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Medicaid reimbursements for physician services are determined by each state. However, how these reimbursements vary between states, and how these reimbursements vary in comparison to Medicare reimbursements is unknown for musculoskeletal radiology studies.To evaluate the variability in Medicaid and Medicare physician reimbursements for musculoskeletal imaging studies between states.We evaluated the Medicare and Medicaid physician reimbursements for the most commonly performed musculoskeletal radiology studies (15 radiographs and 10 MRIs) based on Medicare's 2017 National Summary Data File. Medicare and Medicaid reimbursements for these studies were compared by dollar difference (difference in reimbursement in dollars between Medicare and Medicaid). State-wide variability in these reimbursements was quantified by the coefficient of variation (COV) and by the dollar difference in reimbursement amounts. Medicaid and Medicare reimbursement rates were compared using a paired t-test, since the data was paired by state.The mean Medicaid reimbursement rates were lower for musculoskeletal radiographs (p 0.05) but higher for musculoskeletal MRI studies than the Medicare rates (p 0.05). As hypothesized, there was variation in both Medicare and Medicaid imaging reimbursements between states, however, the variation was substantially higher for Medicaid reimbursements. We found the Medicare reimbursement COV between states was 0.07 for all imaging studies, whereas the Medicaid reimbursement COV between states varied from 0.23 to 0.55 for radiographs and from 0.31 to 0.45 for MRIs.The data show that there is mild, but constant variation across imaging studies in Medicare reimbursement for musculoskeletal imaging studies between states. However, there is more variation in the Medicaid reimbursements across imaging studies and between states. More appropriate reimbursement may increase access to care for Medicaid patients.

The sugarcane cystatin (CaneCPI-5) was recently cloned and showed strong binding force to dental enamel and protection against initial erosion. However, evaluations on its safety and efficacy in a situation closer to the clinical condition are necessary. In the present study we analyzed 1) the cytotoxicity of CaneCPI-5 on human gingival fibroblasts (HGFs); 2) the ability of CaneCPI-5 to reduce enamel erosion and erosion+abrasion in situ. In part 1, HGFs were treated with CaneCPI-5 (0.025, 0.05, 0.1, 0.5 or 1.0 mg/mL) or no treatment (control). The cytotoxicity was assessed after 60 s and 24 h by mitochondrial activity (MTT), confocal microscopy, and hematoxylin/eosin staining. In part 2, 15 volunteers participated in a double-blind crossover protocol consisting of 3 phases, according to the following treatments: 1) 0.1 mg/mL CaneCPI-5; 2) SnCl2/NaF/AmF (Elmex; positive control); 3) water (negative control). The volunteers wore an appliance containing 4 bovine enamel specimens for 5 d. Each day, the specimens were individually treated with 50 µL of the tested solutions per 60 s and then subjected to erosive challenges (0.1% citric acid, pH 2.5, for 90 s, 4 times per day). After the first and last erosive challenge each day, 2 samples were abraded (toothbrushing, 15 s). Enamel wear was measured by contact profilometry. One or two-way analysis of variance (ANOVA)/Tukey’s or Sidak’s tests ( P < 0.05) were applied. Regardless of the concentration and the experimental time, CaneCPI-5 did not decrease the cell viability compared to the negative control ( P < 0.05). Erosion+abrasion led to significantly greater wear compared to erosion only. For both conditions, the lowest wear was found for SnCl2 and CaneCPI-5, which did not differ significantly from each other, but showed significant protection when compared to the negative control. In conclusion, CaneCPI-5 is safe on HGFs and reduces enamel erosive wear to the same extent as a commercial solution used to control erosive tooth wear (ETW).

Neurogenesis is a biological process characterized by new neurons formation from stem cells. For decades, it was believed that neurons only multiplied during development and in the postnatal period but the discovery of neural stem cells (NSCs) in mature brain promoted a revolution in neuroscience field. In mammals, neurogenesis consists of migration, differentiation, maturation, as well as functional integration of newborn cells into the pre-existing neuronal circuit. Actually, NSC density drops significantly after the first stages of development, however in specific places in the brain, called neurogenic niches, some of these cells retain their ability to generate new neurons and glial cells in adulthood. The subgranular (SGZ), and the subventricular zones (SVZ) are examples of regions where the neurogenesis process occurs in the mature brain. There, the potential of NSCs to produce new neurons has been explored by new advanced methodologies and in neuroscience for the treatment of brain damage and/or degeneration. Based on that, this review highlights endogenous factors and drugs capable of stimulating neurogenesis, as well as the perspectives for the use of NSCs for neurological and neurodegenerative diseases.

Introduction: Coronavirus disease 2019 (COVID-19) has spread rapidly throughout the world. Smell and/or taste disorders have emerged as a very frequent symptom as the disease has spread in Europe. Spain is one of the European countries with the highest number of infections. Objective: This study aimed to investigate the clinical progression of smell and taste disorders in Spanish patients with mild COVID-19. Methods: An online survey was used to conduct a cross-sectional study of patients who presented sudden smell and/or taste disorders during the 2 months of total lockdown due to COVID-19 in Spain. Results: In our sample, 91.18% of respondents with impaired smell and/or taste and who were able to undergo PCR testing were positive for SARS-CoV-2 infection. Anosmia and ageusia presented in isolation in 6.5% of participants. The remaining 93.5% presented other mild symptoms: headache (51.6%), cough (51.6%), myalgia (45.2%), asthaenia (38.7%), nasal congestion or rhinorrhoea (35.5%), fever (41.9%), low-grade fever (29.0%), odynophagia (25.8%), or diarrhoea (6.5%). The mean duration of anosmia was 8.33 days, with patients subsequently manifesting hyposmia; complete resolution occurred after a mean of 17.79 days. In 22.6% of respondents, olfactory deficits persisted. All participants recovered their sense of taste. Conclusions: Olfactory and gustatory disorders are prevalent symptoms in mild COVID-19. Most patients do not present associated nasal congestion or rhinorrhoea and a small group of patients present these alterations in isolation. Resumen: Introducción: La enfermedad por coronavirus-2019 (COVID-19), se ha expandido con gran rapidez en todo el mundo. Las alteraciones del olfato y/o gusto han emergido como un síntoma muy frecuente a medida que la enfermedad se propagó en Europa. Uno de los países con mayor número de contagios en este continente ha sido España. Objetivo: Investigar la evolución clínica de los trastornos del olfato y el gusto en la enfermedad leve por COVID-19 en pacientes españoles. Métodos: Se realizó un estudio transversal a través de encuesta on‐line, en pacientes que presentaron afección súbita del olfato y/o el gusto, durante los dos meses de confinamiento total por COVID-19 en España. Resultados: El 91,18% de los sujetos con afectación del olfato y/o el gusto, que tuvieron a acceso a la realización de PCR, fueron positivos para COVID-19. El 6,5% presentó anosmia y ageusia de forma aislada. El 93,5% manifestó otros síntomas leves asociados: cefalea (51,6%), tos (51,6%), mialgias (45,2%), astenia (38,7%), congestión nasal o rinorrea (35,5%), fiebre (41,9%), febrícula (29,0%), odinofagia (25.8%) y diarrea (6,5%). La duración media de la anosmia fue de 8,33 días, posteriormente los pacientes manifestaron hiposmia, con resolución completa en 17,79 días de media. En el 22,6% de los pacientes el déficit olfatorio persistió. Todos los sujetos recuperaron el sentido del gusto. Conclusiones: Los trastornos olfativos y gustativos son síntomas prevalentes en la infección leve por COVID-19. Gran parte de los pacientes no presentan congestión nasal o rinorrea asociada y un grupo reducido de pacientes los presentan de forma aislada.

Fetuses with a diagnosis of congenital lung malformations (CLM) on prenatal imaging are commonly referred to a multi-disciplinary specialty team for prenatal assessment and postnatal management. The net effect of such services is broadly stated to improve the outcomes of affected newborns. However, these claims are relatively unsubstantiated.After IRB approval, a retrospective review of children diagnosed with CLM from 2008 to 2018 and referred to a large urban children's hospital was performed. A comparison was performed between prenatally diagnosed patients having a multi-disciplinary fetal center evaluation (FC) and prenatally diagnosed patients who did not receive a referral or were seen prior to the establishment of the center (NON-FC).Eighty-eight live-born patients with a prenatal diagnosis of CLM were identified, with 49 in the FC group and 39 NON-FC. Thirty-four (63%) and 23 (59%) patients underwent operative resection of CLM, respectively. FC patients presented earlier at first postnatal follow-up (42 vs. 145 days,Children with a prenatal diagnosis of CLM appear to benefit from an organized multi-specialty team approach in several impactful parameters. Hospital systems and providers that invest in similar strategies are likely to achieve improved outcomes in the care of newborns prenatally diagnosed with a CLM.

Background. Asthma is a chronic pulmonary disease that affects about 300 million people worldwide. Previous studies have associated antimicrobial use with allergies, but the real impact of antibiotics on asthma is still elusive. We investigated the potential impact of amoxicillin (Amox), trimethoprim/sulfamethoxazole (TMP/SMX), and metronidazole (Metro) in a murine model of OVA-induced allergic airway inflammation. Methods. BALB/c mice received three cycles of 7 days of antibiotics in drinking water followed by 7 days washout and were sensitized i.p. with OVA/Alum at days 0 and 14. After the end of the last antibiotic washout, the mice were challenged with aerosolized OVA. Pulmonary parameters were evaluated, and serum, BAL, and feces were collected for analysis. Results. Amox- and TMP/SMX-treated animals displayed more severe allergic airway inflammation parameters with increased airway hyperresponsiveness, reduced lung alveolar volume, and increased levels in BAL of IL-4 and IL-6. In contrast, Metro-treated mice showed preserved FEV-50, decreased lung inflammation, and higher levels of butyrate and propionate in their feces. Metro treatment was associated with increased OVA-specific IgA in serum. BAL microbiota was abundant in allergic groups but not in nonallergic controls with the Amox-treated group displaying the increased frequency of Proteobacteria, while Metro and TMP/SMX showed increased levels of Firmicutes. In the gut, we observed the enrichment of Akkermansia muciniphila associated with reduced airway inflammation phenotype in the Metro group, even after the recovery period. Conclusion. Our data suggest that different antibiotic treatments may impact the course of experimental allergic airway inflammation in diverse ways by several mechanisms, including modulation of short-chain fat acids production by intestinal microbiota.

Internationally, inland waterways are identified as leading locations for drowning. 'Nippers' programs provide coastal lifesaving and water safety knowledge and skills to children aged 5-14 years in Australia. However, a 49% increase in Victorian inland waterway drowning compared with the 10-year average, necessitated adapting the Nippers water safety program to inland regions: Bush Nippers.Overall, 105 participants from two age groups (under 9 and under 12) were involved across three Bush Nippers programs delivered at river and/or pool locations in regional Victoria, Australia. Surveys and observations assessed participants' water safety knowledge and competencies, and used alongside interviews to obtain program feedback from parents, instructors and communities. Costs were compared to other aquatic programs to determine feasibility of replicating the program.Significant increases in knowledge from pre to immediate posttest were recorded (P .05) and water competencies were high posttest. Communities were grateful for the regional program delivery and understood the necessity of learning lifesaving skills, particularly in open water environments. Costs were akin to other similar programs indicating program replicability and enhancing likelihood of uptake.Bush Nippers increased water safety knowledge in children and was well received by the community. Wider uptake of the program is encouraged to diversify aquatic education for regional Victorian children. SO WHAT?: Given the high regard and demand for the program, and importance of learning lifesaving skills, provision of a scalable lifesaving program in inland regions may address the drowning trend and improve aquatic participation.

Diffuse lung disease in early childhood due to mutations in the filamin A gene has been recently reported. Clinical outcomes vary among individuals indicating variability in phenotype but a substantial proportion of reported cases in early life have ended up in death or lung transplantation. We recently encountered a school-aged child in whom the diagnosis of a filamin A mutation was delayed and the natural history of emphysematous lung disease was altered by serial lung volume reduction surgeries. She eventually underwent a bilateral lung transplant and we report the natural history of her disease and treatments applied herein.

Background Despite improvements in fetal survival for pregnancies that are affected by twin-twin transfusion syndrome since the introduction of laser photocoagulation, prematurity remains a major source of neonatal morbidity and death. Objective To investigate the indications and factors that influence the timing of delivery after laser treatment, we collected delivery information regarding twin-twin transfusion syndrome cases in a large multicenter cohort. Study Design Eleven North American Fetal Therapy Network centers conducted a retrospective review of twin-twin transfusion syndrome patients who underwent laser photocoagulation. Clinical, demographic, and ultrasound variables that included twin-twin transfusion syndrome stage and gestational age at treatment and delivery were recorded. Primary and secondary maternal and fetal indications for delivery were identified. Univariate analysis was used to select candidate variables with significant correlation with latency and gestational age at delivery. Multivariable Cox regression with competing risk analysis was used to determine the independent associations. Results A total of 847 pregnancies were analyzed. After laser therapy, the average latency to delivery was 10.11±4.8 weeks, and the mean gestational age at delivery was 30.7±4.5 weeks. Primary maternal indications for delivery comprised 79% of cases. The leading indications included spontaneous labor (46.8%), premature rupture of membranes (17.1%), and placental abruption (8.4%). Primary fetal indications accounted for 21% of cases; the most frequent indications included donor nonreassuring status (20.5%), abnormal donor Doppler evaluations (15.1%), and donor growth restriction (14.5%). The most common secondary indications for delivery were premature rupture of membranes, spontaneous labor, and donor growth restriction. Multivariate modeling found gestational age at diagnosis, stage, history of previous amnioreduction, cerclage, intertwin membrane disruption, procedure complications, and chorioamniotic membrane separation to be predictors for both gestational age at delivery and latency. Conclusion Premature delivery after laser therapy for twin-twin transfusion syndrome is primarily the result of spontaneous labor, preterm premature rupture of membranes, and nonreassuring status of the donor fetus. Placental abruption was found to be a frequent complication that resulted in early delivery. Future research should be directed toward the goal of prolonging gestation after laser photocoagulation to further reduce morbidity and mortality rates that are associated with twin-twin transfusion syndrome.

Stem cell therapy is an interesting approach for neural repair, once it can improve and increase processes, like angiogenesis, neurogenesis, and synaptic plasticity. In this regard, adult neural stem cells (NSC) are studied for their mechanisms of proliferation, differentiation and functionality in neural repair. Here, we describe novel neural differentiation methods. NSC from adult mouse brains and human adipose-derived stem cells (hADSC) were isolated and characterized regarding their neural differentiation potential based on neural marker expression profiles. For both cell types, their capabilities of differentiating into neuron-, astrocyte- and oligodendrocytes-like cells (NLC, ALC and OLC, respectively) were analyzed. Our methodologies were capable of producing NLC, ALC and OLC from adult murine and human transdifferentiated NSC. NSC showed augmented gene expression of NES, TUJ1, GFAP and PDGFRA/Cnp. Following differentiation induction into NLC, OLC or ALC, specific neural phenotypes were obtained expressing MAP2, GalC/O4 or GFAP with compatible morphologies, respectively. Accordingly, immunostaining for nestin

Background Increased levels of inflammatory cytokines are associated with severe dengue evolution, but the source of such hypercytokinemia is elusive. We investigated the contribution of innate lymphocytes, innate lymphoid cells (ILCs), and natural killer (NK) cells in cytokine production in early dengue infection. Methods Peripheral blood mononuclear cells of individuals with dengue without warning signs (DWS–) and dengue with warning signs and severe dengue (SD) presentation combined (DWS+) were obtained between 2 and 7 days since fever onset and submitted to flow cytometry without specific antigen stimulation to evaluate cytokines in ILC and NK cell subpopulations. Results ILCs and NK cells were found to be important sources of cytokines during dengue. ILCs of the DWS+/SD group displayed higher production of interferon gamma (IFN-γ) and interleukin (IL) 4/IL-13 when compared to DWS– individuals. On the other hand, NK Eomes+ cells of DWS– patients displayed higher IFN-γ production levels compared with the DWS+/SD group. Interestingly, when NK cells were identified by CD56 expression, DWS+/SD displayed higher frequency of IL-17 production compared with the DWS– group. Conclusions These results indicate that ILCs and NK cells are important sources of inflammatory cytokines during acute dengue infection and display distinct profiles associated with different clinical forms.

Las innovaciones técnicas han permitido realizar un sinnúmero de cirugías endoscópicas y laparoscópicas, entre ellas la mastectomía preservadora de piel y pezón por puerto único, que ha sido reportada como bien tolerada, con un excelente resultado cosmético y con el mismo pronóstico oncológico que la cirugía tradicional. Esta técnica, común en Asia, presenta diversos retos técnicos y económicos. Presentamos la primera aproximación en nuestro país sobre este abordaje en una paciente con cáncer de mama. Para realizar esta cirugía es preciso el entrenamiento en mínima invasión y en cirugía mamaria, así como una adecuada selección de las pacientes.Technical innovations and scientific advances have allowed to perform countless endoscopic and laparoscopic surgical procedures. Among these, Single port endoscopic Mastectomy has been reported as well tolerated, with great aesthetic results and the same oncologic prognosis as traditional surgery. This popular approach in Asian countries presents many technical and economic challenges. We present the first endoscopic approach in our country: a female patient with infiltrating ductal carcinoma in the left breast. We understand that to carry out this procedure, adequate patient selection, great minimal invasive and breast surgery skills are necessary.

Programmed death-ligand 1 (PD-L1) is used as a biomarker for anti-programmed cell death protein-1 (PD-1) or anti-PD-L1 immunotherapies in NSCLC. We report here the results of population-based PD-L1 testing using the 22C3 IHC pharmDx Assay (Agilent Technologies) in a large Canadian regional reference pathology laboratory.Testing was conducted reflexively on biopsies and resections for NSCLC during an 8-month period. Tumor proportion score (TPS) cutoffs for low and high expression were 1% and 50%, respectively.Altogether, 2031 PD-L1 tests were performed on specimens from 1795 patients, with 107 inconclusive results (5.3%). Excluding cases with inconclusive/missing data, proportions for the remaining 1713 patients were 41.6% for TPS less than 1%, 28.6% for TPS 1% to 49%, and 29.8% for TPS greater than or equal to 50%. Higher PD-L1 expression rates were noted in EGFR wild-type versus mutant tumors (p0.001), squamous versus adenocarcinoma (p0.001), and metastatic versus primary tumors (p0.001). PD-L1 among 103 patients with paired biopsy and resection specimens revealed moderate concordance (κ = 0.67). A total of 52% (25 of 48) of biopsies with TPS less than 1% had TPS greater than 1% in resection, whereas 84.6% (22 of 26) of biopsies with TPS greater than or equal to 50% were concordant in resected tumors. Discordance rates between biopsy and resection were 71.4% for biopsies with less than 8 mmIntratumoral heterogeneity of PD-L1 expression may result in misclassification of PD-L1 status in a substantial proportion of PD-L1-negative small biopsy samples. Biopsy of metastatic site may increase proportion of patients with high PD-L1 expression.

Magnetic resonance imaging (MRI) assesses pulmonary hypoplasia in fetal congenital diaphragmatic hernia (CDH). Neonatal mortality may occur with CDH.To quantify MRI parameters associated with neonatal survival in fetuses with isolated CDH.Fetal MRI for assessing CDH included region of interest (ROI) measurements for total lung volume (TLV), herniated liver volume, herniated other organ volume and predicted lung volume. Ratios of observed lung volume and liver up volume to predicted lung volume (observed to predicted TLV, percentage of the thorax occupied by liver) were calculated and compared to neonatal outcomes. Analyses included Wilcoxon rank sum test, multivariate logistic regression and receiver operating characteristic (ROC) curves.Of 61 studies, the median observed to predicted TLV was 0.25 in survivors and 0.16 in non-survivors (P=0.001) with CDH. The median percentage of the thorax occupied by liver was 0.02 in survivors and 0.22 in non-survivors (P0.001). The association of observed to predicted TLV and percentage of the thorax occupied by liver with survival for gestational age (GA)28 weeks was greater compared to GA ≤28 weeks. The ROC analysis demonstrated an area under the curve of 0.96 (95% confidence interval 0.91-1.00) for the combined observed to predicted TLV, percentage of the thorax occupied by liver and GA.The percentage of the thorax occupied by liver and observed to predicted TLV was predictive of neonatal survival in fetuses with CDH.

Phytocystatins are tight-binding cysteine protease inhibitors produced by plants. The first phytocystatin described was isolated from Oryza sativa and, since then, cystatins from several plant species were reported, including from sugarcane. Sugarcane cystatins were unraveled in Sugarcane EST project database, after sequencing of cDNA libraries from various sugarcane tissues at different developmental stages and six sugarcane cystatins were cloned, expressed and characterized (CaneCPI-1 to CaneCPI-6). These recombinant proteins were produced in different expression systems and inhibited several cysteine proteases, including human cathepsins B and L, which can be involved in pathologies, such as cancer. In this review, we summarize a comprehensive history of all sugarcane cystatins, presenting an updated phylogenetic analysis; chromosomal localization, and genomic organization. We also present protein docking of CaneCPI-5 in the active site of human cathepsin B, insights about canecystatins structures; recombinant expression in different systems, comparison of their inhibitory activities against human cysteine cathepsins B, K, L, S, V, falcipains from Plasmodium falciparum and a cathepsin L-like from the sugarcane weevil Sphenophorus levis; and enlighten their potential and current applications in agriculture and health.

Infants prenatally suspected of having a choledochal cyst (CDC) typically undergo ultrasound imaging shortly after birth. This study sought to evaluate features on the initial postnatal ultrasound (IPU) that could identify newborns at risk for early complications.Following IRB approval, patients from four US fetal centers with prenatal suspicion for CDC and postnatal imaging from 2000 to 2017 were reviewed. Imaging and clinical courses were assessed.Forty-two patients had prenatal ultrasounds suspicious for CDC. Nineteen (45.2%) were excluded due to diagnostic revision (In newborns with prenatally diagnosed CDC, a cyst size ≥ 4.5 cm on IPU is associated with symptom development during the first month after birth and therefore early cyst excision is recommended.

Background Approximately 20% of fetuses diagnosed with congenital lung malformations (CLMs) are found to have additional anomalies. We aim to determine if additional anomalies have an impact on postnatal outcomes for patients with CLMs. Methods After institutional review board approval, we performed a retrospective review of live-born patients with CLMs from 2008 to 2018. All patients were prenatally diagnosed with CLMs. Clinical information pertaining to additional congenital anomalies and outcomes was collected from the electronic health record and analyzed. Results Of the 88 patients who had a prenatal diagnosis of CLMs, 20.5% had additional anomalies. Ten of the 18 patients (56%) were considered to have a major anomaly in addition to CLMs. Outcomes for patients electing nonoperative management of CLMs were similar between those with and without an additional anomaly. Although patients with an additional anomaly were more likely to have perinatal respiratory complications (44% versus 17%, P = 0.03), the number of preoperative clinic and emergency department visits, age at surgery, minimally invasive approach to surgical resection of CLM, estimated blood loss, length of hospital stay, intubation, duration of intubation, 30-day postoperative complications, and long term sequelae were not statistically different. This held true when stratified for major versus minor anomalies. Conclusions Twenty percent of fetuses diagnosed with CLM in our population have additional anomalies. Newborns with additional anomalies have a higher risk of pre-excision pulmonary complications. However, the overall outcomes of all patients with CLMs are similar.

Background To study the clinical outcomes of pigment epithelial detachment (PED) associated with neovascular age-related macular degeneration (nAMD) in patients switched from Ranibizumab to Aflibercept. Methods Retrospective non-comparative case series. 50 eyes with active nAMD and fovea involving PED of ≥100 μm measured manually using the caliper on the OCT, initially treated with intravitreal Ranibizumab (0.5 mg/0.05 ml) and later switched to Aflibercept (2.0 mg/0.05 ml). The outcome measures of best corrected visual acuity (BCVA), PED height, PED width and number of injections were measured at baseline and at time point of switch, 4 months, 1 year and at last follow up visit post-switch. Three paired t-tests and Pearson’s correlations were calculated to analyze variables at switch and change in variables at 1 year. Results After switch to Aflibercept, the improvement of BCVA was 1.84 (p = 0.11), 1.74 (p = 0.21) and 1.16 (p = 0.45) letters, the change in PED height was − 65.6μm (p

Background The aim of the article was to determine if anatomical findings on fetal magnetic resonance imaging (MRI) of venolymphatic malformations of the face and neck (VLMFN) can be used to create a staging system predictive of airway outcomes. Methods We reviewed 13 fetuses evaluated for VLMFN. Stage was assigned based on anatomical findings on fetal MRI. Stage I: no evidence of polyhydramnios with free egress of amniotic fluid and clear visualization of the aryepiglottic folds and larynx. Stage II: lesions of the tongue or epiglottis but with normal aryepiglottic folds without polyhydramnios. Stage III: lesions of the tongue or larynx; nonvisualization of the aryepiglottic folds without free egress of amniotic fluid along with polyhydramnios. Results Six met stage I criteria with no airway involvement, nor any subsequent issues. Two met stage II criteria and were managed by ex-utero intrapartum therapy and intubated. One had minimal involvement of the upper airway, was extubated, and had no subsequent issues. Child two had involvement of the tongue and larynx and received a tracheostomy. Five were assigned stage III, delivered by ex-utero intrapartum therapy and intubated. Postnatal evaluation showed involvement of the upper airway by the lesion and was managed with tracheostomy. All treated by tracheostomy remain cannulated because of persistent symptomatic lesions at follow-up (relative risk 4.0; confidence interval 1.2-13.3). Median follow-up was 4 y (range 2-7 y). Conclusions Although numbers are small, data suggest anatomical details obtained by antenatal fetal MRI appear to correlate with airway outcomes in children affected by a VLMFN. This information may be useful when counseling expectant families of affected fetuses.

Purpose Pre and post-operative administration of sevoflurane in myocardial revascularization surgery provides enhanced cardioprotective effects exerted by pharmacologic pre- and post-conditioning, as compared to propofol. The identification of the enzymes involved in conditioning mechanisms is crucial to the understanding of the effects of sevoflurane in cardiac surgery patients. The impact of sevoflurane on another crucial target organ—the kidney—was also assessed. Methods Ninety patients undergoing off-pump myocardial revascularization surgery were allocated to receive either intra- and postoperative sevoflurane (SS), intraoperative sevoflurane and postoperative propofol (SP), or intra- and postoperative propofol (PP)). Troponin I and hemodynamic parameters were monitored during the first 48 postoperative hours; blood and urine samples were collected at baseline and at 24h to determine Akt, ERK1/2, PKG, iNO, bradykinin receptor, caspase 3, NT proBNP and urinary NGAL. Results The enzymes were overexpressed in the SS group, remained unchanged in the SP group, and decreased in the PP group. Renal function was best preserved in the SS group. Conclusions The overexpression of enzymes induced by intraoperative anesthesia and postoperative sedation with sevoflurane reduces myocardial damage and improves renal function in patients undergoing off-pump myocardial revascularization surgery.

Zika is an important emerging infectious disease in which the role of T cells remains elusive. This study aimed to evaluate the phenotype of multifunctional T cells in individuals 2 yr after exposure to Zika virus (ZIKV). We used a library of 671 synthetic peptides covering the whole polyprotein of ZIKV in pools corresponding to each viral protein (i.e., capsid, membrane precursor or prM, envelope, NS1 [nonstructural protein], NS2A + NS2B, NS3, NS4A + NS4B, and NS5) to stimulate PBMCs from individuals previously exposed to ZIKV. We observed an increased frequency of ZIKV-specific IFNγ, IL-17A, TNF, and IL-10 production by T cell populations. IFNγ and TNF production were especially stimulated by prM, capsid, or NS1 in CD8+ T cells and by capsid or prM in CD4+ T cells. In addition, there was an increase in the frequency of IL-10+ CD8+ T cells after stimulation with prM, capsid, NS1, NS3, or NS5. Multifunctional properties were observed in ZIKV-specific T cells responding especially to prM, capsid, NS1 or, to a smaller extent, NS3 antigens. For example, we found a consistent IFNγ + TNF+ CD8+ T cell population in response to most virus antigens and CD4+ and CD8+ T cells that were IFNγ + IL-17A+ and IL-17A+IL-10+, which could also produce TNF, in response to capsid, prM, NS1, or NS3 stimulation. Interestingly, CD8+ T cells were more prone to a multifunctional phenotype than CD4+ T cells, and multifunctional T cells were more efficient at producing cytokines than single-function cells. This work provides relevant insights into the quality of ZIKV-specific T cell responses and ZIKV immunity.

Background/AimsProspective data on switching anti-vascular endothelial growth factors in patients with neovascular age-related macular degeneration (nAMD) who have previously shown no/partial response are limited. This prospective study assessed the effect of switching from aflibercept to ranibizumab on anatomical and functional outcomes in patients with persistent/recurrent disease activity.MethodsSAFARI (NCT02161575) was a 6-month, prospective, single-arm study conducted in the UK and Germany. Patients, meeting strict eligibility criteria for one of two subgroups (primary treatment failure or suboptimal treatment response), received 3 monthly intravitreal ranibizumab injections (0.5 mg). Thereafter, ranibizumab was administered pro re nata at monthly visits. The primary endpoint was change from baseline (CfB) to day 90 in central subfield retinal thickness (CSRT). Best-corrected visual acuity (BCVA) and retinal morphology parameters were assessed.ResultsOne hundred patients were enrolled (primary treatment failure, 1; suboptimal treatment response, 99). In the overall population, there was a significant CfB in median CSRT of −30.75 µm (95% CI −59.50,–20.50; pConclusionSwitching from aflibercept to ranibizumab led to a significant improvement in CSRT, with ~60% experiencing stabilised/improved BCVA. Therefore, patients with nAMD who have shown a suboptimal response to aflibercept may benefit from switching to ranibizumab.

Aim: The aim of this study was to evaluate oxidative stress from glutathione depletion in critically ill patients with a septic shock through the abnormal presence of pyroglutamic acid (PyroGlu) in the urine (indirectly) and through its serum level (directly). Methods: This was a prospective analytical study of 28 critically ill patients with a septic shock who were monitored from admission (initial) to 3 days of stay (final) in the intensive care unit (ICU). Data collected included PyroGlu and glutamic acid (Glu) using liquid chromatography/mass spectrometry, and glutathione peroxidase (GPX) activity with a colorimetric assay. The differences in Glu, PyroGlu, and GPX activity between the septic shock group and healthy control group serving as reference values were evaluated using the Mann–Whitney test. The correlations between Glu, PyroGlu, and GPX activity and clinical outcomes were determined using Spearman’s correlation coefficient. Results: In patients with septic shock, serum and urine PyroGlu levels were higher, erythrocyte GPX activity/gr Hb was lower, and urine Glu levels were lower compared to healthy control reference values, for both initial and final values. Initial serum Glu levels were also lower. Serum PyroGlu levels had a correlation with both initial and final serum Glu levels; levels also correlated in the urine. Initial serum Glu correlated with the days of mechanical ventilation (P = 0.016) and the days of ICU stay (P = 0.05). Urine Glu/mg creatinine correlated with APACHE II (P = 0. 030). This positive correlation observed for serum Glu was not observed for PyroGlu. Conclusions: The current study found that septic patients have higher levels of PyroGlu, lower levels of Glu, and lower erythrocyte GPX activity, suggesting that these biomarkers could be used as an indicator of glutathione depletion. In addition, Glu is related to severity parameters. This study can guide future studies on the importance of monitoring the levels of pyroglutamic acidosis in critical patients with septic shock in order to preserve the oxidative status and its evolution during the stay in the ICU., Financial support for the study was provided by Project FIS PI10/1993 from the Spanish Carlos III Health Institute and FEDER European Funds.

Zika virus (ZIKV) clinical presentation and frequency/duration of shedding need further clarification. Symptomatic ZIKV-infected individuals identified in two hospitals in Sao Paulo State, Brazil, were investigated regarding clinical characteristics, shedding in body fluids, and serodynamics. Ninety-four of 235 symptomatic patients (Site A: 58%; Site B: 16%) had Real-Time PCR-confirmed ZIKV infection; fever, headache and gastrointestinal symptoms were less frequent, and rash was more frequent compared to ZIKV-negative patients. Real-Time PCR in serum had worse performance compared to plasma, while urine had the highest sensitivity. Shedding in genital fluids and saliva was rare. IgM positivity was the highest 28 days (24%); IgG positivity increased >14 days (96%) remaining positive in 94% of patients >28 days. ZIKV prevalence varied importantly in two neighboring cities during the same transmission season. Urine Real-Time PCR can improve diagnostic sensitivity; serum testing is less useful. Accurate serological tests are needed to improve diagnosis and surveillance.

Objectives This paper describes recommendations from a panel of UK retina experts on aflibercept in diabetic macular oedema (DMO). Methods A roundtable meeting was held in London, UK in March 2018. The meeting was sponsored by Bayer. Results Recommendations are based on clinical experience and level 1 evidence. Clinical experience supports the evidence base, reinforcing that aflibercept should be initiated with intensive proactive dosing at 2 mg every 4 weeks. Most panel members use six initial 4-weekly doses as in Protocol T, rather than five initial monthly doses as recommended in the Summary of product characteristics (SmPC). After intensive proactive dosing, patients with a good response (meet Protocol T ‘improvement’ criteria ≥5-letter improvement in visual acuity [VA] and/or ≥10% improvement in central subfield thickness [CST] from baseline) but who are not yet stable should continue with 4-weekly aflibercept until stability is reached. Patients with a good response and stability should initiate monitor-and-extend (not in line with SmPC). Those with a sub-optimal response (meet ‘improvement’ criteria but with additional concerns e.g. fluid worsening on macular volume map) should continue with 4-weekly aflibercept but additional treatments should be considered (aflibercept is not licensed for combination treatment). For patients with no response (no change, or meeting Protocol T ‘worsening’ criteria [≥5-letter decrease in VA and/or ≥ 10% increase in CST] from baseline), switching to a non-anti-vascular endothelial growth factor treatment should be considered. Conclusions Clinical experience reinforces that, when using aflibercept in DMO, the licensed posology or Protocol T regimens achieve the best outcomes.

Among the various hypotheses put forward to explain the modulatory influence of helminth infection on allergic effector responses in humans, the IL-10–induced suppression of Th2-associated responses has been the leading candidate. To explore this helminth/allergy interaction more fully, parasite- and allergen-specific CD4+ T cell responses in 12 subjects with filarial infections, and coincident allergic sensitization (filarial [Fil]+allergy [A]+) were compared with the responses to three appropriate control groups (Fil−A− [n = 13], Fil−A+ [n = 12], Fil+A− [n = 11]). The most important findings revealed that Fil+A+ had marked (p < 0.0001 for all cytokines) increases in parasite Ag-driven Th2 (IL-4, IL-5, IL-13), Th9 (IL-9), and the regulatory (IL-10) cytokines when compared with Fil+A−. Moreover, using multiparameter flow cytometry, filarial parasite Ag induced a marked increase in not only the frequency of CD4+ T cells producing IL-4, IL-5, IL-2, and TNF-α in Fil+A+ when compared with Fil+A− patients, but also in the frequencies of polyfunctional Th2-like (CD4+IL-4+IL-5+ and CD4+IL-2+IL-4+IL-5+TNF-α+) cells. The Th2-associated responses seen in the Fil+A+ group were correlated with serum IgE levels (p < 0.01, r = 0.5165 for IL-4; p < 0.001, r = 0.5544 for IL-5; and p < 0.001, r = 0.4901 for IL-13) and levels of circulating eosinophils (p < 0.0116, r = 0.5656) and their degranulation/activation products (major basic protein [p < 0.001, r = 0.7353] and eosinophil-derived neurotoxin [p < 0.01, r = 0.7059]). CD4+ responses to allergen were not different (to a large extent) among the groups. Taken together, our data suggest that allergic sensitization coincident with filarial infection drives parasite Ag-specific T cell hyperresponsiveness, which is characterized largely by an augmented Th2-dominated immune response.

Objectives To use 3-dimensional endovaginal ultrasound to describe the location and distribution of bulking agent after an uncomplicated transurethral injection. Methods Endovaginal ultrasound was performed in 24 treatment-naive patients immediately after bulking agent was injected. The distance between the center of the hyperechoic density of bulking agent and the urethrovesical junction (UVJ) was measured in the sagittal and axial views. This was calculated in percentile length of urethra. Also, the pattern of tracking of bulking agent was assessed if it is presented. Results After the 2 subjects were excluded because of the poor quality of images, 22 patients were included in this study. Eighteen (82%) subjects showed 2 sites of bulking agents, and mostly, they were located around 3- and 9-o'clock positions. The average distance of bulking agent from left UVJ was at 16.9% of the length of the urethra (6.2 mm; range, 0.5-17 mm) and at 25.5% of the length of the urethra (8.9 mm; range, 0-24.8 mm) in the right side. The average length of urethra was 36.7 mm. Eleven of the 22 subjects (50%) had both sides within upper one third of urethra. The difference in distance between the 2 sides was less than 10 mm in 12 of 22 patients (54%). Nine of the 22 patients (41%) had a significant spread of bulking agent mostly either into the bladder neck or toward the distal urethra. Conclusions Although the bulking agent is most often found at 3- and 9-o'clock positions as intended, the distance from the UVJ is highly variable after an uncomplicated office-based transurethral injection. The bulking material does not form the characteristic spheres in 41% of cases and tracks toward the bladder neck or the distal urethra.

Purpose Aflibercept has the potential advantage of reducing capacity problems by allowing 2 monthly visits for patients with neovascular macular degeneration (nAMD) compared with monthly pro re nata regimens that are the most commonly used in the United Kingdom. This study aimed to report the visual outcomes achieved in routine clinical practice using the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) protocol at 1 year and compare with trials data and other real-world reports. Design Retrospective data analysis from an electronic medical record. Participants Consecutive series of treatment-naive patients initiated on aflibercept for nAMD at least 1 year before data extraction. Methods Data were anonymized and remotely extracted from 16 centers in the United Kingdom that use the same electronic medical record (EMR) system (Medisoft Ophthalmology; Medisoft Limited, Leeds, UK). Main Outcome Measures The minimum data set defined before first data entry and mandated by the EMR included age, gender, visual acuity, injection episodes, and complications. Results The mean age was 80.0 years (median, 81.0 years) and 63.7% were women. During the first year of treatment with aflibercept, 1840 treatment-naive eyes of 1682 patients received a median of 8 (mean, 7.0) injections at a median of 8 (mean, 7.3) visits. The mean baseline visual acuity was 53.7 letters, improving to 58.8 letters (+5.1-letter gain) at 1 year. In first-treated eyes, the respective figures were 52.7 letters at baseline and 58.2 letters at 1 year, a gain of +5.5 letters. The proportion achieving 70 letters or more increased from 16.4% at baseline to 33.7% at 1 year, and 92% avoided moderate visual loss at 1 year. Conclusions The visual acuity outcomes are comparable to randomized trials and better than many previous real-world data collections, with a mean +5.1-letter gain at 1 year compared with +8.4 letters in the integrated analysis of the VIEW 1 and VIEW 2 studies. Early visual gains were maintained through the year. Collection of outcomes beyond clinical trials can have limitations but better reflect the full pool of patients actually treated and are important to determine whether a particular treatment is performing as expected. Such data also have the potential to improve services by setting up a mechanism to compare sites.

Several countries have local transmission of multiple arboviruses, in particular, dengue and Zika viruses, which have recently spread through many American countries. Cross reactivity among Flaviviruses is high and present a challenge for accurate identification of the infecting agent. Thus, we evaluated the level of cross reactivity of anti-dengue IgM/G Enzyme-Linked Immunosorbent Assays (ELISA) from three manufacturers against 122 serum samples obtained at two time-points from 61 patients with non-dengue confirmed Zika virus infection. All anti-dengue ELISAs cross reacted with serum from patients with acute Zika infection at some level and a worrisome number of seroconversion for dengue IgG and IgM was observed. These findings may impact the interpretation of currently standard criteria for dengue diagnosis in endemic regions.

The short duration of viremia, low blood viral load, inaccessibility to timely specific diagnostic tests, and cross-reactions with other flaviviruses have hindered laboratory confirmation of Congenital Zika Syndrome (CZS). This study analyzes the positivity of the plaque reduction neutralization test (PRNT) in children with clinical or imaging characteristics of CZS and its association with laboratory, clinical, and imaging characteristics. The 94 clinical cases of CZS submitted to the ZIKV PRNT90 test were followed from 2016 to 2018. The mean age of children at PRNT90 collection was 22 &plusmn, 6 months Standard Deviation. The ZIKV PRNT90 was positive (titer &ge, 10) in 40 (42.5%) children. ZIKV PRNT90 positivity was associated with severe microcephaly in newborns (p = 0.016), lower head circumference z-score at birth (p = 0.043) and 24 months of age (p = 0.031), and severe reduction of the cerebral parenchyma volume (p = 0.021), expressing greater disease severity. Negative PRNT90 in children with characteristic signs of CZS may be due to false-negative results, indicating that the diagnosis of CZS should be primarily syndromic.

Objectives: This study was performed to determine whether neutralizing antibodies against yellow fever virus (YFV) generated by YFV vaccine could interfere in the specificity of dengue virus (DENV) and Zika virus (ZIKV) IgG ELISA tests. Methods: Seventy-nine pairs of serum samples (pre- and post-vaccination), collected during the years 1997–1998 from children with no history of yellow fever disease who had been vaccinated against YFV, were tested. The seroconversion post-vaccination was evaluated through plaque reduction neutralization test (PRNT), and four different commercial ELISA kits were used for the detection of DENV and ZIKV IgG antibodies. Results: A cross-reactivity rate of 3.9% with DENV IgG antibodies was found only with the Dengue Virus IgG Dx Select kit (Focus Diagnostics). Conclusions: As several countries have local transmission of multiple arboviruses, the absence of cross-reactivity or minimum cross-reactivity of YFV neutralizing antibodies with DENV and ZIKV antigens is a relevant finding, since the interpretation of sero-epidemiological investigations would be seriously impacted in many regions where YFV vaccination is mandatory. Keywords: Serological tests, Yellow fever, Dengue, Zika, Cross-reactivity

The purpose of this study is to determine which MRI parameters of fetal head and neck masses predict high-morbidity neonatal outcomes, including ex utero intrapartum treatment (EXIT) procedure.This retrospective study (2004-2016) included parameters of polyhydramnios (based on largest vertical pocket), mass effect on the trachea, mass midline extension, and morphologic grade and size of masses. The morbid cohort included those requiring an EXIT procedure, difficult intubation at delivery, or lethal outcome. Predictive modeling with a multivariable logistic regression and ROC analysis was then performed.Of 36 fetuses, five were delivered by EXIT procedures, there was one neonatal death within 12 hours after delivery, and another neonate required multiple intubation attempts. The remaining 29 fetuses were delivered at outside institutions with no interventions or neonatal morbidity. The largest vertical pocket and mass effect on the trachea were selected as independent predictors by the logistic regression. The cross-validated ROC AUC was 0.951 (95% CI, 0.8795-1).The largest vertical pocket measurement and mass effect on the trachea were the most contributory MRI parameters that predicted significant morbidity in fetuses with masses of the face and neck, along with other significant parameters. These parameters predict significant morbid neonatal outcomes, including the need for EXIT procedures.

Summary Background Yellow fever virus infection results in death in around 30% of symptomatic individuals. The aim of this study was to identify predictors of death measured at hospital admission in a cohort of patients admitted to hospital during the 2018 outbreak of yellow fever in the outskirts of Sao Paulo city, Brazil. Methods In this observational cohort study, we enrolled patients with yellow fever virus from two hospitals in Sao Paolo—the Hospital das Clinicas, University of Sao Paulo and the Infectious Diseases Institute “Emilio Ribas”. Patients older than 18 years admitted to hospital with fever or myalgia, headache, arthralgia, oedema, rash, or conjunctivitis were consecutively screened for inclusion in the present study. Consenting patients were included if they had travelled to geographical areas in which yellow fever virus cases had been previously confirmed. Yellow fever infection was confirmed by real-time PCR in blood collected at admission or tissues at autopsy. We sequenced the complete genomes of yellow fever virus from infected individuals and evaluated demographic, clinical, and laboratory findings at admission and investigated whether any of these measurements correlated with patient outcome (death). Findings Between Jan 11, 2018, and May 10, 2018, 118 patients with suspected yellow fever were admitted to Hospital das Clinicas, and 113 patients with suspected yellow fever were admitted to Infectious Diseases Institute “Emilio Ribas”. 95 patients with suspected yellow fever were included in the study, and 136 patients were excluded. Three (3%) of 95 patients with suspected yellow fever who were included in the study were excluded because they received a different diagnosis, and 16 patients with undetectable yellow fever virus RNA were excluded. Therefore, 76 patients with confirmed yellow fever virus infection, based on detectable yellow fever virus RNA in blood (74 patients) or yellow fever virus confirmed only at the autopsy report (two patients), were included in our analysis. 27 (36%) of 76 patients died during the 60 day period after hospital admission. We generated 14 complete yellow fever virus genomes from the first 15 viral load-detectable samples. The genomes belonged to a single monophyletic clade of the South America I genotype, sub-genotype E. Older age, male sex, higher leukocyte and neutrophil counts, higher alanine aminotransferase, aspartate transaminase (AST), bilirubin, and creatinine, prolonged prothrombin time, and higher yellow fever virus RNA plasma viral load were associated with higher mortality. In a multivariate regression model, older age, elevated neutrophil count, increased AST, and higher viral load remained independently associated with death. All 11 (100%) patients with neutrophil counts of 4000 cells per mL or greater and viral loads of 5·1 log10 copies/mL or greater died (95% CI 72–100), compared with only three (11%) of 27 (95% CI 2–29) among patients with neutrophil counts of less than 4000 cells per mL and viral loads of less than 5·1 log10 copies/mL. Interpretation We identified clinical and laboratory predictors of mortality at hospital admission that could aid in the care of patients with yellow fever virus. Identification of these prognostic markers in patients could help clinicians prioritise admission to the intensive care unit, as patients often deteriorate rapidly. Moreover, resource allocation could be improved to prioritise key laboratory examinations that might be more useful in determining whether a patient could have a better outcome. Our findings support the important role of the virus in disease pathogenesis, suggesting that an effective antiviral could alter the clinical course for patients with the most severe forms of yellow fever. Funding Sao Paulo Research Foundation (FAPESP).

Background The use of molecularly targeted therapy is becoming widespread in oncology. These agents cause tumour-specific genetic alterations in signal transduction pathways, hence less generalised toxicity. Dabrafenib, a BRAF inhibitor and Trametinib, a MEK inhibitor are two molecularly targeted agents recently approved for treatment of advanced, unresectable melanomas. MEK retinopathy is a recently introduced term describing retinal toxicity secondary to MEK inhibitors. Case presentation A 71-year-old man presented with ‘circular, green patches’ in his central vision for 2 weeks. He had multiple relapsed stage IV BRAF gene mutant malignant melanoma. He was on treatment with Dabrafenib (Tafinlar) for 7 months and Trametinib (Mekinist) for 4 months respectively. The fundus looked normal. The OCT scan showed bilateral symmetrical cystoid macular edema, intraretinal and subretinal fluid, thickening of elliposoid zone and subretinal granular deposits. The symptoms resolved with temporary cessation of chemotherapy but OCT signs persisted. Conclusion This case report identifies two new remarkable features of MEK retinopathy as thickening of ellipsoid zone and ‘starry sky’ pattern of distribution of subretinal granular deposits. These changes signify photoreceptors/ RPE toxicity and dysfunction. The subretinal granular deposits showed increased autofluorescence suggested abnormal lipofuscin clearance due to RPE dysfunction. The molecularly targeted therapy has revolutionized the cancer treatment and increased the survival rate. These agents are relatively new and recently approved for clinical use and most of them are associated with ocular toxicities. Awareness of ocular symptoms, side-effect profile of drugs, monitoring regime and liaison between oncologist and eye care professional with ocular imaging is key to early diagnosis and management of ocular adverse events.

Previous cross-sectional studies have reported the involvement of thalamus, pallidum, superior cerebellar peduncle, temporal cortex, and fronto-parietal white matter in multiple sclerosis (MS)-related fatigue. However, the longitudinal imaging correlates of fatigue severity variation in MS remain unclear.Structural and diffusion tensor imaging (DTI) data were collected from 43 relapsing remitting MS (RRMS) patients with fatigue (Fatigue Severity Scale [FSS] range: 1-7). Subcortical nuclei volume using FreeSurfer and cortical diffusion indices using a cross-modality technique were measured at baseline and year 1.The pallidal volume had significantly decreased (P = .002) by year 1, although the fatigue score variation was not significant. At year 1, the pallidal volume (P = .023) and fractional anisotropy (FA, P = .013) of right temporal cortex (RTC) correlated significantly with FSS.The pallidal volume and the FA-RTC may be used to evaluate longitudinal fatigue severity variation. Our study proposes new biomarkers to monitor fatigue severity in MS patients.

OBJECTIVES The purpose of this study was to estimate the utility of sonography to detect small-for-gestational-age (SGA) neonates in pregnancies with gastroschisis and to evaluate neonatal outcomes according to birth weight percentile. METHODS We conducted a retrospective cohort study of singleton pregnancies with fetal gastroschisis delivered at our hospital between August 1997 and December 2012. Diagnosis of growth restriction was based on estimated fetal weight below the 10th percentile using the nomogram of Hadlock et al (Am J Obstet Gynecol 1985; 151:333-337), evaluated at 4-week intervals throughout gestation and compared with subsequent birth weight, to evaluate the accuracy of sonography to detect and exclude SGA neonates. Pregnancy and neonatal outcomes were evaluated according to birth weight percentile. RESULTS There were 111 births with gastroschisis (6 per 10,000), and one-third (n = 37) had birth weight below the 10th percentile. The sensitivity and negative predictive value of sonography for an SGA neonate both approached 90% by 32 weeks and were approximately 95% thereafter. Detection increased with advancing gestational age (P = .02). The birth weight percentile was not associated with preterm birth, infection, bowel complications requiring surgery, duration of hospitalization, or perinatal mortality. Delayed closure of the gastroschisis defect was more frequent with birth weights at or below the 3rd percentile (P = .03). CONCLUSIONS Sonography reliably identified SGA neonates with gastroschisis in our series, and its utility improved with advancing gestation. Apart from delayed closure of the defect, a low birth weight percentile was not associated with an increased risk of morbidity or mortality in the immediate neonatal period.

German Centre for Infection Research European Union's Horizon research and innovation program (ZIKAlliance) EVAg We conducted an external quality assessment of Zika virus molecular diagnostic tests in Brazil using a new Zika virus standard. Of 15 laboratories, 73% showed limited sensitivity and specificity. Viral load estimates varied significantly. Continuous quality assurance is required for adequate estimates of Zika virus-associated disease and determination of patient care. Charite, German Ctr Infect Res, Berlin, Germany Hosp Univ Prof Edgard Santos, LAPI, Salvador, BA, Brazil Fdn Prosangue Hemoctr Sao Paulo, Sao Paulo, Brazil Inst Oswaldo Cruz, Rio De Janeiro, Brazil Fed Univ Para, Belem, Para, Brazil Univ Brasilia, Brasilia, DF, Brazil Univ Sao Paulo, Sao Paulo, Brazil Fundacao Oswaldo Cruz, Pernambuco, Brazil Univ Fed Bahia, Salvador, BA, Brazil Diagnost Amer DASA, Sao Paulo, Brazil Hosp Israelita Albert Einstein, Sao Paulo, Brazil Fac Med Sao Jose do Rio Preto, Sao Jose De Rio Preto, Brazil Fdn Med Trop Dr Heitor Vieira Dourado, Manaus, Amazonas, Brazil Fundacao Oswaldo Cruz, Salvador, BA, Brazil Univ Fed Sao Paulo, Sao Paulo, Brazil Aix Marseille Univ, Marseille, France Assistance Publ Hop Marseille, Marseille, France Univ Bonn, Med Ctr, Bonn, Germany Robert Koch Inst, Berlin, Germany Univ Fed Sao Paulo, Sao Paulo, Brazil ZIKAlliance: 734548 EVAg: 653316 Web of Science

BACKGROUND The risk factors for acute episodes of respiratory disease in current and former smokers who do not have COPD are unknown. METHODS Eight thousand two hundred forty-six non-Hispanic white and black current and former smokers in the Genetic Epidemiology of COPD (COPDGene) cohort had longitudinal follow-up (LFU) every 6 months to determine acute respiratory episodes requiring antibiotics or systemic corticosteroids, an ED visit, or hospitalization. Negative binomial regression was used to determine the factors associated with acute respiratory episodes. A Cox proportional hazards model was used to determine adjusted hazard ratios (HRs) for time to first episode and an acute episode of respiratory disease risk score. RESULTS At enrollment, 4,442 subjects did not have COPD, 658 had mild COPD, and 3,146 had moderate or worse COPD. Nine thousand three hundred three acute episodes of respiratory disease and 2,707 hospitalizations were reported in LFU (3,044 acute episodes of respiratory disease and 827 hospitalizations in those without COPD). Major predictors included acute episodes of respiratory disease in year prior to enrollment (HR, 1.20; 95% CI, 1.15-1.24 per exacerbation), airflow obstruction (HR, 0.94; 95% CI, 0.91-0.96 per 10% change in % predicted FEV 1 ), and poor health-related quality of life (HR, 1.07; 95% CI, 1.06-1.08 for each 4-unit increase in St. George's Respiratory Questionnaire score). Risks were similar for those with and without COPD. CONCLUSIONS Although acute episode of respiratory disease rates are higher in subjects with COPD, risk factors are similar, and at a population level, there are more episodes in smokers without COPD.

Objectives The aims of this study were to determine the association between x-ray funneling and ultrasound urethral sphincter complex measurements and to compare the reliability of funneling versus urethral volume measurement in the detection of intrinsic sphincter deficiency (ISD). Methods This was a retrospective analysis, which included 54 stress incontinent women dichotomized into those with (1) ISD and (2) no ISD. The presence of bladder neck funneling was diagnosed by fluoroscopic images obtained at the time of video-urodynamics testing. Measurements of the urethral sphincter complex were obtained from ultrasound volumes. Reliability measures were obtained for both funneling and urethral volume measurements. Results Rhabdomyosphincter length and area were found to be smaller in patients with funneling compared with those with no funneling (P = 0.0161, P = 0.0359). The urethral volume was significantly smaller in the ISD versus no-ISD group (P = 0.0002). For those who had funneling, the ISD group had smaller urethral volume compared with the no-ISD group (P = 0.0019). For those who did not have funneling, the ISD group still had a smaller urethral volume compared with the no-ISD group (P = 0.0054). An ultrasound urethral volume of less than 3.5 cm had a sensitivity of 81% and a specificity of 64% for the presence of ISD, whereas x-ray funneling had a sensitivity of 76% and a specificity of 73%. Conclusions Smaller rhabdomyosphincter length and area on ultrasound are associated with x-ray funneling. Ultrasound urethral volume of 3.5 cm as a cutoff provides the same reliability as x-ray funneling for the diagnosis of ISD.

SUMMARY Zika virus (ZKV) infection is a huge public health problem in Brazil because of the increased incidence of microcephaly in neonates from infected mothers. Detection of specific IgG antibodies in maternal serum samples constitutes an important approach for diagnosing ZKV infection and evaluating its relationship with neonatal microcephaly. However, as there is no serological test produced in Brazil to detect IgM and IgG antibodies against ZKV, we sought to examine specific IgG in serum samples from patients or suspected mothers to detect previous infection and to test for specificity with regard to flaviviral infections occurring in the same area. Brazilian Zika virus native antigens were obtained from infected Vero cell layers or free virions in the culture medium and then used in ELISA. We tested sera from eight ZKV RNA-diagnosed infected patients (ZKVR), seven neonates with microcephaly and their mothers after delivery (MM), 140 dengue virus IgM-positive (DM) and IgG (DG)-positive patients, and 100 yellow fever (YF)-vaccinated patients. According to the ELISA, ZKVR samples were mostly positive (7/8), and all the MM serum samples were positive for ZKV IgG (7/7). In contrast, cross-reactions for dengue or yellow fever-vaccinated patients were observed, including DM (48/95), DG (10/45) or YF (3/100) serum samples; however, these cross-reactions exhibited low antigen avidity so that 6 M urea largely removed this cross-reactivity, with only a few cross-reacting samples remaining (8/140). ELISA based on extracted virions was much more specific, with all ZKVR (8/8) and MM sera being positive for ZKV IgG (7/7) and only borderline cross-reactivity found for DM (6/95), DG (3/45) or YF (4/100)-vaccinated serum samples. This technique (ELISA) can identify specific IgG in ZKV-infected patients and may be helpful in diagnosing congenital infetions after maternal RNA virus clearance or in epidemiological studies.

There is much debate about the interaction between helminths and allergic disease. The “Hygiene Hypothesis,” a very popular concept among scientists and the lay public, states that infections, especially during childhood, can protect against allergic diseases. Indeed, helminth infections are known to induce regulatory responses in the host that can help the control of inflammation (including allergic inflammation). However, these infections also induce type-2-associated immune responses including helminth-specific IgE that can cross-react against environmental allergens and mediate IgE-driven effector responses. Thus, it is the delicate balance between the parasites' anti- and pro-allergenic effects that define the helminth/allergy interface.

Implied under the rubric of the hygiene hypothesis is that helminth infection can protect against allergic disease. It is well known that helminths induce processes associated with type 2 immune responses, but they also induce important regulatory responses that can modulate these type 2-associated responses-modulation that influences responses to bystander antigens including allergens. Indeed, most epidemiological studies demonstrate a beneficial effect of helminth infection on atopy, but there are also convincing data to demonstrate that helminth infection can precipitate or worsen allergic inflammation/disease. Reasons for these disparate findings are much debated, but there is a school of thought that suggests that helminth-triggered type 2-associated responses, including IgE to cross-reactive aeroallergens, can offset the regulatory effects imposed by the same organisms. The cross-reactivity among helminths and allergenic tropomyosins dominated the antigen/allergen cross-reactivity field, but recent data suggest that cross-reactivity is much more common than previously appreciated. It has been demonstrated that a high degree of molecular similarity exists between allergens and helminth proteins. Thus, an understanding of the mechanisms underlying the response induced by helminth infection and their impact on the induction of allergic disease in the host are critical for designing therapies using iatrogenic infections or parasite products to treat inflammatory diseases and for developing vaccines against helminth parasites.

Background/aims:\ud Retinal screening programmes in England and Scotland have similar photographic grading schemes for background (non-proliferative) and proliferative diabetic retinopathy, but diverge over maculopathy. We looked for the most cost-effective method of identifying diabetic macular oedema from retinal photographs including the role of automated grading and optical coherence tomography, a technology that directly visualises oedema. \ud \ud Methods: Patients from seven UK centres were recruited. The following features in at least one eye were required for enrolment: microaneurysms/dot haemorrhages or blot haemorrhages within one disc diameter, or exudates within one or two disc diameters of the centre of the macula. Subjects had optical coherence tomography and digital photography. Manual and automated grading schemes were evaluated. Costs and QALYs were modelled using microsimulation techniques. \ud \ud Results: 3540 patients were recruited, 3170 were analysed. For diabetic macular oedema, England’s scheme had a sensitivity of 72.6% and specificity of 66.8%; Scotland’s had a sensitivity of 59.5% and specificity of 79.0%. When applying a ceiling ratio of £30 000 per quality adjusted life years (QALY) gained, Scotland’s scheme was preferred. Assuming automated grading could be implemented without increasing grading costs, automation produced a greater number of QALYS for a lower cost than England’s scheme, but was not cost effective, at the study’s operating point, compared with Scotland’s. The addition of optical coherence tomography, to each scheme, resulted in cost savings without reducing health benefits. \ud \ud Conclusions: Retinal screening programmes in the UK should reconsider the screening pathway to make best use of existing and new technologies.

Hookworms digest hemoglobin from erythrocytes via a proteolytic cascade that begins with the aspartic protease, APR-1. Ac-APR-1 from the dog hookworm, Ancylostoma caninum, protects dogs against hookworm infection via antibodies that neutralize enzymatic activity and interrupt blood-feeding. Toward developing a human hookworm vaccine, we expressed both wild-type (Na-APR-1wt) and mutant (Na-APR-1mut—mutagenesis of the catalytic aspartic acids) forms of Na-APR-1 from the human hookworm, Necator americanus. Refolded Na-APR-1wt was catalytically active, and Na-APR-1mut was catalytically inactive but still bound substrates. Vaccination of canines with Na-APR-1mut and heterologous challenge with A. caninum resulted in significantly reduced parasite egg burdens (P=0.034) and weight loss (P=0.022). Vaccinated dogs also had less gut pathology, fewer adult worms, and reduced blood loss compared to controls but these did not reach statistical significance. Vaccination with Na-APR-1mut induced antibodies that bound the native enzyme in the parasite gut and neutralized enzymatic activity of Na-APR-1wt and APR-1 orthologues from three other hookworm species that infect humans. IgG1 against Na-APR-1mut was the most prominently detected antibody in sera from people resident in high-transmission areas for N. americanus, indicating that natural boosting may occur in exposed humans. Na-APR-1mut is now a lead antigen for the development of an antihematophagy vaccine for human hookworm disease.—Pearson, M. S., Bethony, J. M., Pickering, D. A., de Oliveira, L. M., Jariwala, A., Santiago, H., Miles, A. P., Zhan, B., Jiang, D., Ranjit, N., Mulvenna, J., Tribolet, L., Plieskatt, J., Smith, T., Bottazzi, M. E., Jones, K., Keegan, B., Hotez, P. J., Loukas, A. An enzymatically inactivated hemoglobinase from Necator americanus induces neutralizing antibodies against multiple hookworm species and protects dogs against heterologous hookworm infection.

Objective To analyze various possibilities of using dimeric inhibin A (DIA) as a first-trimester marker, during week 13, for diverse sequential strategies together with the combined test (CT) [which uses pregnancy-associated plasma protein A, free beta-human chorionic gonadotrophin and nuchal translucency]. Method We analyzed three sequential strategies (nondisclosure, stepwise and contingent) for measuring DIA in week 13. Multivariate Gaussian modelling was used to estimate second-trimester, false-positive and detection rates. Model parameters were taken from the Serum, Urine and Ultrasound Screening Study (SURUSS) assay. Results The three sequential strategies provided high and comparable levels of effectiveness, with false-positive rate for fixed detection rate of 85% and detection rate for fixed false-positive rate of 5% values of about 91 and 2%, respectively. The contingent strategy (with two CT risk cutoffs, of 1 in 50 and 1 in 2000) produced a screening-positive rate of 0.8% with CT, while only 23% of the women needed subsequent DIA measurement. Conclusions First-trimester sequential screening using CT together with DIA measurement in week 13 is capable of producing results that are comparable with those of the integrated test, with the additional advantage that the final result is obtained earlier. It is recommended that this strategy be evaluated in large-scale prospective studies. Copyright © 2008 John Wiley & Sons, Ltd.

Cardiac tamponade is a life-threatening condition that results from slow or rapid heart compression secondary to accumulation of fluid, pus, blood, gas, or tissue within the pericardial cavity. This condition can be associated with multiple causes including trauma, inflammation, scarring, or neoplastic involvement of the pericardial space among others. The main pathophysiologic event leading to tamponade is an increase in intrapericardial pressure sufficient to compress the heart with resultant hemodynamic impairment, which leads to limited cardiac inflow, decreased stroke volume, and reduced blood pressure. These events result in diminished cardiac output, which manifests clinically as a distinctive form of cardiogenic shock. Although cardiac tamponade is a clinical diagnosis, imaging studies play an important role in assessment and possible therapeutic intervention. Computed tomographic (CT) findings associated with cardiac tamponade include pericardial effusion, usually large, with distention of the superior and inferior venae cavae; reflux of contrast material into the azygos vein and inferior vena cava; deformity and compression of the cardiac chambers and other intrapericardial structures; and angulation or bowing of the interventricular septum. Familiarity with the clinical and pathophysiologic features of cardiac tamponade and correlation with the associated CT findings are essential for early and accurate diagnosis.

Objectives Two methods have been proposed for standardizing measures of nuchal translucency thickness (NT) for risk calculation in first-trimester screening for chromosomal defects: differential delta NT (delta-NT) and multiples of the median (MoM) of NT. There is currently some debate as to which of these is more appropriate. The aims of this study were to determine whether delta-NT could be extrapolated successfully from one center-specific NT reference curve to another and thus to empirically calculate the likelihood ratios (LRs) of delta-NT. Methods This was a retrospective analysis of a database of 4248 singleton pregnancies, including 13 cases of Down syndrome. The delta-NT was extrapolated to the reference curve of the NT values of the original group of patients for whom the LRs were calculated empirically, using a scale factor. The Down syndrome risk was calculated by standardizing the NT, using both extrapolated delta-NT and MoM methods, both for the screening based on maternal age and NT alone, and for the combined screening, in which biochemical markers are also taken into account. We analyzed detection rates and false positives, the precision of the risk prediction obtained by each of the methods and the effectiveness when each of the methods was used with a cut-off point based on a fixed post-test risk. Results The risk calculation using extrapolated delta-NT presented an effectiveness profile that was similar to that obtained using MoMs, both when NT was used as the sole marker and when it was used in combination with biochemical markers. The precision of the risk prediction was similar with both methods. Conclusions Delta-NT can be extrapolated for use in risk calculation between two populations with different distributions and medians of NT values. The precision of the risk estimate obtained is similar to that derived using MoMs. Copyright © 2007 ISUOG. Published by John Wiley & Sons, Ltd.

Invasive cervical cancer (ICC) is the third most frequent cancer among women worldwide and is associated with persistent infection by carcinogenic human papillomaviruses (HPVs). The combination of large populations of viral progeny and decades of sustained infection may allow for the generation of intra-patient diversity, in spite of the assumedly low mutation rates of PVs. While the natural history of chronic HPVs infections has been comprehensively described, within-host viral diversity remains largely unexplored. In this study we have applied next generation sequencing to the analysis of intra-host genetic diversity in ten ICC and one condyloma cases associated to single HPV16 infection. We retrieved from all cases near full-length genomic sequences. All samples analyzed contained polymorphic sites, ranging from 3 to 125 polymorphic positions per genome, and the median probability of a viral genome picked at random to be identical to the consensus sequence in the lesion was only 40%. We have also identified two independent putative duplication events in two samples, spanning the L2 and the L1 gene, respectively. Finally, we have identified with good support a chimera of human and viral DNA. We propose that viral diversity generated during HPVs chronic infection may be fueled by innate and adaptive immune pressures. Further research will be needed to understand the dynamics of viral DNA variability, differentially in benign and malignant lesions, as well as in tissues with differential intensity of immune surveillance. Finally, the impact of intralesion viral diversity on the long-term oncogenic potential may deserve closer attention., Funded by Grants # 2011/24035-2 and # 2012/23290-1, São Paulo Research Foundation (FAPESP)

Activation of innate immune cells by Trypanosoma cruzi-derived molecules such as GPI anchors and DNA induces proinflammatory cytokine production and host defense mechanisms. In this study, we demonstrate that DNA from T. cruzi stimulates cytokine production by APCs in a TLR9-dependent manner and synergizes with parasite-derived GPI anchor, a TLR2 agonist, in the induction of cytokines by macrophages. Compared with wild-type animals, T. cruzi-infected Tlr9−/− mice displayed elevated parasitemia and decreased survival. Strikingly, infected Tlr2−/−Tlr9−/− mice developed a parasitemia equivalent to animals lacking MyD88, an essential signaling molecule for most TLR, but did not show the acute mortality displayed by MyD88−/− animals. The enhanced susceptibility of Tlr9−/− and Tlr2−/−Tlr9−/− mice was associated with decreased in vivo IL-12/IFN-γ responses. Our results reveal that TLR2 and TLR9 cooperate in the control of parasite replication and that TLR9 has a primary role in the MyD88-dependent induction of IL-12/IFN-γ synthesis during infection with T. cruzi.