyes,respectively.Uveitis and hyphema resolved in all cases after IOL surgery.The mean IOP was reduced from 26.4±4.5 mm Hg preoperatively to 14.7±4.9 postoperatively(P=0.01).The mean number of glaucoma medications used was reduced from 1.7±1.1 medications preoperatively to 0.8±1.08(P=0.04)postoperatively.CONCLUSION:IOL repositioning or exchange is an effective treatment in many cases for medically resistant contemporary UGH syndrome.

Escalating complexity of endoscopic retrograde cholangiopancreatography over the last decade with increasing reliance on advanced cannulation techniques

BACKGROUND At our academic tertiary care medical center, we have noted patients referred for endoscopic retrograde cholangiopancreatography(ERCP) who increasingly require advanced cannulation techniques. This trend is noted despite increased endoscopist experience and annual ERCP volume over the same period.AIM To evaluate this phenomenon of perceived escalation in complexity of cannulation at ERCP and assessed potential underlying factors.METHODS Demographic/clinical variables and records of ERCP patients at the beginning(2008), middle(2013) and end(2018) of the last decade were reviewed retrospectively. Cannulation approaches were classified as "standard" or "advanced" and duodenoscope position was labeled as "standard"(short position) or "non-standard"(e.g., long, semi-long).RESULTS Patients undergoing ERCP were older in 2018 compared to 2008(69.7 ± 15.2 years vs 55.1 ± 14.7, P < 0.05). Increased ampullary distortion and peri-ampullary diverticula were noted in 2018(P < 0.001). ERCPs were increasingly performed with a non-standard duodenoscope position, from 2.2%(2008) to 5.6%(2013) and 16.1%(2018)(P < 0.001). Utilization of more than one advanced cannulation technique for a given ERCP increased from 0.7%(2008) to 0.9%(2013) to 6.6%(2018)(P < 0.001). Primary mass size > 4 cm, pancreatic uncinate mass, and bilirubin > 10 mg/d L predicted use of advanced cannulation techniques(P < 0.03 for each).CONCLUSION Complexity of cannulation at ERCP has sharply increased over the past 5 years, with an increased proportion of elderly patients and those with malignancy requiring advanced cannulation approaches. These data suggest that complexity of cannulation at ERCP may be predicted based on patient/ampulla characteristics. This may inform selection of experienced, high-volume endoscopists to perform these complex procedures.

Prognostic impact of atrial fibrillation on clinical outcomes of acute coronary syndromes,heart failure and chronic kidney disease

Atrial fibrillation(AF) is the most common type of sustained arrhythmia,which is now on course to reach epidemic proportions in the elderly population. AF is a commonly encountered comorbidity in patients with cardiac and major non-cardiac diseases. Morbidity and mortality associated with AF makes it a major healthcare burden. The objective of our article is to determine the prognostic impact of AF on acute coronary syndromes,heart failure and chronic kidney disease. Multiple studies have been conducted to determine if AF has an independent role in the overall mortality of such patients. Our review suggests that AF has an independent adverse prognostic impact on the clinical outcomes of acute coronary syndromes,heart failure and chronic kidney disease.

Exploring the role of interleukin-27 as a regulator of neuronal survival in central nervous system diseases

Interleukin-27 is a pleiotropic cytokine that is involved in tissue responses to infection,cell stress,neuronal disease,and tumors.Recent studies in various tissues indicate that interleukin-27 has complex activating and inhibitory properties in innate and acquired immunity.The availability of recombinant interleukin-27 protein and mice with genetic deletions of interleukin-27,its receptors and signaling mediators have helped define the role of interleukin-27 in neurodegenerative diseases.Interleukin-27 has been well-characterized as an important regulator of T cell activation and differentiation that enhances or suppresses T cell responses in autoimmune conditions in the central nervous system.Evidence is also accumulating that interleukin-27 has neuroprotective activities in the retina and brain.Interleukin-27 is secreted from and binds to infiltrating microglia,macrophage,astrocytes,and even neurons and it promotes neuronal survival by regulating pro-and anti-inflammatory cytokines,neuroinflammatory pathways,oxidative stress,apoptosis,autophagy,and epigenetic modifications.However,interleukin-27 can have the opposite effect and induce inflammation and cell death in certain situations.In this review,we describe the current understanding of regulatory activities of interleukin-27 on cell survival and inflammation and discuss its mechanisms of action in the brain,spinal cord,and retina.We also review evidence for and against the therapeutic potential of interleukin-27 for dampening harmful neuroinflammatory responses in central nervous system diseases.

Increased prevalence of parent ratings of ADHD symptoms among children with bilateral congenital cataracts

AIM: To investigate the behavioral and psychological disorders and the prevalence of parent ratings of attention deficit hyperactivity disorder(ADHD) symptoms among children with bilateral congenital cataracts(CCs). METHODS: This cross-sectional study investigated children with bilateral CC aged 3-8 y(CC group) using Conners’ Parent Rating Scale-48(CPRS-48) from July to December 2016. The abnormal rates of psychological symptoms in CC children and normal vision(NV) children were compared using the Chi-square test. The scores of CC children were compared with those of NV children and the Chinese urban norm using the independent samples t-test and one-sample t-test, respectively. RESULTS: A total of 262 valid questionnaires were collected. The ratio of CC children to NV children was 119:143. The overall rate of psychological symptoms in CC children was 2.28 times higher than that in NV children(46.22% vs 20.28%, Pearson’s χ2=20.062;P<0.001). CC children showed higher scores for conduct problems, learning problems, impulsiveness/hyperactivity, anxiety, and hyperactivity index than NV children and the Chinese urban norm, particularly between the ages of 3 and 5 y. Furthermore, male children aged between 6 and 8 y showed a higher impulsive/hyperactive score than females of the same age(t=6.083, P<0.001). CONCLUSION: Children with bilateral CCs have a higher rate of ADHD symptoms than children with NV. This study provides clinical evidence that screening for psychological symptoms and particularly for ADHD symptoms in children with bilateral CC are recommended for an early diagnosis and timely treatment.

Widefield optical coherence tomography of foveal dragging in retinopathy of prematurity

Dear Editor,Despite substantial advances in neonatal medicine, retinopathy of prematurity (ROP) continues to be a serious therapeutic challenge⑴.Visual acuity loss in patients with ROP has been associated with structural retinal abnormalities (including retinal detachment, retinal folds, and pigmentary retinopathy), cataract, glaucoma, and amblyopia due to refractive error or strabismus[2].

Improving quality of life in self-reported gastrointestinal disorders: An open trial of a food elimination diet guided by the ImmunoBloodprint food sensitivity test

Purpose: Irritable bowel syndrome (IBS) and gastrointestinal (GI) disorders are genuine health problems that have serious consequences on a patient’s quality of life (QoL). IBS is a functional disorder characterized by chronically recurring symptoms, including abdominal pain or discomfort, altered stool frequency and consistency, and abdominal bloating in the absence of structural or biochemical abnormalities. Studies have indicated that symptoms and disability related to IBS and GI disorders correlate with QoL measures. Additionally, those who respond to therapy have an improvement in QoL. Therefore, we explored an open trial of a food elimination diet guided by the ImmunoBloodprint food sensitivity test and its effect on QoL in patients self-reporting an unresolved GI disorder. Methods: Eighty-four subjects aged 18 and above participated in the study. Subjects eliminated all IgG-mediated reactive foods from their diet for 90 days. QoL was assessed with the Irritable Bowel Syndrome-36 (IBS-36) and the Medical Outcomes Study Short Form-36 (SF-36) at baseline and 30-, 60-, and 90-day follow-up. The data were analyzed with linear mixed models. Results: Subjects had statistically significant improvements in all indicators of QoL according to the IBS-36 and SF-36 from baseline to 90- day follow-up. Conclusions: Subjects with unresolved self-reported GI disorders were able to improve all indicators of QoL in response to eliminating IgG- reactive foods from the diet. Given the inconvenience of keeping track of foods and symptoms to eliminate intolerant foods, a food sensitivity test combined with an elimination diet may be an effective method for improving subjective markers of QoL and health.

Role of post-translational modifications of HTLV-1 Tax in NF-κB activation

Human T-cell leukemia virus type 1(HTLV-1),the first human retrovirus discovered,is the etiological agent of adult-T-cell leukemia/lymphoma.The HTLV-1 encoded Tax protein is a potent oncoprotein that deregulates gene expression by constitutively activating nuclear factor-κB(NF-κB).Tax activation of NF-κB is critical for the immortalization and survival of HTLV-1-infected T cells.In this review,we summarize the present knowledge on mechanisms underlying Tax-mediated NF-κB activation,with an emphasis on post-translational modifications of Tax.