Pulmonary Valve Repair for Patients With Acquired Pulmonary Valve Insufficiency.
Pulmonary valve (PV) insufficiency is often an acquired condition after treatment for pulmonary stenosis. It is recognized that PV insufficiency has serious deleterious effects. Although surgical replacement of the PV is efficacious, artificial valves inevitably fail and require re-intervention. The purpose of this study was to summarize our experience with PV repair in patients with acquired PV insufficiency. This was a retrospective review of 16 patients with marked PV insufficiency who underwent PV repair. Thirteen of these patients were born with tetralogy of Fallot (TOF) and had undergone a previous transannular patch repair. Three patients were born with critical pulmonary stenosis and had a surgical valvotomy or balloon valvuloplasty. The 13 patients with TOF had resection of their previously placed transannular patch with re-approximation of the anterior commissure. All 13 patients experienced a marked reduction in the degree of pulmonary insufficiency. None of these patients have experienced any increase in insufficiency during follow-up. The 3 patients with critical pulmonary stenosis had a variety of pathologic findings identified at the surgical procedure. One patient had a large gap between a commissure and underwent closure of that commissure. The second and third patients had torn leaflets repaired with pericardial and Gore-Tex patches (Gore, Inc, Flagstaff, AZ). The degree of PV insufficiency was decreased to mild in all 3 patients. However, 2 of these 3 patients have subsequently had an increase in the degree of pulmonary insufficiency. Patients with TOF who underwent a previous transannular patch may be candidates for bicuspidization of their native PV, and the results of this procedure have been quite stable at follow-up. PV repair for torn leaflets was effective in the short term but was less stable over time.


Associations Between Objectively Measured Physical Activity, Body Composition and Sarcopenia: Findings from the Hertfordshire Sarcopenia Study (HSS).
Regular physical activity (PA) is associated with reduced risk of the development and progression of musculoskeletal, metabolic and vascular disease. However, PA declines with age and this can contribute to multiple adverse outcomes. The aims of this study were to describe the relationship between accelerometer-determined PA, body composition and sarcopenia (the loss of muscle mass and function with age). Seven-day PA was measured using the GENEactiv accelerometer among 32 men and 99 women aged 74-84 years who participated in the Hertfordshire Sarcopenia Study. We measured mean daily acceleration and minutes/day spent in non-sedentary and moderate-to-vigorous physical activity (MVPA) levels. Body composition was measured by dual-energy X-ray absorptiometry, muscle strength by grip dynamometry and function by gait speed. Sarcopenia was defined according to the EWGSOP diagnostic algorithm. Men and women spent a median (inter-quartile range) of 138.8 (82, 217) and 186 (122, 240) minutes/day engaging in non-sedentary activity but only 14.3 (1.8, 30.2) and 9.5 (2.1, 18.6) min in MVPA, respectively. Higher levels of PA were associated with reduced adiposity, faster walking speed and decreased risk of sarcopenia. For example, a standard deviation (SD) increase in mean daily acceleration was associated with an increase in walking speed of 0.25 (95% CI 0.05, 0.45) SDs and a reduction in the risk of sarcopenia of 35% (95% CI 1, 57%) in fully adjusted analyses. PA was not associated with hand grip strength. Community-dwelling older adults in this study were largely sedentary but there was evidence that higher levels of activity were associated with reduced adiposity and improved function. PA at all intensity levels in later life may help maintain physical function and protect against sarcopenia.


Utilisation of pain counselling in osteopathic practice: secondary analysis of a nationally representative sample of Australian osteopaths.
Advice, reassurance and education are recommended as first line treatments for musculoskeletal pain conditions such as low back pain. Osteopaths are registered primary contact allied health professionals in the Australian healthcare system who primarily manage acute and chronic musculoskeletal pain conditions. This study aimed to investigate the proportion of Australian osteopaths who do and do not utilise advice, reassurance and education (pain counselling) in their clinical practice, and determine the characteristics associated with the frequency of using pain counselling in clinical practice. A secondary analysis of practice characteristics from a nationally representative sample of Australian osteopaths was undertaken. Participants completed a 27-item practice characteristics questionnaire between July-December 2016. Bivariate analyses were used to identify significant variables for inclusion in a backward multiple logistic regression model. Adjusted odds ratios (OR) were calculated for significant variables. Responses were received from 991 Australian osteopaths, representing 49% of the profession. Of these 264 (26.64%) indicated often utilising pain counselling, and 727 (73.36%) reported not often utilising pain counselling. Those who utilised pain counselling were more than twice as likely to report research evidence had a high impact on their clinical practice (OR 2.11), and nearly twice as likely to discuss physical activity with their patients (OR 1.84). Pain counselling is under-utilised by nearly three quarters of the Australian osteopathic profession as a management strategy. Future studies are required to explore the reasons why most in the profession comprised in this sample are infrequently utilising this guideline recommendation. Given the frequency of chronic musculoskeletal pain conditions presenting to Australian osteopaths, strategies appear to be needed to advance the profession via professional development in accessing and using evidence-based care for pain conditions.


High-Throughput Phenotyping of Dynamic Canopy Traits Associated with Stay-Green in Grain Sorghum.
Drought is a recurring phenomenon that puts crop yields at risk and threatens the livelihoods of many people around the globe. Stay-green is a drought adaption phenotype found in sorghum and other cereals. Plants expressing this phenotype show less drought-induced senescence and maintain functional green leaves for longer when water limitation occurs during grain fill, conferring benefits in both yield per se and harvestability. The physiological causes of the phenotype are postulated to be water saving through mechanisms such as reduced canopy size or access to extra water through mechanisms such as deeper roots. In sorghum breeding programs, stay-green has traditionally been assessed by comparing visual scores of leaf senescence either by identifying final leaf senescence or by estimating rate of leaf senescence. In this study, we compared measurements of canopy dynamics obtained from remote sensing on two sorghum breeding trials to stay-green values (breeding values) obtained from visual leaf senescence ratings in multienvironment breeding trials to determine which components of canopy development were most closely linked to the stay-green phenotype. Surprisingly, canopy size as estimated using preflowering canopy parameters was weakly correlated with stay-green values for leaf senescence while postflowering canopy parameters showed a much stronger association with leaf senescence. Our study suggests that factors other than canopy size have an important role in the expression of a stay-green phenotype in grain sorghum and further that the use of UAVs with multispectral sensors provides an excellent way of measuring canopy traits of hundreds of plots grown in large field trials.


Inflammatory Mechanisms as New Biomarkers and Therapeutic Targets for Diabetic Kidney Disease.
Diabetic kidney disease (DKD) is the leading cause of CKD and end-stage kidney disease (ESKD) worldwide. Approximately 30-40% of people with diabetes develop this microvascular complication, placing them at high risk of losing kidney function as well as of cardiovascular events, infections, and death. Current therapies are ineffective for arresting kidney disease progression and mitigating risks of comorbidities and death among patients with DKD. As the global count of people with diabetes will soon exceed 400 million, the need for effective and safe treatment options for complications such as DKD becomes ever more urgent. Recently, the understanding of DKD pathogenesis has evolved to recognize inflammation as a major underlying mechanism of kidney damage. In turn, inflammatory mediators have emerged as potential biomarkers and therapeutic targets for DKD. Phase 2 clinical trials testing inhibitors of monocyte-chemotactic protein-1 chemokine C-C motif-ligand 2 and the Janus kinase/signal transducer and activator of transcription pathway, in particular, have produced promising results.


Blood clearance of (1-->3)-beta-D-glucan in MRL lpr/lpr mice.
(1-->3)-beta-D-Glucans have a variety of biological and immunopharmacological properties, and they are used clinically as biological response modifiers (BRMs). Clinically, these glucans have often been used for long periods by multiple dosing. During studies on the clearance and metabolism of the glucans in mice, we have found that, in the case of a single dose, the glucan was cleared from blood eventually, and remained constant in the organs for at least one month. Here, we investigated the clearance of glucans from the blood following multiple dosing using MRL lpr/lpr mice with an autoimmune disease. Two kinds of glucans, GRN from Grifola frondosa and SSG from Sclerotinia sclerotiorum, were administered to the mice once a week for more than 35 weeks (250 micrograms/week/mouse by the intraperitoneal route). Examination of the blood clearance of the glucans in these mice revealed that the glucan concentrations were always high (about 20 micrograms/ml for GRN and 200 micrograms/ml for SSG). It is also shown that the glucans were significantly deposited in the liver and spleen of these mice. These findings suggest that administration of a large quantity of the glucan saturated the reticuloendothelial system, resulting in circulation of the glucan in the blood.


Displacement of mammillary bodies by craniopharyngiomas involving the third ventricle: surgical-MRI correlation and use in topographical diagnosis.
Accurate diagnosis of the topographical relationships of craniopharyngiomas (CPs) involving the third ventricle and/or hypothalamus remains a challenging issue that critically influences the prediction of risks associated with their radical surgical removal. This study evaluates the diagnostic accuracy of MRI to define the precise topographical relationships between intraventricular CPs, the third ventricle, and the hypothalamus. An extensive retrospective review of well-described CPs reported in the MRI era between 1990 and 2009 yielded 875 lesions largely or wholly involving the third ventricle. Craniopharyngiomas with midsagittal and coronal preoperative and postoperative MRI studies, in addition to detailed descriptions of clinical and surgical findings, were selected from this database (n = 130). The position of the CP and the morphological distortions caused by the tumor on the sella turcica, suprasellar cistern, optic chiasm, pituitary stalk, and third ventricle floor, including the infundibulum, tuber cinereum, and mammillary bodies (MBs), were analyzed on both preoperative and postoperative MRI studies. These changes were correlated with the definitive CP topography and type of third ventricle involvement by the lesion, as confirmed surgically. The mammillary body angle (MBA) is the angle formed by the intersection of a plane tangential to the base of the MBs and a plane parallel to the floor of the fourth ventricle in midsagittal MRI studies. Measurement of the MBA represented a reliable neuroradiological sign that could be used to discriminate the type of intraventricular involvement by the CP in 83% of cases in this series (n = 109). An acute MBA (< 60°) was indicative of a primary tuberal-intraventricular topography, whereas an obtuse MBA (> 90°) denoted a primary suprasellar CP position, causing either an invagination of the third ventricle (pseudointraventricular lesion) or its invasion (secondarily intraventricular lesion; p < 0.01). A multivariate model including a combination of 5 variables (the MBA, position of the hypothalamus, presence of hydrocephalus, psychiatric symptoms, and patient age) allowed an accurate definition of the CP topography preoperatively in 74%-90% of lesions, depending on the specific type of relationship between the tumor and third ventricle. The type of mammillary body displacement caused by CPs represents a valuable clue for ascertaining the topographical relationships between these lesions and the third ventricle on preoperative MRI studies. The MBA provides a useful sign to preoperatively differentiate a primary intraventricular CP originating at the infundibulotuberal area from a primary suprasellar CP, which either invaginated or secondarily invaded the third ventricle.


Network meta-analysis of indomethacin versus ibuprofen versus placebo for PDA in preterm infants.
To evaluate the effects of indomethacin or ibuprofen compared with placebo on closure, morbidity and mortality in preterm infants <37 weeks' gestation with echocardiographically and/or clinically important patent ductus arteriosus (PDA) at >24 h of life. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, Cochrane Library, clinicaltrials.gov, controlled-trials.com, American Pediatric and European Paediatric Research Societies and Effective Care of the Newborn Infant. Systematic review with network meta-analysis of randomised studies comparing intravenous indomethacin, ibuprofen or placebo for PDA in preterm infants at >24 h of life. Ten trials compared intravenous indomethacin versus intravenous ibuprofen, nine intravenous indomethacin versus placebo and one intravenous ibuprofen versus placebo. Both intravenous indomethacin (pooled RR 2.39 (95% CI 2.05 to 2.78)) and intravenous ibuprofen (RR 2.40 (95% CI 2.03 to 2.84)) closed a PDA more effectively than placebo. Intravenous ibuprofen was associated with approximately 30% greater risk of chronic lung disease than intravenous indomethacin (RR 1.28 (95% CI 1.03 to 1.60)) or placebo (RR 1.29 (95% CI 0.99 to 1.70)). Differences in risk or benefit were not significant between any combination of intravenous indomethacin, intravenous ibuprofen or placebo groups for intraventricular haemorrhage, necrotising enterocolitis and death. Reporting on neurological outcomes was insufficient for pooling. Intravenous indomethacin or ibuprofen administered to preterm infants for PDA at >24 h of life promoted ductal closure, but other short-term benefits were not seen. Treatment with intravenous ibuprofen may increase the risk of chronic lung disease. Good-quality evidence of treatment effect on morbidity, mortality and improved neurodevelopment is urgently needed.


MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib.
In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFR(T790M) mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFR(T790M) mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.


The psycho-social and clinical profile of women referred for psycho-legal evaluation to forensic mental health units in South Africa.
There is a paucity of research on women offenders in the South African context, particularly those referred for forensic psychiatric observation. Little is known about their life histories, the nature of their offences or the psycho-social contexts that enable, or are antecedents to, women's criminal offending. This research study, the largest of its kind in South Africa, examined the psycho-social contexts within which women offenders referred for psychiatric evaluation come to commit offences. The profiles of both offenders and victims, as well as reasons for referral and forensic mental health outcomes, were investigated. A retrospective record review of 573 cases, spanning a 12-year review period, from six different forensic psychiatric units in South Africa, was conducted. The findings describe a population of women offenders who come from backgrounds of socio-demographic and socio-economic adversity, with relatively high pre-offence incidences of being victims of abuse themselves, with significant levels of mental ill-health and alcohol abuse permeating their life histories. The majority of index offences which led to court-ordered forensic evaluations were for violent offences against the person, with murder being the single most common index offence in the sample. Most victims of violence were known to the accused. There were also relatively high rates of psychotic and mood-spectrum disorders present, with relatively low rates of personality disorders. The majority of women were deemed to be trial competent and criminally responsible in relation to their index offences. It is recommended that more standardised and gender-sensitive forensic mental health assessment approaches, documentation and reporting be employed throughout the country. Future research should compare male and female offending patterns and forensic mental health profiles.


Ti:sapphire laser pumped by a frequency-doubled diode-pumped Nd:YLF laser.
We report on the operation of a tunable all-solid-state (holosteric) laser system consisting of a tunable Ti:sapphire laser pumped by a frequency-doubled diode-laser-pumped Nd:YLF laser. With a 1-W pump diode, the Nd:YLF laser has been frequency-modulation mode locked and Q switched at 1.047 microm. This produces a pulse envelope of 75-nsec duration with 45 microJ of energy in 21-psec pulses at a 360-MHz repetition rate. This output was frequency doubled in 90 degrees phase-matched MgO:LiNbO(3) with a 47% energy conversion efficiency. The Ti:sapphire cavity was a three-mirror astigmatically compensated arrangement.The threshold absorbed pump energy was 3.9 microJ, with an output energy of 1.3 microJ at 10.8-microJ absorbed pump power.The tuning range was 746-838 nm and was limited by the mirror reflectivities.


A Remote Intervention to Prevent or Delay Cognitive Impairment in Older Adults: Design, Recruitment, and Baseline Characteristics of the Virtual Cognitive Health (VC Health) Study.
A growing body of evidence supports the use of lifestyle interventions for preventing or delaying the onset of Alzheimer disease and other forms of dementia in at-risk individuals. The development of internet-delivered programs would increase the scalability and reach of these interventions, but requires validation to ensure similar effectiveness to brick-and-mortar options. We describe the study design, recruitment process, and baseline participant characteristics of the sample in the Virtual Cognitive Health (VC Health) study. Future analyses will assess the impact of the remotely delivered lifestyle intervention on (1) cognitive function, (2) depression and anxiety, and (3) various lifestyle behaviors, including diet, exercise, and sleep, in a cohort of older adults with subjective memory decline. Additional analyses will explore feasibility outcomes, as well as the participants' engagement patterns with the program. Older adults (aged 60-75 years) with subjective memory decline as measured by the Subjective Cognitive Decline 9-item (SCD-9) questionnaire, and who reported feeling worried about their memory decline, were eligible to participate in this single-arm pre-post study. All participants enrolled in the yearlong digital intervention, which consists of health coach-guided lifestyle change for improving diet, exercise, sleep, stress, and cognition. All components of this study were conducted remotely, including the collection of data and the administration of the intervention. We assessed participants at baseline, 12 weeks, 24 weeks, and 52 weeks with online surveys and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test. We will conduct intention-to-treat analysis on all outcomes. A total of 85 participants enrolled in the intervention and 82 are included in the study sample (3 participants withdrew). The study cohort of 82 participants comprises 61 (74%) female, 72 (88%) white, and 64 (78%) overweight or obese participants, and 55 (67%) have at least a college degree. The average baseline RBANS score was 95.9 (SD 11.1), which is within age-adjusted norms. The average SCD-9 score was 6.0 (SD 2.0), indicating minor subjective cognitive impairment at the beginning of the study. The average baseline Generalized Anxiety Disorder 7-item scale score was 6.2 (SD 4.5), and the average Patient Health Questionnaire 9-item score was 8.5 (SD 4.9), indicating mild levels of anxiety and depression at baseline. Internet-delivered lifestyle interventions are a scalable solution for the prevention or delay of Alzheimer disease. The results of this study will provide the first evidence for the effectiveness of a fully remote intervention and lay the groundwork for future investigations. ClinicalTrials.gov NCT02969460; http://clinicaltrials.gov/ct2/show/NCT02969460 (Archived by WebCite at http://www.webcitation.org/71LkYAkSh). RR1-10.2196/11368.


CT and MRI of diffuse lobar involvement pattern in liver pathology.
Focal, segmental, and diffuse liver pathologies have been described in the literature. This article describes a pattern in which liver pathology is confined to a lobe. This lobar pattern has not been described previously to our knowledge. Herein, we illustrate computed tomography (CT) and magnetic resonance imaging (MRI) findings of diffuse lobar involvement patterns in various liver conditions. Diffuse lobar involvement can be observed in benign (steatosis, hepatic iron overload, cholestasis, perfusion alterations, infarction, alveolar hydatid cysts, trauma, and hemangiomas) and primary malignant (hepatocellular carcinoma) pathologies. Diffuse lobar involvement in metastatic disease appears to be rare. Due in part to their potentially unusual appearances, the diagnosis of lobar pathologies using imaging can be challenging, and entities with lobar patterns can cause diagnostic confusion. Liver MRI can be used as a problem-solving tool for diffuse lobar pathologies detected on ultrasonography and CT. Inand out-of-phase MRI can help in the assessment of lobar fat accumulation.


From motherhood penalties to husband premia: the new challenge for gender equality and family policy, lessons from Norway.
Given the key role that processes occurring in the family play in creating gender inequality, the family is a central focus of policies aimed at creating greater gender equality. We examine how family status affects the gender wage gap using longitudinal matched employer-employee data from Norway, 1979-96, a period with extensive expansion of family policies. The motherhood penalty dropped dramatically from 1979 to 1996. Among men the premia for marriage and fatherhood remained constant. In 1979, the gender wage gap was primarily due to the motherhood penalty, but by 1996 husband premia were more important than motherhood penalties.


Motor Cortex Inputs at the Optimum Phase of Beta Cortical Oscillations Undergo More Rapid and Less Variable Corticospinal Propagation.
Brain oscillations involve rhythmic fluctuations of neuronal excitability and may play a crucial role in neural communication. The human corticomuscular system is characterized by beta activity and is readily probed by transcranial magnetic stimulation (TMS). TMS inputs arriving at the excitable phase of beta oscillations in the motor cortex are known to lead to muscle responses of greater amplitude. Here we explore two other possible manifestations of rhythmic excitability in the beta band; windows of reduced response variability and shortened latency. We delivered single-pulse TMS to the motor cortex of healthy human volunteers (10 females and 7 males) during electroencephalography recordings made at rest. TMS delivered at a particular phase of the beta oscillation benefited from not only stronger, but also less variable and more rapid transmission, as evidenced by the greater amplitude, lower coefficient of variation, and shorter latency of motor evoked potentials. Thus, inputs aligned to the optimal phase of the beta EEG in the motor cortex enjoy transmission amplitude gain, but may also benefit from less variability and shortened latencies at subsequent synapses. Neuronal phase may therefore impact corticospinal communication.SIGNIFICANCE STATEMENT Brain oscillations involve rhythmic fluctuations of neuronal excitability. Therefore, motor responses to transcranial magnetic stimulation are larger when a cortical input arrives at a particular phase of the beta activity in the motor cortex. Here, we demonstrate that inputs to corticospinal neurons which coincide with windows of higher excitability also benefit from more rapid and less variable corticospinal transmission. This shortening of latency and increased reproducibility may confer additional advantage to inputs at specific phases. Moreover, these benefits are conserved despite appreciable corticospinal conduction delays.


Peer victimization among Chinese adolescents: A longitudinal validation study.
Peer victimization is a social problem for children and adolescents worldwide. This study examined the factor structure of peer victimization in relation to school life among Chinese adolescent students. The Multidimensional Peer-Victimization Scale (MPVS) was used to measure this phenomenon. We examined psychometric properties such as factor structure, factorial invariance across genders, area types (urban vs. rural), and time (Time 1 vs. Time 2), nomological network validity in relation to the symptoms of depression and anxiety, and internal consistency reliability of the MPVS in Chinese culture. We analyzed the results of a survey of 2,764 adolescents from six public secondary schools in Fujian Province, China; 50.8% of these participants were female, and their mean age was 13.967 years (SD = .843). Of these participants, 2,217 (51.2% female), with a mean age of 13.839 years (SD = .802), also completed the survey at Time 2. Four-factor models were tested: a null model, a one-factor model, the hypothesized four-factor model, and a hierarchical model. The results revealed that the four-factor model exhibited the best fit and demonstrated factorial invariance across genders, area types, and time points. Future directions for research among Chinese adolescents were also discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


NHE8 plays important roles in gastric mucosal protection.
Sodium/hydrogen exchanger (NHE) 8 is an apically expressed membrane protein in the intestinal epithelial cells. It plays important roles in sodium absorption and bicarbonate secretion in the intestine. Although NHE8 mRNA has been detected in the stomach, the precise location and physiological role of NHE8 in the gastric glands remain unclear. In the current study, we successfully detected the expression of NHE8 in the glandular region of the stomach by Western blotting and located NHE8 protein at the apical membrane in the surface mucous cells by a confocal microscopic method. We also identified the expression of downregulated-in-adenoma (DRA) in the surface mucous cells in the stomach. Using NHE8(-/-) mice, we found that NHE8 plays little or no role in basal gastric acid production, yet NHE8(-/-) mice have reduced gastric mucosal surface pH and higher incidence of developing gastric ulcer. DRA expression was reduced significantly in the stomach in NHE8(-/-) mice. The propensity for gastric ulcer, reduced mucosal surface pH, and low DRA expression suggest that NHE8 is indirectly involved in gastric bicarbonate secretion and gastric mucosal protection.


Further assessment of fomites and personnel as vehicles for the mechanical transport and transmission of porcine reproductive and respiratory syndrome virus.
This study re-evaluated the role of fomites and personnel in the mechanical transport and transmission of porcine reproductive and respiratory syndrome virus (PRRSV) between pig populations. Swabs were collected from hands, boots, coveralls, and other fomites following contact with infected pigs and compared with identical samples collected in the absence of PRRSV exposure. Naïve pigs were provided contact with contaminated fomites/personnel and blood tested periodically post-exposure [positive exposure population (PEP)] and compared with populations that did not gain exposure via these routes [negative exposure population (NEP)]. The majority of swab samples from hands, coveralls, and boots from personnel and fomite samples (cable snare and bleeding equipment) following contact with the PRRSV-infected Source Population. Transmission of PRRSV to the PEP was observed (7/7) cases but not in the NEP. In conclusion, under the proper conditions, transport and transmission of PRRSV by fomites and personnel may occur between swine populations in the absence of intervention.


Weather and climate in the assessment of tourism-related walkability.
Walking is an important outdoor recreational and tourism activity, both in natural surroundings and in urban settings. Walkability is the extent to which the built environment promotes walking, and addresses issues such as comfort, connectivity, safety and aesthetic values. The paper explores a relatively overlooked domain of recreation- and tourism-related walkability: the extent to which weather and climatic conditions are incorporated into assessments of walkability and their influence on walking behaviour. Following a discussion of the assessment of walkability, the results of a scoping review of weather- and climate-related variables in walkability articles published up to June 2018 are presented. The review indicates there is little research on walkability from a tourist perspective, although there is substantial interest in walking for leisure and recreation. Four major themes were identified. The descriptive theme focuses on the general importance of weather and climate to walkability; the passive analyses the weather and climate conditions as barriers to, or as promoters of, walking; proactive studies refer to adapting to and managing weather, such as provision of shade or snow-clearing. The proactive perspective gains less attention than the passive analysis. Finally, statistical controlling was only employed by a minority of studies that adjusted their results to the impacts of weather conditions. The work concludes that the sub-field has been poorly served with respect to concept and variable definition and consistency of use mean that present knowledge is of limited scientific value. Strategies for future research are suggested.


Enhanced Temporal Resolution with Ion Channel-Functionalized Sensors Using a Conductance-Based Measurement Protocol.
The binding of a target analyte to an ion channel (IC), which is readily detected electrochemically in a label-free manner with single-molecule selectivity and specificity, has generated widespread interest in using natural and engineered ICs as transducers in biosensing platforms. To date, the majority of developments in IC-functionalized sensing have focused on IC selectivity or sensitivity or development of suitable membrane environments and aperture geometries. Comparatively little work has addressed analytical performance criteria, particularly criteria required for temporal measurements of dynamic processes. We report a measurement protocol suitable for rapid, time-resolved monitoring (≤30 ms) of IC-modulated membrane conductance. Key features of this protocol include the reduction of membrane area and the use of small voltage steps (10 mV) and short duration voltage pulses (10 ms), which have the net effect of reducing the capacitive charging and decreasing the time required to achieve steady state currents. Application of a conductance protocol employing three sequential, 10 ms voltage steps (-10 mV, -20 mV, -30 mV) in an alternating, pyramid-like arrangement enabled sampling of membrane conductance every 30 ms. Using this protocol, dynamic IC measurements on black lipid membranes (BLMs) functionalized with gramicidin A were conducted using a fast perfusion system. BLM conductance decreased by 76 ± 7.5% within 30 ms of switching from solutions containing 0 to 1 M Ca2+, which demonstrates the feasibility of using this approach to monitor rapid, dynamic chemical processes. Rapid conductance measurements will be broadly applicable to IC-based sensors that undergo analyte-specific gating.


Susceptibility of Bagrada hilaris (Hemiptera: Pentatomidae) to Insecticides in Laboratory and Greenhouse Bioassays.
Field-collected nymphs and adults of Bagrada hilaris (Burmeister) (Hemiptera: Penatatomidae) from three locations were evaluated for susceptibility to insecticides representing 10 classes of insecticide chemistry. Although relative susceptibilities differed between leaf-spray and leaf-dip Petri dish bioassays, consistently low LC50 values were determined for chlorpyrifos, bifenthrin, and lambda-cyhalothrin. Fenpropathrin and methomyl had intermediate values. Susceptibility to dinotefuran varied depending on the bioassay, possibly owing to leaf substrates used in the two bioassays. In soil systemic bioassays, the LC50 value of dinotefuran was significantly greater than that of two other neonicotinoids, imidacloprid and thiamethoxam, and the anthranilic diamide, cyantraniliprole. Mortality and feeding damage of B. hilaris and plant growth on insecticide-treated plants in greenhouse trials were consistent with the laboratory bioassays; the best results were seen with bifenthrin, methomyl, and chlorpyrifos. Mortality to the neonicotinoids was not evident; however, feeding damage and plant growth responses on dinotefuran-treated plants damage were similar to the noninfested control. This highlights the apparent antifeedant properties of dinotefuran that may have prevented adults from injuring broccoli plants after exposure to foliar spray residues. Data presented serve as baseline susceptibilities that can be used to monitor for resistance development in field populations of B. hilaris.


Requirement for a non-specific glycoprotein cytoplasmic domain sequence to drive efficient budding of vesicular stomatitis virus.
The cytoplasmic domains of viral glycoproteins are often involved in specific interactions with internal viral components. These interactions can concentrate glycoproteins at virus budding sites and drive efficient virus budding, or can determine virion morphology. To investigate the role of the vesicular stomatitis virus (VSV) glycoprotein (G) cytoplasmic and transmembrane domains in budding, we recovered recombinant VSVs expressing chimeric G proteins with the transmembrane and cytoplasmic domains derived from the human CD4 protein. These unrelated foreign sequences were capable of supporting efficient VSV budding. Further analysis of G protein cytoplasmic domain deletion mutants showed that a cytoplasmic domain of only 1 amino acid did not drive efficient budding, whereas 9 amino acids did. Additional studies in agreement with the CD4-chimera experiments indicated the requirement for a short cytoplasmic domain on VSV G without the requirement for a specific sequence in that domain. We propose a model for VSV budding in which a relatively non-specific interaction of a cytoplasmic domain with a pocket or groove in the viral nucleocapsid or matrix proteins generates a glycoprotein array that promotes viral budding.


Experimental investigation of evaporation from low-contact-angle sessile droplets.
Evaporating sessile drops remain pinned at the contact line during much of the evaporation process, and leave a ring of residue on the surface upon dryout. The intensive mass loss near the contact line causes solute particles to flow to the edge of the droplet and deposit at the contact line. The high vapor diffusion gradient and the low thermal resistance of the film near the contact line are responsible for very efficient mass transfer in this region. Although heat and mass transfer at the contact line have been extensively studied, well-characterized experiments remain scarce. The local mass transport in a 100-400 microm region near the contact line of a water droplet of radius 1810 microm on a glass substrate is experimentally quantified in the present work. Microparticle image velocimetry measurements of the three-dimensional flow field near the contact line are conducted to map the velocity field. Combined with high-resolution transient liquid profile shapes, the measured velocity field yields transient local evaporative mass fluxes near the contact line. The spatial and temporal distribution of the local evaporative flux is also documented. The temperature distribution in the droplet near the contact line is deduced from the local evaporative fluxes and interface mass transport theory.


Impact of exercise pulmonary hypertension on postoperative outcome in primary mitral regurgitation.
The management of asymptomatic patients with mitral regurgitation (MR) remains controversial. Exercise-induced pulmonary hypertension (ExPHT) was recently reported as a strong predictor of rapid onset of symptoms. We hypothesised that ExPHT is a predictor of postoperative cardiovascular events in patients with primary MR. One hundred and two patients with primary MR, no or mild symptoms (New York heart association (NYHA) ≤2), and no LV dysfunction/dilatation, were prospectively recruited in 3 centres and underwent exercise-stress echocardiography. The presence of ExPHT was defined as an exercise systolic pulmonary arterial pressure >60 mm Hg. All patients were closely followed up and operated on when indication for surgery was reached. Postoperative events were defined as the occurrence of atrial fibrillation (AF), stroke, cardiac-related hospitalisation or death. Among the 102 patients included, 59 developed ExPHT (58%). These patients were significantly older than those without ExPHT (p=0.01). During a mean postoperative follow-up of 50±23 months, 28 patients (26%) experienced a predefined cardiovascular event. Patients with ExPHT had significantly higher rate of postoperative events (39% vs 12%, p=0.005); the rate of events was still higher in these patients (32% vs 9%, p=0.013), even when excluding early postoperative AF (ie, within 48 h). Event-free survival was significantly lower in the ExPHT group (all events: 5-year: 60±8% vs 88±5%, p=0.007, events without early AF: 5-year: 67±7% vs 90±4%, p=0.02). Using Cox multivariable analysis, ExPHT remained independently associated with higher risk of postoperative events in all models (all p≤0.04). ExPHT is associated with increased risk of adverse cardiac events following mitral valve surgery in patients with primary MR.


Detecting Dysglycemia Using the 2015 United States Preventive Services Task Force Screening Criteria: A Cohort Analysis of Community Health Center Patients.
In 2015, the United States Preventive Services Task Force (USPSTF) recommended targeted screening for prediabetes and diabetes (dysglycemia) in adults who are aged 40 to 70 y old and overweight or obese. Given increasing prevalence of dysglycemia at younger ages and lower body weight, particularly among racial/ethnic minorities, we sought to determine whether the current screening criteria may fail to identify some high-risk population subgroups. We investigated the performance of the 2015 USPSTF screening recommendation in detecting dysglycemia among US community health center patients. A retrospective analysis of electronic health record (EHR) data from 50,515 adult primary care patients was conducted. Longitudinal EHR data were collected in six health centers in the Midwest and Southwest. Patients with a first office visit between 2008 and 2010 were identified and followed for up to 3 y through 2013. We excluded patients who had dysglycemia at baseline and those with fewer than two office visits during the follow-up period. The exposure of interest was eligibility for screening according to the 2015 USPSTF criteria. The primary outcome was development of dysglycemia during follow-up, determined by: (1) laboratory results (fasting/2-h postload/random glucose ≥ 100/140/200 mg/dL [5.55/7.77/11.10 mmol/L] or hemoglobin A1C ≥ 5.7% [39 mmol/mol]); (2) diagnosis codes for prediabetes or type 2 diabetes; or (3) antidiabetic medication order. At baseline, 18,846 (37.3%) participants were aged ≥40 y, 33,537 (66.4%) were overweight or obese, and 39,061 (77.3%) were racial/ethnic minorities (34.6% Black, 33.9% Hispanic/Latino, and 8.7% Other). Overall, 29,946 (59.3%) patients had a glycemic test within 3 y of follow-up, and 8,478 of them developed dysglycemia. Only 12,679 (25.1%) patients were eligible for screening according to the 2015 USPSTF criteria, which demonstrated the following sensitivity and specificity (95% CI): 45.0% (43.9%-46.1%) and 71.9% (71.3%-72.5%), respectively. Racial/ethnic minorities were significantly less likely to be eligible for screening yet had higher odds of developing dysglycemia than whites (odds ratio [95% CI]: Blacks 1.24 [1.09-1.40]; Hispanics 1.46 [1.30-1.64]; and Other 1.33 [1.16-1.54]). In addition, the screening criteria had lower sensitivity in all racial/ethnic minority groups compared to whites. Limitations of this study include the ascertainment of dysglycemia only among patients with available test results and findings that may not be generalizable at the population level. Targeted diabetes screening based on new USPSTF criteria may detect approximately half of adult community health center patients with undiagnosed dysglycemia and proportionately fewer racial/ethnic minorities than whites. Future research is needed to estimate the performance of these screening criteria in population-based samples.


Cactus pear (Opuntia ficus-indica) juice fermented with autochthonous Lactobacillus plantarum S-811.
The present study aimed at investigating the lactic fermentation of cactus pear (Opuntia ficus-indica) fruit juice with the autochthonous and potentially probiotic strain Lactobacillus plantarum S-811. L. plantarum S-811 was able to quickly acidify the juice with a decrease in the pH from 5.5 to 3.7 and a production of 5.06 g l-1 of lactic acid. Fermentation of cactus pear juice led to conservation of its health-promoting properties and it markedly promoted antioxidant mechanisms in yeast cells, showing in a Saccharomyces cerevisiae model a protective effect of up to 11 times against H2O2 (4 mM), compared to yeasts not supplemented with the fermented juice. Administration of fermented juice to obese mice caused a significant decrease in the body weight gain and ameliorated the insulin resistance, hyperglycemia, and hyperlipemia that characterize obesity. These results reveal the potential of the cactus pear juice fermented with L. plantarum S-811 as a functional beverage for the prevention of obesity and related pathologies.


Determination of penicillin susceptibility of Streptococcus pneumoniae using the polymerase chain reaction.
To develop a polymerase chain reaction (PCR) based method to detect penicillin susceptibility in isolates of Streptococcus pneumoniae (SP). PCR primers were designed to amplify differential nucleotide sequences of the penicillin-binding protein (PBP) genes 2b, 2x, and 1a in penicillin susceptible and resistant strains of SP. Primers derived from the PBP 2x and 2b genes were designed to amplify products from penicillin susceptible S pneumoniae (PSSP), whereas primers derived from the PBP 1a gene were designed to amplify gene sequences of penicillin resistant S pneumoniae (PRSP). Two hundred and thirty clinical isolates of SP from the USA, UK, Kenya, Romania, and the Kingdom of Saudi Arabia were tested. Of the isolates, 116 were penicillin susceptible, 65 were intermediately resistant, and 49 were highly resistant. PCR identified 108 (93%) of 116 of PSSP isolates, 55 (85%) of 65 intermediately resistant isolates, and all of the 49 highly resistant isolates of SP. The susceptibility of 16 (7%) isolates could not be determined using PCR. All of these 16 isolates had a minimum inhibitory concentration (MIC) of penicillin < 1 mg/l. None of the highly resistant isolates was identified as penicillin susceptible by PCR, although two of the isolates with intermediate resistance (MIC = 0.125 mg/l) were. Using primers that differentially identify the genotypes of susceptible and resistant strains of SP, PCR provides a rapid method for determining the penicillin susceptibility of SP isolates and could potentially be used for testing clinical samples.


Spectral tunability of a plasmonic antenna with a dielectric nanocrystal.
We show that the positioning of a nanometer length scale dielectric object, such as a diamond nanocrystal, in the vicinity of a gold bowtie nanoantenna can be used to tune the plasmonic mode spectrum on the order of a linewidth. We further show that the intrinsic luminescence of gold enhanced in the presence of nanometer-scale roughness couples efficiently to the plasmon mode and carries the same polarization anisotropy. Our findings have direct implications for cavity quantum electrodynamics related applications of hybrid antenna-emitter complexes.


Triple-sensor multiplexed frequency-modulated continuous-wave interferometric fiber-optic displacement sensor.
A triple-sensor multiplexed fiber-optic displacement sensor, which can measure the displacements of three different objects or the three-dimensional displacement of a single object, is introduced. The sensor is based on the principles of optical frequency-modulated continuous-wave interference and frequency-division multiplexing. The beat signals from the individual sensors are assigned in the frequency domain and separated with different electrical bandpass filters. The displacements of objects can be determined simultaneously by detecting the phase shifts of the corresponding signals. The cross talk between the individual sensors is evaluated, and an accuracy of 0.08 microm in a dynamic range of 1000 microm is achieved.


Treatment of lateral epicondylitis.
Lateral epicondylitis is a common overuse syndrome of the extensor tendons of the forearm. It is sometimes called tennis elbow, although it can occur with many activities. The condition affects men and women equally and is more common in persons 40 years or older. Despite the prevalence of lateral epicondylitis and the numerous treatment strategies available, relatively few high-quality clinical trials support many of these treatment options; watchful waiting is a reasonable option. Topical nonsteroidal anti-inflammatory drugs, corticosteroid injections, ultrasonography, and iontophoresis with nonsteroidal anti-inflammatory drugs appear to provide short-term benefits. Use of an inelastic, nonarticular, proximal forearm strap (tennis elbow brace) may improve function during daily activities. Progressive resistance exercises may confer modest intermediate-term results. Evidence is mixed on oral nonsteroidal antiinflammatory drugs, mobilization, and acupuncture. Patients with refractory symptoms may benefit from surgical intervention. Extracorporeal shock wave therapy, laser treatment, and electromagnetic field therapy do not appear to be effective.


Expression and Role of IL-1β Signaling in Chondrocytes Associated with Retinoid Signaling during Fracture Healing.
The process of fracture healing consists of an inflammatory reaction and cartilage and bone tissue reconstruction. The inflammatory cytokine interleukin-1β (IL-1β) signal is an important major factor in fracture healing, whereas its relevance to retinoid receptor (an RAR inverse agonist, which promotes endochondral bone formation) remains unclear. Herein, we investigated the expressions of IL-1β and retinoic acid receptor gamma (RARγ) in a rat fracture model and the effects of IL-1β in the presence of one of several RAR inverse agonists on chondrocytes. An immunohistochemical analysis revealed that IL-1β and RARγ were expressed in chondrocytes at the fracture site in the rat ribs on day 7 post-fracture. In chondrogenic ATDC5 cells, IL-1β decreases the levels of aggrecan and type II collagen but significantly increased the metalloproteinase-13 (Mmp13) mRNA by real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. An RAR inverse agonist (AGN194310) inhibited IL-1β-stimulated Mmp13 and Ccn2 mRNA in a dose-dependent manner. Phosphorylated extracellular signal regulated-kinases (pERK1/2) and p-p38 mitogen-activated protein kinase (MAPK) were increased time-dependently by IL-1β treatment, and the IL-1β-induced p-p38 MAPK was inhibited by AGN194310. Experimental p38 inhibition led to a drop in the IL-1β-stimulated expressions of Mmp13 and Ccn2 mRNA. MMP13, CCN2, and p-p38 MAPK were expressed in hypertrophic chondrocytes near the invaded vascular endothelial cells. As a whole, these results point to role of the IL-1β via p38 MAPK as important signaling in the regulation of the endochondral bone formation in fracture healing, and to the actions of RAR inverse agonists as potentially relevant modulators of this process.


The influence of physical activity, body composition, and lower extremity strength on walking ability.
We examined the relationship among objective measures of body composition, lower extremity strength, physical activity, and walking performance and determined whether this interaction differed according to walking ability. Participants were 126 adults ages 60-91 yr. Stepwise multiple regression analysis showed that the 30-s chair stand test (30sCST), appendicular lean mass index (aLMI), body mass index, and age were independent contributors to walking performance, explaining 44.3% of the variance. For slower walkers, appendicular fat mass index (aFMI), moderate to vigorous physical activity (MVPA), 30sCST, and aLMI (r2 = .49, p < .001) largely explained variance in walking performance. For faster walkers, aFMI and aLMI explained 31.4% (p < .001) of the variance. These data suggest that both fat and lean mass are associated with walking performance in higher- and lower-functioning older adults, whereas MPVA and muscle strength influence walking ability only among lower-functioning older adults.


Effect of contact angle hysteresis on the removal of the sporelings of the green alga Ulva from the fouling-release coatings synthesized from polyolefin polymers.
Wettability is one of the surface characteristics that is controlled by the chemical composition and roughness of a surface. A number of investigations have explored the relationship between water contact angle and surface free energy of polymeric coatings with the settlement (attachment) and adhesion strength of various marine organisms. However, the relationship between the contact angle hysteresis and fouling-release property is generally overlooked. In the present work, coatings were prepared by using commercial hydrophobic homopolymer and copolymer polyolefins, which have nearly the same surface free energy. The effects of contact angle hysteresis, wetting hysteresis, and surface free energy on the fouling-release properties for sporelings of the green alga Ulva from substrates were then examined quantitatively under a defined shear stress in a water channel. The ease of removal of sporelings under shear stress from the polymer surfaces was in the order of PP>HDPE>PPPE>EVA-12 and strongly and positively correlated with contact angle and wetting hysteresis; i.e., the higher the hysteresis, the greater the removal.


Clinical features and treatment with botulinum toxin in blepharospasm: a 17-year experience.
It was to analyze clinical aspects of patients with blepharospasm, including outcomes of botulinum toxin treatment. Additionally, clinical characteristics of isolated blepharospasm were compared to those of blepharospasm plus other movement disorders. Clinical data recorded during 17 years were reviewed. The variables included age, gender, age of onset, past medical history, head trauma, smoking history, family history of dystonia, severity, duration of botulinum toxin relief and adverse effects. A total of 125 patients were included and 75.2% were female. The mean age of onset was 54.3 years; 89.6% of the individuals started with contractions in eye region, and 39.2% of them spread to lower face or neck. Isolated blepharospasm group was compared with blepharospasm-plus group for demographic and clinical features, and therapeutic outcomes, without significant differences. Botulinum toxin treatment improved the severity of contractions (p=0.01) with low rate of side effects (14%). Both groups - isolated blepharospasm and blepharospasm-plus - shared similar results concerning epidemiology, clinical features and therapeutic response to botulinum toxin.


The transmissibility and control of pandemic influenza A (H1N1) virus.
Pandemic influenza A (H1N1) 2009 (pandemic H1N1) is spreading throughout the planet. It has become the dominant strain in the Southern Hemisphere, where the influenza season has now ended. Here, on the basis of reported case clusters in the United States, we estimated the household secondary attack rate for pandemic H1N1 to be 27.3% [95% confidence interval (CI) from 12.2% to 50.5%]. From a school outbreak, we estimated that a typical schoolchild infects 2.4 (95% CI from 1.8 to 3.2) other children within the school. We estimated the basic reproductive number, R0, to range from 1.3 to 1.7 and the generation interval to range from 2.6 to 3.2 days. We used a simulation model to evaluate the effectiveness of vaccination strategies in the United States for fall 2009. If a vaccine were available soon enough, vaccination of children, followed by adults, reaching 70% overall coverage, in addition to high-risk and essential workforce groups, could mitigate a severe epidemic.


Emergence of New Non-Clonal Group 258 High-Risk Clones among Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Isolates, France.
The worldwide spread of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) isolates was reported to be caused by dissemination of 1 clonal complex (i.e., clonal group [CG] 258, which includes sequence types [STs] 258 and 512). We conducted whole-genome sequencing and epidemiologic analysis of all KPC-Kp isolates in France in 2018 and found that new successful high-risk clones of ST147, ST307, ST231, and ST383 are now the main drivers of blaKPC genes. The blaKPC genes were mostly carried by Tn4401a and Tn4401d structures and a new non-Tn4401 element. Our epidemiologic investigations showed that the emergence of these non-CG258 KPC-Kp isolates in France was linked to dissemination of these clones from Portugal. Thus, KPC-Kp epidemiology has changed in Europe, at least in several non-KPC-endemic countries of western Europe, such as France and Portugal, where CG258 is not the most prevalent clone.


Training in High-Throughput Sequencing: Common Guidelines to Enable Material Sharing, Dissemination, and Reusability.
The advancement of high-throughput sequencing (HTS) technologies and the rapid development of numerous analysis algorithms and pipelines in this field has resulted in an unprecedentedly high demand for training scientists in HTS data analysis. Embarking on developing new training materials is challenging for many reasons. Trainers often do not have prior experience in preparing or delivering such materials and struggle to keep them up to date. A repository of curated HTS training materials would support trainers in materials preparation, reduce the duplication of effort by increasing the usage of existing materials, and allow for the sharing of teaching experience among the HTS trainers' community. To achieve this, we have developed a strategy for materials' curation and dissemination. Standards for describing training materials have been proposed and applied to the curation of existing materials. A Git repository has been set up for sharing annotated materials that can now be reused, modified, or incorporated into new courses. This repository uses Git; hence, it is decentralized and self-managed by the community and can be forked/built-upon by all users. The repository is accessible at http://bioinformatics.upsc.se/htmr.


Management of Graves Thyroidal and Extrathyroidal Disease: An Update.
Invited update on the management of systemic autoimmune Graves disease (GD) and associated Graves orbitopathy (GO). Guidelines, pertinent original articles, systemic reviews, and meta-analyses. Thyrotropin receptor antibodies (TSH-R-Abs), foremost the stimulatory TSH-R-Abs, are a specific biomarker for GD. Their measurement assists in the differential diagnosis of hyperthyroidism and offers accurate and rapid diagnosis of GD. Thyroid ultrasound is a sensitive imaging tool for GD. Worldwide, thionamides are the favored treatment (12-18 months) of newly diagnosed GD, with methimazole (MMI) as the preferred drug. Patients with persistently high TSH-R-Abs and/or persistent hyperthyroidism at 18 months, or with a relapse after completing a course of MMI, can opt for a definitive therapy with radioactive iodine (RAI) or total thyroidectomy (TX). Continued long-term, low-dose MMI administration is a valuable and safe alternative. Patient choice, both at initial presentation of GD and at recurrence, should be emphasized. Propylthiouracil is preferred to MMI during the first trimester of pregnancy. TX is best performed by a high-volume thyroid surgeon. RAI should be avoided in GD patients with active GO, especially in smokers. Recently, a promising therapy with an anti-insulin-like growth factor-1 monoclonal antibody for patients with active/severe GO was approved by the Food and Drug Administration. COVID-19 infection is a risk factor for poorly controlled hyperthyroidism, which contributes to the infection-related mortality risk. If GO is not severe, systemic steroid treatment should be postponed during COVID-19 while local treatment and preventive measures are offered. A clear trend towards serological diagnosis and medical treatment of GD has emerged.


Diet-dependent effects of the Drosophila Mnk1/Mnk2 homolog Lk6 on growth via eIF4E.
The control of cellular growth is tightly linked to the regulation of protein synthesis. A key function in translation initiation is fulfilled by the 5' cap binding eukaryotic initiation factor 4E (eIF4E), and dysregulation of eIF4E is associated with malignant transformation and tumorigenesis . In mammals, the activity of eIF4E is modulated by phosphorylation at Ser209 by mitogen-activated protein kinases (MAPK)-interacting kinases 1 and 2 (Mnk1 and Mnk2) , which themselves are activated by ERK and p38 MAPK in response to mitogens, cytokines or cellular stress . Whether phosphorylation of eIF4E at Ser209 exerts a positive or inhibitory effect on translation efficiency has remained controversial. Here we provide a genetic characterization of the Drosophila homolog of Mnk1/2, Lk6. Lk6 function is dispensable under a high protein diet, consistent with the recent finding that mice lacking both Mnk1 and Mnk2 are not growth-impaired . Interestingly, loss of Lk6 function causes a significant growth reduction when the amino acid content in the diet is reduced. Overexpression of Lk6 also results in growth inhibition in an eIF4E-dependent manner. We propose a model of eIF4E regulation that may reconcile the contradictory findings with regard to the role of phosphorylation by Mnk1/2.


A meta-analysis of kidney microarray datasets: investigation of cytokine gene detection and correlation with rt-PCR and detection thresholds.
Microarrays provide a means to simultaneously examine the gene expression of the entire transcriptome in a single sample. Many studies have highlighted the need for novel software and statistical approaches to assess the measured gene expression. Less attention has been directed toward whether genes considered undetectable by microarray can be detected by other strategies or whether these genes can provide accurate gene expression determinations. In the kidney this is a concern for genes such as cytokines which dramatically influence the immune response but are often considered low abundance genes produced by a small number of cells. Using both publicly available and our own microarray datasets we analyzed the detection p-value and detection call values for 81 human kidney samples run on the U133A or U133Plus2.0 Affymetrix microarrays (Affymetrix, Santa Clara, CA). For the cytokine genes, the frequency of detection in each sample group (normal, transplant and renal cell carcinoma) was examined and revealed that a majority of cytokine related genes are not detectable in human kidney by microarray. Using a subset of 29 Mayo transplant samples, a group of seven transplant-related cytokines and eight non-cytokine genes were evaluated by real-time PCR (rt-PCR). For these 15 genes we compared the impact of decreasing microarray detection frequency with the changes in gene expression observed by both microarray and rt-PCR. We found that as microarray detection frequency decreased the correlation between microarray and rt-PCR data also decreased. We conclude that, when analyzing microarray data from human kidney samples, genes generally expressed at low abundance (i.e. cytokines) should be evaluated with more sensitive approaches such as rt-PCR. In addition, our data suggest that the use of detection frequency cutoffs for inclusion or exclusion of microarray data may be appropriate when comparing microarray and rt-PCR gene expression data and p-value calculations.


Renal cell apoptosis and new treatment options in sepsis-induced acute kidney injury.
Sepsis is a common and important cause of mortality in critically ill patients. Acute kidney injury (AKI) is one of the most important factors determining morbidity and mortality in the prognosis of sepsis. Recent studies have indicated that the pathogenetic mechanism in septic AKI is totally different from that in non-septic AKI. Our understanding of sepsis-associated AKI pathophysiology is shifting from renal vasoconstriction, ischemia, and acute tubular necrosis to heterogeneous vasodilation, hyperemia, and acute tubular apoptosis. Especially, apoptosis is gradually gaining importance in the understanding of the development of renal injury. The frequency of renal tubular apoptosis on biopsies of septic patients has been pointed out in recently published studies. Apoptosis can be triggered by ischemia, exogen toxins, or endogen mediators. It has been shown in some animal models that hyperglycemia, which is common in critically ill patients, causes apoptosis in renal tubular cells. New treatment options have emerged in the light of recent findings. Ghrelin that inhibits pro-inflammatory cytokines, caspase inhibitors that block the apoptotic pathway, and suppression of anti-inflammatory reactions are under study. Among the existing methods of treatment, usage of arginine, which is a vasopressor agent, ventilation with a low tidal volume, and hemofiltration methods cleaning toxic mediators from the circulation should be considered in the first place. Hyperglycemia treatment is of major importance, since, besides its anti-inflammatory effect, it has a protective role on the kidney. Regarding pathogenesis, rates of morbidity and mortality are aimed to be reduced through the new agents of therapy that have been studied on.


When to treat myelodysplastic syndromes.
The myelodysplastic syndromes represent a heterogeneous series of clonal hematologic neoplasms characterized by morphologic dysplasia, aberrant hematopoiesis and a variable risk of progression to acute myeloid leukemia. These syndromes have a complex pathobiology, and ineffective hematopoiesis is a well-recognized feature of all of them. Normal blood cell maturation, differentiation, function, and survival are impaired, and these abnormalities contribute to the development of peripheral blood pancytopenia. The majority of patients succumb to complications of either bone marrow failure or leukemic progression. The fact that the majority of patients are elderly and have other comorbidities complicates therapeutic decision making and necessitates the development of individualized treatment strategies.


Peptide binding predictions for HLA DR, DP and DQ molecules.
MHC class II binding predictions are widely used to identify epitope candidates in infectious agents, allergens, cancer and autoantigens. The vast majority of prediction algorithms for human MHC class II to date have targeted HLA molecules encoded in the DR locus. This reflects a significant gap in knowledge as HLA DP and DQ molecules are presumably equally important, and have only been studied less because they are more difficult to handle experimentally. In this study, we aimed to narrow this gap by providing a large scale dataset of over 17,000 HLA-peptide binding affinities for a set of 11 HLA DP and DQ alleles. We also expanded our dataset for HLA DR alleles resulting in a total of 40,000 MHC class II binding affinities covering 26 allelic variants. Utilizing this dataset, we generated prediction tools utilizing several machine learning algorithms and evaluated their performance. We found that 1) prediction methodologies developed for HLA DR molecules perform equally well for DP or DQ molecules. 2) Prediction performances were significantly increased compared to previous reports due to the larger amounts of training data available. 3) The presence of homologous peptides between training and testing datasets should be avoided to give real-world estimates of prediction performance metrics, but the relative ranking of different predictors is largely unaffected by the presence of homologous peptides, and predictors intended for end-user applications should include all training data for maximum performance. 4) The recently developed NN-align prediction method significantly outperformed all other algorithms, including a naïve consensus based on all prediction methods. A new consensus method dropping the comparably weak ARB prediction method could outperform the NN-align method, but further research into how to best combine MHC class II binding predictions is required.


From chromatogram to analyte to metabolite. How to pick horses for courses from the massive web resources for mass spectral plant metabolomics.
The grand challenge currently facing metabolomics is the expansion of the coverage of the metabolome from a minor percentage of the metabolic complement of the cell toward the level of coverage afforded by other post-genomic technologies such as transcriptomics and proteomics. In plants, this problem is exacerbated by the sheer diversity of chemicals that constitute the metabolome, with the number of metabolites in the plant kingdom generally considered to be in excess of 200 000. In this review, we focus on web resources that can be exploited in order to improve analyte and ultimately metabolite identification and quantification. There is a wide range of available software that not only aids in this but also in the related area of peak alignment; however, for the uninitiated, choosing which program to use is a daunting task. For this reason, we provide an overview of the pros and cons of the software as well as comments regarding the level of programing skills required to effectively exploit their basic functions. In addition, the torrent of available genome and transcriptome sequences that followed the advent of next-generation sequencing has opened up further valuable resources for metabolite identification. All things considered, we posit that only via a continued communal sharing of information such as that deposited in the databases described within the article are we likely to be able to make significant headway toward improving our coverage of the plant metabolome.


Flea market finds and global exports: Four multistate outbreaks of human Salmonella infections linked to small turtles, United States-2015.
Zoonotic transmission of Salmonella infections causes an estimated 11% of salmonellosis annually in the United States. This report describes the epidemiologic, traceback and laboratory investigations conducted in the United States as part of four multistate outbreaks of Salmonella infections linked to small turtles. Salmonella isolates indistinguishable from the outbreak strains were isolated from a total of 143 ill people in the United States, pet turtles, and pond water samples collected from turtle farm A, as well as ill people from Chile and Luxembourg. Almost half (45%) of infections occurred in children aged <5 years, underscoring the importance of the Centers for Disease Control and Prevention recommendation to keep pet turtles and other reptiles out of homes and childcare settings with young children. Although only 43% of the ill people who reported turtle exposure provided purchase information, most small turtles were purchased from flea markets or street vendors, which made it difficult to locate the vendor, trace the turtles to a farm of origin, provide education and enforce the United States federal ban on the sale and distribution of small turtles. These outbreaks highlight the importance of improving public awareness and education about the risk of Salmonella from small turtles not only in the United States but also worldwide.


Diabetes Induced Alterations in Murine Vitreous Proteome Are Mitigated by IL-6 Trans-Signaling Inhibition.
Diabetic retinopathy (DR) is a microvascular complication caused by prolonged hyperglycemia and characterized by leaky retinal vasculature and ischemia-induced angiogenesis. Vitreous humor is a gel-like biofluid in the posterior segment of the eye between the lens and the retina. Disease-related changes are observed in the biochemical constituents of the vitreous, including proteins and macromolecules. Recently, we found that IL-6 trans-signaling plays a significant role in the vascular leakage and retinal pathology associated with DR. Therefore, in this study, comprehensive proteomic profiling of the murine vitreous was performed to identify diabetes-induced alterations and to determine effects of IL-6 trans-signaling inhibition on these changes. Vitreous samples from mice were collected by evisceration, and proteomic analyses were performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 154 proteins were identified with high confidence in control mice and were considered to be characteristic of healthy murine vitreous fluid. The levels of 72 vitreous proteins were significantly altered in diabetic mice, including several members of heat shock proteins, 14-3-3 proteins, and tubulins. Alterations in 52 out of 72 proteins in diabetic mice were mitigated by IL-6 trans-signaling inhibition. Proteomic analysis of murine vitreous fluid performed in this study provides important information about the changes caused by diabetes in the ocular microenvironment. These diabetes-induced alterations in the murine vitreous proteome were mitigated by IL-6 trans-signaling inhibition. These findings further support that IL-6 trans-signaling may be an important therapeutic target for the treatment of DR.


Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy.
To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC). Ambulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype. At 36 months, eteplirsen-treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping. Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC.


Driving Human Motor Cortical Oscillations Leads to Behaviorally Relevant Changes in Local GABAA Inhibition: A tACS-TMS Study.
Beta and gamma oscillations are the dominant oscillatory activity in the human motor cortex (M1). However, their physiological basis and precise functional significance remain poorly understood. Here, we used transcranial magnetic stimulation (TMS) to examine the physiological basis and behavioral relevance of driving beta and gamma oscillatory activity in the human M1 using transcranial alternating current stimulation (tACS). tACS was applied using a sham-controlled crossover design at individualized intensity for 20 min and TMS was performed at rest (before, during, and after tACS) and during movement preparation (before and after tACS). We demonstrated that driving gamma frequency oscillations using tACS led to a significant, duration-dependent decrease in local resting-state GABAA inhibition, as quantified by short interval intracortical inhibition. The magnitude of this effect was positively correlated with the magnitude of GABAA decrease during movement preparation, when gamma activity in motor circuitry is known to increase. In addition, gamma tACS-induced change in GABAA inhibition was closely related to performance in a motor learning task such that subjects who demonstrated a greater increase in GABAA inhibition also showed faster short-term learning. The findings presented here contribute to our understanding of the neurophysiological basis of motor rhythms and suggest that tACS may have similar physiological effects to endogenously driven local oscillatory activity. Moreover, the ability to modulate local interneuronal circuits by tACS in a behaviorally relevant manner provides a basis for tACS as a putative therapeutic intervention.SIGNIFICANCE STATEMENT Gamma oscillations have a vital role in motor control. Using a combined tACS-TMS approach, we demonstrate that driving gamma frequency oscillations modulates GABAA inhibition in the human motor cortex. Moreover, there is a clear relationship between the change in magnitude of GABAA inhibition induced by tACS and the magnitude of GABAA inhibition observed during task-related synchronization of oscillations in inhibitory interneuronal circuits, supporting the hypothesis that tACS engages endogenous oscillatory circuits. We also show that an individual's physiological response to tACS is closely related to their ability to learn a motor task. These findings contribute to our understanding of the neurophysiological basis of motor rhythms and their behavioral relevance and offer the possibility of developing tACS as a therapeutic tool.


The experimental dose ranges influence the LETd dependency of the proton minimum RBE (RBEmin).
Cell experiments have shown the proton relative biological effectiveness (RBE) to vary with dose and linear energy transfer (LET), which has led to development of variable RBE models. The RBE is normally estimated from two independent functions, the RBEmax and RBEmin, describing the extreme RBE at low and high doses. While there is consensus that RBEmax increases with increasing LET, the RBEmin is not uniformly defined and its dependency on LET is deviating. In this work, we analysed this dependency and its sensitivity to variations of the experimental dose range. We performed a literature search to find data from existing monoenergetic proton cell survival experiments with (α/β) x values below 5 Gy and dose averaged LET (LETd) values below 20 keV µm-1. From the experiments the doses and their corresponding survival data were extracted. Based on these data, multiple restricted databases were generated by sequential exclusion of low dose data in the experiments followed by a linear-quadratic (LQ) fit. The quadratic component from the LQ-fit was used to estimate RBEmin. The LETd dependency of RBEmin was determined by fitting a linear function to the RBEmin values estimated from the restricted databases. Our analysis showed the LETd dependency of RBEmin to be significantly influenced by the experimental dose range. By including experiments with doses below 1 Gy in the database, we found that RBEmin increased with increasing LETd. By excluding the low dose experiments in our database, the RBEmin became constant for all LETd values. For an LETd value of 5 keV µm-1, a restricted database including the data with the lowest doses gave an RBEmin of 1.4 ± 0.1, while databases with only high dose data (>2 Gy) gave an RBEmin of 1.0 ± 0.1. None of our restricted databases gave a decreasing RBEmin with increasing LETd. Our study showed that RBEmin has a small yet significant dependency on LETd for tissues with low (α/β) x ratio. The LETd dependency of RBEmin varied substantially with the experimental dose range. Including experiments with high minimum dose in RBE models may lead to underestimation of the RBE.


G-protection mechanisms afforded by the anti-G suit abdominal bladder with and without pressure breathing.
G protection afforded by the abdominal bladder of a pneumatic anti-G suit is usually attributed to counteraction of G-induced caudad displacement of the heart and pooling of blood in the abdominal veins. The study examined whether the abdominal bladder might provide G protection also via other mechanisms. Each subject was exposed to +Gz loads while sitting relaxed, wearing a full-coverage anti-G suit modified to permit separate pressurization of the abdominal and leg bladders. In two experimental series (N = 8, N = 14), subjects were breathing at positive airway pressure (PPB); in a third series, five subjects were breathing at atmospheric airway pressure. Intrathoracic pressures were estimated by use of esophageal catheters. During PPB at high G loads, intrathoracic pressure was higher with than without the pressurized abdominal bladder. In 7 of the 14 subjects, basilar intrathoracic pressure exceeded airway pressure during PPB when the abdominal bladder was pressurized. The mean arterial pressure response at high G loads was higher in this subset of subjects (55 +/- 23 mmHg) than in the subjects in whom airway pressure exceeded intrathoracic pressure (41 +/- 27 mmHg). Without PPB at increased G load, the intrathoracic pressure gradient was higher with than without the pressurized abdominal bladder. During PPB, the abdominal bladder acts as an airway counterpressure, thereby facilitating pressure transmission from the airways to the thorax and hence improving G protection. It also appears that in several individuals, pressure may be transmitted from the abdominal bladder to the thorax and heart.


Women's risk of repeat abortions is strongly associated with alcohol consumption: a longitudinal analysis of a Russian national panel study, 1994-2009.
Abortion rates in Russia, particularly repeat abortions, are among the highest in the world, and abortion complications make a substantial contribution to the country's high maternal mortality rate. Russia also has a very high rate of hazardous alcohol use. However, the association between alcohol use and abortion in Russia remains unexplored. We investigated the longitudinal predictors of first and repeat abortion, focussing on women's alcohol use as a risk factor. Follow-up data from 2,623 women of reproductive age (16-44 years) was extracted from 14 waves of the Russian Longitudinal Monitoring Survey (RLMS), a nationally representative panel study covering the period 1994-2009. We used discrete time hazard models to estimate the probability of having a first and repeat abortion by social, demographic and health characteristics at the preceding study wave. Having a first abortion was associated with demographic factors such as age and parity, whereas repeat abortions were associated with low education and alcohol use. After adjustment for demographic and socioeconomic factors, the risk of having a repeat abortion increased significantly as women's drinking frequency increased (P<0.001), and binge drinking women were significantly more likely to have a repeat abortion than non-drinkers (OR 2.28, 95% CI 1.62-3.20). This association was not accounted for by contraceptive use or a higher risk of pregnancy. Therefore the determinants of first and repeat abortion in Russia between 1994-2009 were different. Women who had repeat abortions were distinguished by their heavier and more frequent alcohol use. The mechanism for the association is not well understood but could be explained by unmeasured personality factors, such as risk taking, or social non-conformity increasing the risk of unplanned pregnancy. Heavy or frequent drinkers constitute a particularly high risk group for repeat abortion, who could be targeted in prevention efforts.


Examining Second Language Listening, Vocabulary, and Executive Functioning.
Performance on second language (L2) listening tests is influenced by individual differences in listener characteristics (e.g., executive functioning and vocabulary size) and characteristics of the listening measure (e.g., text length or skills measured). For listeners, the amount of linguistic knowledge is most important for comprehension outcomes. As language proficiency increases, non-linguistic factors, like the executive functions (EF) of working memory, purportedly begin to exert influence on listening performance. EF represents the range of functions performed by the central executive (the processing component) of the working memory system and have largely been studied in the context of updating (revising information held in temporary storage) and shifting (switching attentional focus among mental representations). To test these theoretical claims, the relationship among L2 listening, vocabulary size, updating, and shifting was examined. This included a moderation analysis to investigate whether the relationship between EF and listening was dependent upon vocabulary size. The relationships among the variables were also examined for varied test characteristics to see if contributions from EF and vocabulary differed according to text length or skill measured. In total, 209 Japanese senior high school EFL learners completed a standardized listening test and tests measuring updating, shifting, and vocabulary size. Results from structural equation modeling showed that only vocabulary was predictive of listening performance, regardless of text length or skill measured on the test. Results also showed that vocabulary size did not moderate the relationship between EF and listening, suggesting that the non-linguistic factors were not important for listening regardless of vocabulary size. The findings support claims that linguistic knowledge is most important for listening and that non-linguistic factors are less important for low-level listeners. The findings also contribute empirical evidence for the relationship between L2 listening and EF, a novel conceptualization of the working memory construct.


Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice.
We previously demonstrated the essential role of the flt-1 gene in regulating the development of the cardiovascular system. While the inactivation of the flt-1 gene leads to a very severe disorganization of the vascular system, the primary defect at the cellular level was unknown. Here we report a surprising finding that it is an increase in the number of endothelial progenitors that leads to the vascular disorganization in flt-1(-/-) mice. At the early primitive streak stage (prior to the formation of blood islands), hemangioblasts are formed much more abundantly in flt-1(-/-) embryos. This increase is primarily due to an alteration in cell fate determination among mesenchymal cells, rather than to increased proliferation, migration or reduced apoptosis of flt-1(-/-) hemangioblasts. We further show that the increased population density of hemangioblasts is responsible for the observed vascular disorganization, based on the following observations: (1) both flt-1(-/-) and flt-1(+/+) endothelial cells formed normal vascular channels in chimaeric embryos; (2) wild-type endothelial cells formed abnormal vascular channels when their population density was significantly increased; and (3) in the absence of wild-type endothelial cells, flt-1(-/-) endothelial cells alone could form normal vascular channels when sufficiently diluted in a developing embryo. These results define the primary defect in flt-1(-/-) embryos at the cellular level and demonstrate the importance of population density of progenitor cells in pattern formation.


Progesterone and 1,25-dihydroxyvitamin D₃ inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F.
Class 3 semaphorins (SEMA), SEMA3B and SEMA3F, are secreted proteins that regulate angiogenesis, tumor growth, and metastasis by binding to their transmembrane receptor complex consisting of plexins and neuropilins (NP). Expression of SEMAs and their receptors was assessed in tissue microarrays by immunohistochemistry. SEMA3B, SEMA3F, and plexin A3 were expressed strongly in normal endometrial tissues, whereas grade-dependent decreases were found in endometrial carcinomas. No change was observed in the expression of plexin A1, NP1, and NP2 in normal versus endometrial cancer tissues. Endometrial cancer cells showed decreased expression of SEMA3B, SEMA3F, and plexin A3 compared with their normal counterparts. Treatment of cancer cells with progesterone (P4) and 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] for a period of 72 hours induced a significant upregulation of SEMA3B and SEMA3F as well as inhibited growth of cancer cells by increasing caspase-3 activity. Cotreatment of cell lines with P4 or 1,25(OH)(2)D(3) and their respective antagonists confirmed the specificity of their actions. Transfection of siRNA-targeting SEMA3B and SEMA3F in endometrial cancer cells attenuated P4 or 1,25(OH)(2)D(3)-induced growth inhibition. Restoration of SEMA3B or SEMA3F expression in cancer cells caused growth inhibition, reduced soft agar colony formation, and cell invasiveness by inhibiting expression of matrix metalloproteinase-2 (MMP-2), MMP-9, integrin αvβ3, and proangiogenic genes and by upregulating antiangiogenic genes. Thus, we have identified two new P4 and 1,25(OH)(2)D(3)-regulated antitumor genes for endometrial cancer. These results suggest that the loss of SEMAs contribute to the malignant phenotype of endometrial cancer cells and that reexpression of SEMAs by ectopic expression or with anticancer agents P4 or 1,25(OH)(2)D(3) can be a promising therapeutic treatment against endometrial cancer.


Current and emerging treatments for vitiligo.
Clinicians should be aware that vitiligo is not merely a cosmetic disease and that there are safe and effective treatments available for vitiligo. It is important to recognize common and uncommon presentations and those with active disease, as well as their implications for clinical management; these were discussed in the first article in this continuing medical education series. Existing treatments include topical and systemic immunosuppressants, phototherapy, and surgical techniques, which together may serve to halt disease progression, stabilize depigmented lesions, and encourage repigmentation. We discuss how to optimize the currently available treatments and highlight emerging treatments that may improve treatment efficacy in the future.


Post-translational protein modification by carotenoid cleavage products.
Carotenoids are known to generate various aldehydes, known as carotenoid-derived aldehydes (CDAs), which could efficiently react with protein or DNA. In this in vitro model study, interaction between CDA and protein has been studied. Various proteins were incubated with CDA, and protein modification and adduct formation were confirmed by using matrix-assisted laser desorption and ionization time-of-flight, amino acid analysis, and measuring enzyme activity on modification with CDA. Using radiolabeled NaB((3) H)H(4) and Raney nickel as well as sulfhydryl assay (Ellman's reagent), we confirmed that CDA could conjugate with cysteine through a thioether linkage. The carbonyl assay using 2,4-dinitrophenylhydrazine revealed the possible involvement of Schiff's base reaction between CDA and lysine. The adducts formed between β-apo-8-carotenal (BA8C) and N-acetylcysteine and BA8C and N-acetyllysine were confirmed by HPLC and ESI-MS. Our results suggest that CDA could alter protein function by post-translational interaction with cysteine and lysine by thioether linkage and by schiff's based bonds, respectively. Thus, the formation of CDA adducts with proteins could alter functional properties of proteins responsible for maintaining cell homeostasis and thereby cause cellular toxicity. In view of these observations, further studies are required to understand the delicate balance between beneficial and/or harmful effects of carotenoids as a dietary supplement to slow age-related macular degeneration progression.


Enhancing sensitivity and selectivity of long-period grating sensors using structure-switching aptamers bound to gold-doped macroporous silica coatings.
High surface area, sol-gel derived macroporous silica films doped with gold nanoparticles (AuNP) are used as a platform for high-density affinity-based immobilization of functional structure-switching DNA aptamer molecules onto Michelson interferometer long-period grating (LPG) fiber sensors, allowing for label-free detection of small molecular weight analytes such as adenosine triphosphate (ATP). The high surface area afforded by the sol-gel derived material allowed high loading of DNA aptamers, while the inclusion of gold nanoparticles within the silica film provided a high refractive index (RI) overlay, which is required to enhance the sensitivity of the LPG sensor according to our numerical simulations. By using a structure-switching aptamer construct that could release an oligonucleotide upon binding of ATP, the effective change in RI was both enhanced and inverted (i.e., binding of ATP caused a net reduction in molecular weight and refractive index), resulting in a system that prevented signals originating from nonspecific binding. This is the first report on the coupling of aptamers to LPG fiber sensors and the first use of high RI AuNP/silica films as supports to immobilize biomolecules onto the LPG sensor surface. The dual functionality of such films to both improve binding density and LPG sensor cladding refractive index results in a substantial enhancement in the sensitivity of such sensors for small molecule detection.


The effects of Brief Behavioral Activation Therapy for Depression on cognitive control in affective contexts: An fMRI investigation.
Unipolar major depressive disorder (MDD) is characterized by impaired cognitive control in affective contexts, but the potential for psychotherapy to affect the neural correlates of these functions has not been evaluated. Twelve adults with and 15 adults without MDD participated in two identical functional magnetic resonance imaging (fMRI) scans that utilized a task requiring cognitive control in both sad and neutral contexts. Between scans, MDD outpatients received Behavioral Activation Therapy for Depression, a psychotherapy modality designed to increase engagement with positive stimuli and reduce avoidance behaviors. Seventy-five percent of adults with MDD were treatment responders, achieving post-treatment Hamilton Rating Scale for Depression score of six or below. Consistent with predictions, psychotherapy resulted in decreased activation in response to cognitive control stimuli presented within a sad context in prefrontal structures, including the paracingulate gyrus, the right orbital frontal cortex, and the right frontal pole. Furthermore, the magnitude of pretreatment activation in the paracingulate gyrus cluster responsive to psychotherapy predicted the magnitude of depressive symptom change after psychotherapy. Replication with larger samples is needed, as are follow-up studies that involve placebo control groups, wait-list control groups, and alternative forms of antidepressant intervention. Behavioral Activation Therapy for Depression improves depressive symptoms and concomitantly influences brain systems mediating cognitive control in affective contexts.


Assessments of risky driving: a Go/No-Go simulator driving task to evaluate risky decision-making and associated behavioral patterns.
This study sought to develop and validate a Go/No-Go Simulator Driving Task (G/NG-SDT) to evaluate driver risky decision-making and associated behavioral assessments at a situation-specific level. Eighty-four participants were instructed to complete a route in as short time as possible, but avoiding any violations or crashes. To achieve this aim, they had to decide to go or wait in the dilemma scenes, paired with the baseline scenes in several scenarios. High-risk drivers with more Go decisions demonstrated more violations, in both simulator tasks and real road driving, as well as higher scores of Driving Behavior Questionnaire (DBQ) violations and more Balloon Analogue Risk Task (BART) pumps. These high-risk drivers also showed distinguishable behavioral patterns in simulator driving, moderated by the specific driving situations (e.g. scenario and scene). Several behavior assessments were consistently distinguishable in all tested situations, qualified as robust indictors to predict risk-taking in more general driving situations.


Shared decision making in patients with osteoarthritis of the hip and knee: results of a randomized controlled trial.
Despite evidence that shared decision-making tools for treatment decisions improve decision quality and patient engagement, they are not commonly employed in orthopaedic practice. The purpose of this study was to evaluate the impact of decision and communication aids on patient knowledge, efficiency of decision making, treatment choice, and patient and surgeon experience in patients with osteoarthritis of the hip or knee. One hundred and twenty-three patients who were considered medically appropriate for hip or knee replacement were randomized to either a shared decision-making intervention or usual care. Patients in the intervention group received a digital video disc and booklet describing the natural history and treatment alternatives for hip and knee osteoarthritis and developed a structured list of questions for their surgeon in consultation with a health coach. Patients in the control group received information about the surgeon's practice. Both groups reported their knowledge and stage in decision making and their treatment choice, satisfaction, and communication with their surgeon. Surgeons reported the appropriateness of patient questions and their satisfaction with the visit. The primary outcome measure tracked whether patients reached an informed decision during their first visit. Statistical analyses were performed to evaluate differences between groups. Significantly more patients in the intervention group (58%) reached an informed decision during the first visit compared with the control group (33%) (p = 0.005). The intervention group reported higher confidence in knowing what questions to ask their doctor (p = 0.0034). After the appointment, there was no significant difference between groups in the percentage of patients choosing surgery (p = 0.48). Surgeons rated the number and appropriateness of patient questions higher in the intervention group (p < 0.0001), reported higher satisfaction with the efficiency of the intervention group visits (p < 0.0001), and were more satisfied overall with the intervention group visits (p < 0.0001). Decision and communication aids used in orthopaedic practice had benefits for both patients and surgeons. These findings could be important in facilitating adoption of shared decision-making tools into routine orthopaedic practice.