The Profunda Artery Perforator Flap: Investigating the Perforasome Using Three-Dimensional Computed Tomographic Angiography.
The profunda artery perforator flap has been emerging as an alternative method of autologous breast reconstruction. This flap uses upper posterior thigh tissue. The profunda artery perforator perforasome is investigated using three-dimensional computed tomographic angiography. Ten cadaveric thighs were dissected centered over the profunda artery perforator. The perforator was injected with contrast medium and the flap was then subjected to computed tomographic scanning using a GE Lightspeed 16-slice scanner. The three-dimensional images were viewed, and measurements were obtained using Aquarius software, including horizontal and vertical extensions of the flap and areas of perfusion. Clinical examples are presented. A profunda artery perforator (occasionally two) was consistently found in the upper medial thigh region, posterior to the gracilis muscle. The area of vascularity shown by the spread of contrast extends inferiorly beyond the usual lower border of the profunda artery perforator flap, which is usually 7 cm wide. In injected cadaveric flaps, the mean horizontal dimension was 16.7 cm and the mean vertical dimension was 16.5 cm. The mean area perfused was 8812 cm. The profunda artery perforator flap is a vascularly sound flap, and is a good option for autologous breast reconstruction. Advantages include a reliable pedicle, no position changes required, and possibly an improved donor-site contour from a thigh lift. It is an excellent alternative to abdominally based free flaps and can also be used in conjunction with other flaps for further volume enhancement.


Genetics of antigenic variation in Plasmodium falciparum.
Malaria caused by the protozoan parasite Plasmodium falciparum is characterized by long-term, persistent infections that can last for many months. The ability of this parasite to avoid clearance by the human immune system is dependent on its capacity to continuously alter the surface exposed antigenic proteins that that are vulnerable to antibody recognition and attack, a process called antigenic variation. Significant work in recent years has contributed to our understanding of the mechanisms underlying this process, including the genes encoding the antigenic proteins and the DNA sequence elements that control their expression. In addition, the epigenetic "marks" that are associated with activation and silencing of individual genes have been extensively characterized. These studies have led to a model that includes multiple layers of regulation that ultimately lead to the tight coordination of expression of the genes responsible for antigenic variation by malaria parasites. Here we review some more recent data that adds additional complexity to our understanding of these regulatory layers.


Fine-scale activity patterns in high-level visual areas encode the category of invisible objects.
When incompatible images are presented to the two eyes, one image can dominate awareness while the other is suppressed and invisible. We used high-resolution functional neuroimaging in humans to investigate the neural representation of such suppressed stimuli. Overall responses of high-level ventral visual areas to two different types of invisible object stimuli (faces and houses) were very weak and did not differ in amplitude. Despite this, fine-grained spatial activity patterns within these areas allowed us to predict significantly better than chance whether an observer was presented with face or house stimuli not only when these stimuli were visible but also when they were suppressed and entirely invisible. These findings demonstrate the presence of category-specific information in high-level visual areas during profound interocular suppression of object stimuli that can only be retrieved when the fine-scale pattern of activity within these areas is taken into account.


The emergence of qnr-mediated quinolone resistance among Enterobacteriaceae in Jamaica.
Quinolone resistance is usually caused by various chromosomal mutations, but has been more recently associated with plasmids which carry the qnr determinant. The aim of this study is to investigate the prevalence of qnr genes in clinical isolates of Enterobacteriaceae in Jamaica. A total of 255 non-duplicate fluoroquinolone-resistant Enterobacteriaceae clinical isolates, comprising 232 Escherichia coli, 20 Klebsiella species and three Enterobacter spp were collected between October 2007 and November 2008 from hospitalized patients in Jamaica. The presence of the qnr gene was screened by PCR using specific primers for qnrA, qnrB and qnrS in extracted plasmid DNA. Eighty-three (32.5%) of these isolates were qnr-positive, of which 47.0% housed the qnrA gene only, 1.2% qnrB and 9.6% qnrS only. Another 36.1% possessed both qnrA and qnrS genes. Approximately 30% of the quinolone-resistant E coli isolates harboured the qnr gene while 50% Klebsiella spp and all Enterobacter spp were positive. The emergence of qnr-mediated quinolone resistance among clinical Enterobacteriaceae isolates is described for the first time in Jamaica.


Teaching Filipino physiotherapists on-shore: an Australian-Filipino collaborative postgraduate health education initiative.
This paper outlines a collaborative, cross-national educational initiative, commenced in 2001, in which an Australian university provided clinical and research education assistance to a Filipino University. The aim was to establish the first Filipino Master of Science in Physical Therapy program that would train physiotherapists in their home country using best available content and teaching expertise. Principles of quality transnational education underpinned the program design and contractual agreements. Australian educational input was tailored to local constraints to ensure efficient and effective delivery of high quality, relevant material. Approximately 60% of the inaugural program was delivered by Australian educators in one-week intensive courses on-shore in the Philippines, using local facilities and case-scenarios. Follow-up support and evaluation were provided by video, email, written workbooks and assignments once these educators returned to Australia. Filipino graduates, who were competent with course content, taught the remaining subjects. In line with an aim of empowering Filipino graduates to assume responsibility for teaching all aspects of the program by 2006, the Australian educators are now teaching less than 25% of the course content to subsequent student cohorts. After 2006, they will provide mentorship only to the program. In 2003, 12 students in the first cohort graduated with Master of Science in Physical Therapy from the University of Santo Tomas (UST). Twenty-four students subsequently enrolled in the second cohort (commenced 2003) and 21 students into the third cohort (commenced 2004). Six of the inaugural graduate cohort are currently acting as tutors for the Australian educators and will assume full teaching roles in 2006. Comparison of feedback from student evaluations at UST indicates significant improvements in teaching quality for the graduates from the inaugural program. Research activity and publications have also increased as a result of completion of the program. Such a cross-institutional, cross-national program has not been described previously for physiotherapy, and no other similar health program (for nursing) evaluated the educational processes in the manner used in this program. The program met its aims and has produced sustainable educational outcomes and outputs. Future scholarly activities between the two institutions include extension of postgraduate training to other health disciplines, cross-institutional PhD student enrollments and collaborative research.


Prevalence and pattern of basal skull fracture in head injury patients in an academic hospital.
Basal skull fractures (BSFs) have been reported to be a major cause of morbidity and mortality in the literature, particularly in young male patients. However, there are limited data available on the aetiology, prevalence and patterns of such observed in South Africa. To evaluate the prevalence and pattern of BSF in head injury patients referred to Dr George Mukhari Academic Hospital, Gauteng, South Africa. Patients of all ages with head injuries were considered for the study, and those who met the inclusion criteria were scanned using a 128-slice multidetector helical computed tomography (CT) machine after obtaining consent. Data were prospectively obtained over a 6-month period, interpreted on an advanced workstation by two readers and statistically analysed. The prevalence of BSF in this study was found to be 15.2%. The majority of patients (80.5%) were under 40 years old, with a male to female ratio of 3:1. The most common aetiology of BSF was assault, which accounted for 46% of cases. The middle cranial fossa was the most frequently fractured compartment, while the petrous bone was the most commonly fractured bone. There was a statistically significant association between head injury severity and BSF, and between the number of fracture lines and associated signs of BSF (p < 0.001). The sensitivity of clinical signs in predicting BSF was 31%, while specificity was 89.3% (p = 0.004). The prevalence and pattern of BSF found were consistent with data from previously published studies, although, dissimilarly, assault was found to be the most common aetiology in this study.


Experimental design for gene expression microarrays.
We examine experimental design issues arising with gene expression microarray technology. Microarray experiments have multiple sources of variation, and experimental plans should ensure that effects of interest are not confounded with ancillary effects. A commonly used design is shown to violate this principle and to be generally inefficient. We explore the connection between microarray designs and classical block design and use a family of ANOVA models as a guide to choosing a design. We combine principles of good design and A-optimality to give a general set of recommendations for design with microarrays. These recommendations are illustrated in detail for one kind of experimental objective, where we also give the results of a computer search for good designs.


Feeding-induced stimulation of luteinizing hormone secretion in male rhesus monkeys is not dependent on a rise in blood glucose concentration.
Recent studies have suggested a role for glucose availability in the central control of reproductive function. Various experimental paradigms have shown that a large pharmacological reduction in circulating or cellular glucose levels can suppress LH secretion, ovulation, and reproductive behavior. In contrast, states of undernutrition, which are also associated with a suppression of reproductive function, are accompanied by very mild changes in circulating glucose levels. In monkeys, 1 day of fasting leads to a significant suppression of LH secretion before any significant change in blood glucose levels, and by 2 days of fasting, circulating glucose levels only decrease by about 20%. Refeeding a normal meal after 2 days of fasting results in a restoration of euglycemia and a rapid stimulation of LH secretion. To test the hypothesis that physiological changes in glucose levels occurring during brief periods of fasting and refeeding can modulate LH secretion, we provided monkeys that had been fasted for 2 days with meals that differed in the ability to raise blood glucose levels. Meals consisting of mixed nutrients, carbohydrate only, or protein and fat were provided to monkeys through indwelling gastric cannulas. Mixed nutrient infusions and carbohydrate infusions caused a rise in blood glucose as well as a robust stimulation of LH secretion. However, protein and fat meals also stimulated LH secretion, even though no rise in blood glucose concentrations occurred. Thus, the restoration of pulsatile LH secretion when fasted animals are refed is not dependent on an elevation in circulating glucose levels. These results do not support the hypothesis that physiological changes in circulating glucose levels play a necessary role in mediating the changes in LH secretion that occur with fasting and refeeding. Alternatively, these results support the hypothesis that the availability of metabolizable fuels, regardless of their nature, provides a critical cue that regulates the central drive to the reproductive axis under physiological conditions of fasting and feeding.


Immune Reactivity in Mice Thymectomized Soon after Birth: Normal Response after Pregnancy.
Female CBA mice that had been thymectomized soon after birth were mated with normal male T6 mice. After delivery of at least one litter, the parous females exhibited normal immune reactions to sheep erythrocytes and skin homografts. The transplacental passage of a humoral substance from the thymus glands of the developing fetuses is suggested as the mechanism responsible for the restoration of immunological responsiveness in neonatally thymectomized parous female mice.


Chromosome 18 suppresses prostate cancer metastases.
Loss of heterozygosity and allelic imbalance data has shown that there are two distinct regions of loss on chromosome 18q associated with the progression of prostate cancer (CaP). To investigate the functional significance of chromosome 18q loci in CaP, we utilized the technique of microcell-mediated chromosome transfer to introduce an intact chromosome 18 into the human prostate cancer cell line, PC-3. Three of the resulting hybrid lines were compared to the PC-3 cells in vitro and in vivo. The hybrid cell lines, containing an intact copy of the introduced chromosome 18, exhibited a substantial reduction in anchorage-dependent and independent growth in vitro. These hybrid cell lines also made smaller tumors in nude mice following subcutaneous injection compared to PC-3 cells. Because tumor growth was not completely eliminated by introduction of chromosome 18, we assessed the ability of the hybrids to metastasize to bone after intra-cardiac inoculation in a nude mouse model. Mice inoculated with PC-3 hybrids containing intact copies of chromosome 18 had significantly fewer bone metastases and dramatically improved survival compared to PC-3 cells. In addition, the introduction of chromosome 18 significantly reduced tumor burden in extraskeletal sites. This was not because of differences in growth rates because mice bearing hybrids were monitored for metastases over twice as long as mice bearing PC-3 cells. Taken together, these data suggest that chromosome 18 has a functional role in CaP to suppress growth and metastases. Identification of the responsible gene(s) may lead to molecular targets for drug discovery.


Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats.
The function of the endothelium is impaired in hypertension. In spontaneously hypertensive rats (SHR), acetylcholine-induced relaxation is decreased and serotonin-induced constriction is increased. The goal of our study was to evaluate the effect of a long-term treatment with cilazapril, a new angiotensin converting enzyme inhibitor, or hydralazine, a vasodilator, on the endothelium-dependent responses in aorta of SHR. Wistar-Kyoto rats were used as normotensive reference. Isolated aortic rings with or without endothelium were suspended in organ chambers. The rings with intact endothelium were contracted with norepinephrine. Acetylcholine-induced relaxation was markedly enhanced by cilazapril treatment. The tension achieved at maximal relaxation was 8 +/- 4% of norepinephrine contraction in the cilazapril-treated SHR versus 55 +/- 5% in the untreated SHR (p less than 0.001). Hydralazine had no significant effect. The effect of serotonin was also markedly modified by cilazapril. In untreated SHR, serotonin induced the release of a vasoconstrictor substance by the endothelium as assessed by the ratio of maximal tension induced by serotonin in rings with endothelium over maximal tension in rings without endothelium, which was greater than 1. This ratio was reversed in cilazapril-treated SHR but not in hydralazine-treated SHR. Captopril had effects similar to cilazapril. Finally, evaluation of carotid arteries showed that cilazapril also prevented morphological changes of the intima in SHR (i.e., infiltration by mononuclear cells). We conclude that angiotensin converting enzyme inhibitors prevent the functional and morphological alterations in endothelium that are found in hypertension and speculate that this action might participate in their antihypertensive effect.


The impact of salience and visual working memory on the monitoring and control of saccadic behavior: An eye-tracking and EEG study.
In a concurrent eye-tracking and EEG study, we investigated the impact of salience on the monitoring and control of eye movement behavior and the role of visual working memory (VWM) capacity in mediating this effect. Participants made eye movements to a unique line-segment target embedded in a search display also containing a unique distractor. Target and distractor salience was manipulated by varying degree of orientation offset from a homogenous background. VWM capacity was measured using a change-detection task. Results showed greater likelihood of incorrect saccades when the distractor was relatively more salient than when the target was salient. Misdirected saccades to salient distractors were strongly represented in the error-monitoring system by rapid and robust error-related negativity (ERN), which predicted a significant adjustment of oculomotor behavior. Misdirected saccades to less-salient distractors, while arguably representing larger errors, were not as well detected or utilized by the error/performance-monitoring system. This system was instead better engaged in tasks requiring greater cognitive control and by individuals with higher VWM capacity. Our findings show that relative salience of task-relevant and task-irrelevant stimuli can define situations where an increase in cognitive control is necessary, with individual differences in VWM capacity explaining significant variance in the degree of monitoring and control of goal-directed eye movement behavior. The present study supports a conflict-monitoring interpretation of the ERN, whereby the level of competition between different responses, and the stimuli that define these responses, was more important in the generation of an enhanced ERN than the error commission itself.


Multianalyte profiling of serum cytokines for detection of pancreatic cancer.
Early detection of pancreatic cancer might improve clinical outcome. Significant alterations in the levels of individual serum cytokines have been reported in pancreatic cancer. We hypothesized that a multicytokine panel could serve as biomarkers for pancreatic cancer. To evaluate the diagnostic utility of such a panel, we have utilized a novel multianalyte LabMAP profiling technology that allows simultaneous measurement of multiple markers. In this study, a panel of 31 serological markers including cytokines, chemokines, growth and angiogenic factors in combination with CA 19-9 was analyzed in sera of pancreatic cancer patients, patients with chronic pancreatitis, and matched control healthy subjects. Statistical analysis identified a multicytokine panel that was able to distinguish pancreatic cancer from healthy controls with a sensitivity of 85.7% and specificity of 92.3%, which was superior to performance of CA 19-9 alone. Importantly, a multicytokine panel allowed the discrimination of pancreatic cancer from chronic pancreatitis with high sensitivity of 98% and specificity of 96.4%. In conclusion, we demonstrated that analysis of multiple serum cytokines using a novel LabMAP technology is a promising approach for development of a diagnostic assay for pancreatic cancer.


Circulating endothelial progenitor cells predict coronary artery disease severity.
Circulating endothelial progenitor cells (EPCs) may play an important role in the body's defense against atherosclerosis. Previous studies have shown an association between EPC numbers and the presence of traditional coronary artery disease (CAD) risk factors. The relationship between EPC numbers and the severity of atherosclerosis is, however, not known. EPC counts were measured by quantitative cell culture in 122 patients undergoing diagnostic cardiac catheterization. The association between patients' EPC count and the presence of multivessel CAD and traditional cardiac risk factors was assessed using logistic regression analysis. The median age of the study population was 58 years; 37% had multivessel CAD, 29% had diabetes, and 14% had myocardial infarction this admission. EPC counts did not vary significantly with most established cardiac risk factors but were lower in diabetics versus nondiabetics and trended toward lower numbers in older patients. EPC count was the second strongest predictor of multivessel CAD, after patient age. Patients with multivessel disease had significantly lower EPC counts than those without (median, 3 vs 13; P < .0088). For every 10 colony forming unit increase in EPCs, a patient's likelihood for multivessel CAD declined by 20% (P < .001). This study demonstrates an inverse relationship between circulating EPCs and CAD severity, independent of traditional risk factors. If confirmed in ongoing studies, this may represent an important new diagnostic and therapeutic target for coronary disease treatment.


CommunityStat: A Public Health Intervention to Reduce Opioid Overdose Deaths in Burlington, Vermont, 2017-2020.
From 2017 to early 2020, the US city of Burlington, Vermont led a county-wide effort to reduce opioid overdose deaths by concentrating on the widespread, low-barrier distribution of medications for opioid use disorder. As a small city without a public health staff, the initiative was led out of the police department-with an understanding that it would not be enforcement-oriented-and centered on a local adaptation of CompStat, a management and accountability program developed by the New York City Police Department that has been cited as both yielding improvements in public safety and overemphasizing counterproductive police performance metrics if not carefully directed. The initiative was instrumental to the implementation of several novel interventions: low-threshold buprenorphine prescribing at the city's syringe service program, induction into buprenorphine-based treatment at the local hospital emergency department, elimination of the regional waiting list for medications for opioid use disorder (MOUD), and the de-facto decriminalization of diverted buprenorphine by the chief of police and county prosecutor. An effort by local legislators resulted in a state law requiring all inmates with opioid use disorder be provided with MOUD as well. By the end of 2018, these interventions were collectively associated with a 50% (17 vs. 34) reduction in the county's fatal overdose deaths, while deaths increased 20% in the remainder of Vermont. The reduction was sustained through the end of 2019. This article describes the effort undertaken by officials in Burlington to implement these interventions. It provides an example that other municipalities can use to take an evidence-based approach to reducing opioid deaths, provided stakeholders assent to sustained collaboration in the furtherance of a commitment to save lives. In doing so, it highlights that police-led public health interventions are the exception, and addressing the overdose crisis will require reform that shifts away from criminalization as a community's default framework for substance use.


Measuring Inpatient Rehabilitation Facility Quality of Care: Discharge Self-Care Functional Status Quality Measure.
To describe the calculation and psychometric properties of the discharge self-care functional status quality measure implemented in the Centers for Medicare & Medicaid Services' (CMS) Inpatient Rehabilitation Facility (IRF) Quality Reporting Program on October 1, 2016. Medicare fee-for-service (FFS) patients from 38 IRFs that participated in the CMS Post-Acute Care Payment Reform Demonstration were included in this cohort study. Data came from the Continuity Assessment Record and Evaluation Item Set, IRF-Patient Assessment Instrument, and Medicare claims. For each patient, we calculated an expected discharge self-care score, risk-adjusted for demographic and baseline clinical characteristics. The performance score of each IRF equaled the percentage of patient stays where the observed discharge self-care score met or exceeded the expected score. We assessed the measure's discriminatory ability across IRFs and reliability. IRFs. Medicare FFS patients aged ≥21 years (N=4769). Not applicable. Facility-level discharge self-care quality measure performance score. A total of 4769 patient stays were included; 57% of stays were in women, and 12.1% were in patients aged <65 years. Stroke was the most common diagnosis (21.8%). The mean±SD performance score was 55.1%±16.6% (range, 25.8%-100%). About 54% of IRFs had scores significantly different from the percentage of stays that met or exceeded the expected discharge self-care score in the overall demonstration sample. The quality measure showed strong reliability, with intraclass correlation coefficients of .91. The discharge self-care quality measure showed strong discriminatory ability and reliability, representing an important initial step in evaluation of IRF self-care outcomes. A wide range in performance scores suggested a gap in quality of care across IRFs. Future work should include testing the measure with nationwide data from all IRFs.


Late-onset myopathy of the posterior calf muscles mimicking Miyoshi myopathy unrelated to dysferlin mutation: a case report.
Miyoshi myopathy, a type of distal myopathy with predominant involvement of the posterior calf muscles, has been assigned to mutations in the dysferlin gene. However, many of the late-onset limb-girdle and distal myopathies that resemble dysferlinopathy or Miyoshi myopathy remain unclassified, even after extensive immunohistological and genetic analysis. We report the case of a 59-year-old Caucasian man with distal myopathy and exercise-induced myalgia, preferentially of the leg muscles, closely resembling the Miyoshi phenotype. Magnetic resonance imaging of his calf muscles showed typical fatty replacement of the medial heads of the gastrocnemius muscles and soleus muscles, with progression to the adductor longus muscles over a time course of two years. However, genetic analysis revealed that the phenotype of our patient was not related to a mutation in the dysferlin gene but to a novel homozygous splice mutation in the anoctamin 5 gene. Mutations in the anoctamin 5 gene have so far been identified only in some cases of limb-girdle and distal myopathy. Mutations in the anoctamin 5 gene have been assigned to limb-girdle muscular dystrophy type 2L, while distal Miyoshi-like phenotypes have been classified as Miyoshi myopathy type 3. The case presented in this report further strengthens the underlying genetic heterogeneity in Miyoshi myopathy-like phenotypes and adds another family to non-dysferlin, Miyoshi myopathy type 3 of late-onset. Furthermore, our case supports the recent observation that anoctamin 5 mutations are a primary cause of distal non-dysferlin myopathies. Therefore, given the increasing number of anoctamin 5 mutations in Miyoshi-like phenotypes, genetic analysis should include an anoctamin 5 screen in late-onset limb-girdle and distal myopathies.


Influence of an unexpected perturbation on adaptive gait behavior.
During locomotion over uneven terrain, gait must be adapted to avoid a trip. In the event of a foot-obstacle contact, the body reactively responds to the perturbation. However, it is unknown if any proactive adjustments are made in subsequent strides to reduce the likelihood of another contact, and how long any proactive adaptations persist. This study examined gait behavior while stepping over a 10cm obstacle placed in the middle of an 8m walkway. The four obstacle crossings that preceded a spontaneous obstacle contact were compared to the eight obstacle crossings subsequent to the contact. Foot position before the obstacle was not modified following the obstacle contact. However, toe clearance and peak toe elevation increased in the limb that was tripped; the unperturbed limb showed no differences. These findings demonstrate that the sensory information of the perturbed limb proactively influenced the ipsilateral but not the contralateral limb, supporting the idea that the lead and trail limb are controlled independently during obstacle crossing. The proactive adaptation lasted for at least eight trials, suggesting that an unexpected perturbation influences the control of adafptive gait well after obstacle contact.


Neurobeachin and the Kinesin KIF21B Are Critical for Endocytic Recycling of NMDA Receptors and Regulate Social Behavior.
Autism spectrum disorders (ASDs) are associated with mutations affecting synaptic components, including GluN2B-NMDA receptors (NMDARs) and neurobeachin (NBEA). NBEA participates in biosynthetic pathways to regulate synapse receptor targeting, synaptic function, cognition, and social behavior. However, the role of NBEA-mediated transport in specific trafficking routes is unclear. Here, we highlight an additional function for NBEA in the local delivery and surface re-insertion of synaptic receptors in mouse neurons. NBEA dynamically interacts with Rab4-positive recycling endosomes, transiently enters spines in an activity-dependent manner, and regulates GluN2B-NMDAR recycling. Furthermore, we show that the microtubule growth inhibitor kinesin KIF21B constrains NBEA dynamics and is present in the NBEA-recycling endosome-NMDAR complex. Notably, Kif21b knockout decreases NMDAR surface expression and alters social behavior in mice, consistent with reported social deficits in Nbea mutants. The influence of NBEA-KIF21B interactions on GluN2B-NMDAR local recycling may be relevant to mechanisms underlying ASD etiology.


Factors contributing to variability of quantitative viral PCR results in proficiency testing samples: a multivariate analysis.
While viral load testing has gained widespread acceptance, a primary limitation remains the variability of results, particularly between different laboratories. While some work has demonstrated the importance of standardized quantitative control material in reducing this variability, little has been done to explore other important factors in the molecular amplification process. Results of 185 laboratories enrolled in the College of American Pathologists (CAP) 2009 viral load proficiency testing (PT) survey (VLS) were examined. This included 165 labs (89.2%) testing for cytomegalovirus (CMV), 99 (53.5%) for Epstein-Barr virus (EBV), and 64 (34.6%) for BK virus (BKV). At the time of PT, laboratories were asked a series of questions to characterize their testing methods. The responses to these questions were correlated to mean viral load (MVL) and result variability (RV). Contribution of individual factors to RV was estimated through analysis of variance (ANOVA) modeling and the use of backward selection of factors to fit those models. Selection of the quantitative calibrator, commercially prepared primers and probes, and amplification target gene were found most prominently associated with changes in MVL or RV for one or more of the viruses studied. Commercially prepared primers and probes and amplification target gene made the largest contribution to overall variability. Factors contributing to MVL and RV differed among viruses, as did relative contribution of each factor to overall variability. The marked variability seen in clinical quantitative viral load results is associated with multiple aspects of molecular testing design and performance. The reduction of such variability will require a multifaceted approach to improve the accuracy, reliability, and clinical utility of these important tests.


Association Study of Exon Variants in the NF-κB and TGFβ Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy.
The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8 × 10-6). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-κB and TGFβ pathways. The minor allele at rs1883832, in the 5'-untranslated region of CD40, was associated with earlier LoA (p = 3.5 × 10-5). This allele diminishes the expression of CD40, a co-stimulatory molecule for T cell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD.


Twenty percent better with 20 micrograms? A qualitative study of psychedelic microdosing self-rapports and discussions on YouTube.
Psychedelic microdosing is the trending practice of using tiny repeated doses of psychedelic substances to facilitate a range of supposed benefits. With only a few published studies to date, the subject is still under-researched, and more knowledge is warranted. Social media and internet discussion forums have played a vital role in the growing visibility of the microdosing phenomenon, and the present study utilized YouTube contents to improve comprehension of the microdosing practice as well as the social interactions and discussions around microdosing. Microdosing self-disclosure in YouTube videos and their following comments were qualitatively analyzed by inductive thematic analysis. Various software was utilized to enable gathering and sorting relevant data. Microdosing of psychedelic substances, primarily LSD and psilocybin, was used for therapeutic and enhancement purposes, and predominantly beneficial effects were reported. Many different applications and outcomes were discussed, and therapeutic effects for depression appeared especially noteworthy. Intentions for use were recognized as an influencing factor for the progression and outcomes of microdosing. The function of social interactions was mainly to discuss views on the microdosing phenomenon, strategies for optimal results, minimize risks, and share emotional support. Potentially, microdosing could provide some of the same benefits (for certain conditions) as full-dose interventions with less risk of adverse reactions related to the sometimes intense experiences of higher doses. Microdosing may well also mean additional benefits, as well as risks, through the repeated exposure over extended periods.


Changes in functional status among persons over age sixty-five undergoing total knee arthroplasty.
This study assessed changes in physical functional status following receipt of total knee arthroplasty (TKA) for patients diagnosed with osteoarthritis (OA) of the knee in a national sample of persons aged 65+ in the United States relative to a sample of similar OA patients who did not receive TKA. Data from the Health Retirement Survey (HRS) and linked Medicare claims from 1994 to 2006 were used to identify persons with diagnoses of OA of the lower leg who received a TKA (n = 516) and those who did not receive TKA (n = 1756). Predicted probabilities of receiving total knee arthroplasty from logit analysis were used for matching TKA and comparison groups on demographic, socioeconomic, and baseline functional status factors. Functional status measures were: mobility, gross motor function, large muscle, and limitations in activities of daily living (ADL). Average treatment effects of the treated (ATT), which compares changes in functional status between those who received TKA with similar individuals who did not receive TKA, were computed using propensity score matching. Mobility (average treatment effect of the treated (ATT = 0.315; 95% CI: 0.118-0.512), gross motor function (ATT = 0.314; 95% CI: 0.156-0.472), and ADL limitations (ATT = 0.174; 95% CI: 0.055-0.293), improved among persons receiving TKA relative to the comparison group. Relative to the mean values of the physical function at baseline, mobility, gross motor function, and ADL limitations persons receiving TKA had better functional outcomes than the comparison group by 17.5, 39.3, and 46.9 percent, respectively. TKA is effective in improving functional status in elderly persons.


The impact of genotype on outcomes in individuals with Duchenne muscular dystrophy: A systematic review.
Duchenne muscular dystrophy (DMD) is associated with progressive muscle weakness, loss of ambulation (LOA), and early mortality. In this review we have synthesized published data on the clinical course of DMD by genotype. Using a systematic search implemented in Medline and Embase, 53 articles were identified that describe the clinical course of DMD, with pathogenic variants categorizable by exon skip or stop-codon readthrough amenability and outcomes presented by age. Outcomes described included those related to ambulatory, cardiac, pulmonary, or cognitive function. Estimates of the mean (95% confidence interval) age at LOA ranged from 9.1 (8.7-9.6) years among 90 patients amenable to skipping exon 53 to 11.5 (9.5-13.5) years among three patients amenable to skipping exon 8. Although function worsened with age, the impact of genotype was less clear for other outcomes (eg, forced vital capacity and left ventricular ejection fraction). Understanding the distribution of pathogenic variants is important for studies in DMD, as this research suggests major differences in the natural history of disease. In addition, specific details of the use of key medications, including corticosteroids, antisense oligonucleotides, and cardiac medications, should be reported.


Organotypic in vitro block culture model to investigate tissue-implant interface. An experimental study on pig mandible.
In vitro studies of implant-tissue attachment are primarily based on two-dimensional cell culture models, which fail to replicate the three-dimensional native human oral mucosal tissue completely. Thus, the present study aimed to describe a novel tissue culture model using pig mandibular block including alveolar bone and gingival soft tissues to evaluate the tissue attachment to titanium implant provided with hydrothermally induced TiO2 coating. Tissue attachment on TiO2 coated and non-coated implants were compared. Ti-6Al-4V alloy posts were used to function as implants that were inserted in five pig mandibles. Implants were delivered with two different surface treatments, non-coated (NC) titanium and hydrothermal induced TiO2 coated surfaces (HT). The tissue-implant specimens were cultured at an air/liquid interface for 7 and 14 days. The tissue-implant interface was analyzed by histological and immunohistochemical stainings. The microscopic evaluation suggests that pig tissue explants established soft and hard tissue attachment to both implant surfaces. The epithelial cells appeared to attach to the coated implant. The epithelium adjacent to the implant abutment starts to change its phenotype during the early days of the healing process. New bone formation was seen within small pieces of bone in close contact with the coated implant. In conclusion, this in vitro model maintains the viability of pig tissue and allows histologically and immunohistochemically evaluate the tissue-implant interface. HT-induced TiO2 coating seems to have a favorable tissue response. Moreover, this organotypic tissue culture model is applicable for further studies with quantitative parameters to evaluate adhesion molecules present at the implant-tissue interface.


Aerobic fitness and mode of travel to school in English schoolchildren.
Cycling to school is positively associated with aerobic fitness in Danish schoolchildren and adolescents. The aim of the present study was to determine whether a positive association exists between active travel and aerobic fitness in English schoolchildren, where cycling to school is rare. Participants (n = 6085, 47% girls, aged 10.0-15.9 yr) were recruited as part of the East of England Healthy Hearts study. Mass and stature were measured, and body mass index (BMI) was calculated. Aerobic fitness was assessed using the 20-m shuttle run test (20-mSRT); mode of travel to school and physical activity (PA) were assessed by a questionnaire. Differences in BMI, PA, and fitness by travel mode were assessed by ANOVA and ANCOVA. Participants were categorized as "fit" or "unfit" on the basis of existing cutoffs related to adult health. Logistic regression was applied to calculate age, BMI, and PA-adjusted odds of being classified as fit according to travel mode. Walking was the most common travel mode to school (50%), and cycling was least frequent (8%). Walkers and cyclists of both sexes were significantly fitter than passive transport users, even after controlling for PA. Walking and cycling were associated with an increased likelihood of being categorized as fit in boys and girls. After adjustment for PA, this association remained significant only in girls. No association was observed between travel mode and BMI. These data confirm findings from countries where cycling is very common in showing that cycling to school is positively associated with aerobic fitness. This study adds to the existing literature by showing that walkers and cyclists are more likely to be classified as fit using recognized cut points. Those who walk and cycle to school may, therefore, be at reduced risk for developing chronic diseases in adulthood.


[Preventing deaths from dengue: a space and challenge for primary health care].
Dengue is an arthropod-borne viral disease whose frequency has increased steadily in the Americas over the past 25 years. The type of dengue that carries the highest mortality is the clinical variant known as dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Even though no vaccine or drug against the disease is available, successful management consists of preventing serious illness through patient follow-up and monitoring danger signals so as to be able to initiate aggressive intravenous rehydration and prevent shock or treat it early and successfully. These measures are also useful in preventing other complications, such as massive hemorrhage, disseminated intravascular coagulation, multiple organ failure, and respiratory failure due to non-cardiogenic pulmonary edema. Primary health care (PHC) settings and the community are ideal spaces for this type of preventive management based on health education and active case detection. It involves training all medical and nursing staff, students, and community health workers, as well as reorganizing health care in PHC units and hospitals and redistributing available resources during a dengue epidemic.


Health Implications of Racialized State Violence Against South Asians in the USA.
South Asians, one of the fastest growing ethnic groups in the USA today, trace their roots to countries in the Indian subcontinent (e.g., Bangladesh, Bhutan, India, the Maldives, Nepal, Pakistan, Sri Lanka) and its global diaspora. With a wide range of cultural, religious, and linguistic diversity, as well as immigration experiences and inequality, South Asians have experienced racialized violence and discrimination since first arriving in the USA in the 1700s. Following September 11, 2001, South Asians and other groups racialized as "Brown," including Muslim, Sikh, Middle Eastern, and Arab Americans, have experienced a marked increase in state violence, including racist laws, policies, and immigration enforcement. Despite abundant evidence of the adverse effects of violence on mental and physical health, there is limited research examining the impact of this racialized state violence on the health of South Asians in the USA. We summarize and synthesize existing peer-reviewed and gray literature on the prevalence and types of violence experienced by South Asians in the USA and enumerate their potential detrimental health impacts. We highlight the paucity of public health data and propose a conceptual framework describing how racialized violence and hate have significant implications for health among South Asians in the USA. Ultimately, these findings illuminate the need for change at the highest levels of governance to mitigate and resist hate violence, including through political participation and inclusion and equitable allocation of social and economic resources, to improve the health of South Asians in the USA.


Shifting the Demand for Vaccines: A Review of Strategies.
Vaccines prevent millions of deaths, and yet millions of people die each year from vaccine-preventable diseases. The primary reason for these deaths is that a significant fraction of the population chooses not to vaccinate. Why don't people vaccinate, and what can be done to increase vaccination rates besides providing free and easy access to vaccines? This review presents a conceptual framework, motivated by economic theory, of which factors shift the demand for vaccines. Next, it critically examines the literature on these demand shifters and interventions that target these demand shifters. The review concludes with offering directions for future research and lessons for public health decision making.


Classification of selectively constrained DNA elements using feature vectors and rule-based classifiers.
Scarce work has been done in the analysis of the composition of conserved non-coding elements (CNEs) that are identified by comparisons of two or more genomes and are found to exist in all metazoan genomes. Here we present the analysis of CNEs with a methodology that takes into account word occurrence at various lengths scales in the form of feature vector representation and rule based classifiers. We implement our approach on both protein-coding exons and CNEs, originating from human, insect (Drosophila melanogaster) and worm (Caenorhabditis elegans) genomes, that are either identified in the present study or obtained from the literature. Alignment free feature vector representation of sequences combined with rule-based classification methods leads to successful classification of the different CNEs classes. Biologically meaningful results are derived by comparison with the genomic signatures approach, and classification rates for a variety of functional elements of the genomes along with surrogates are presented.


Total arterial inertance as the fourth element of the windkessel model.
In earlier studies we found that the three-element windkessel, although an almost perfect load for isolated heart studies, does not lead to accurate estimates of total arterial compliance. To overcome this problem, we introduce an inertial term in parallel with the characteristic impedance. In seven dogs we found that ascending aortic pressure could be predicted better from aortic flow by using the four-element windkessel than by using the three-element windkessel: the root-mean-square errors and the Akaike information criterion and Schwarz criterion were smaller for the four-element windkessel. The three-element windkessel overestimated total arterial compliance compared with the values derived from the area and the pulse pressure method (P = 0.0047, paired t-test), whereas the four-element windkessel compliance estimates were not different (P = 0.81). The characteristic impedance was underestimated using the three-element windkessel, whereas the four-element windkessel estimation differed marginally from the averaged impedance modulus at high frequencies (P = 0.0017 and 0.031, respectively). When applied to the human, the four-element windkessel also was more accurate in these same aspects. Using a distributed model of the systemic arterial tree, we found that the inertial term results from the proper summation of all local inertial terms, and we call it total arterial inertance. We conclude that the fourelement windkessel, with all its elements having a hemodynamic meaning, is superior to the three-element windkessel as a lumped-parameter model of the entire systemic tree or as a model for parameter estimation of vascular properties.


Spatiotemporal access to emergency medical services in Wuhan, China: accounting for scene and transport time intervals.
Access as a primary indicator of Emergency Medical Service (EMS) efficiency has been widely studied over the last few decades. Most previous studies considered one-way trips, either getting ambulances to patients or transporting patients to hospitals. This research assesses spatiotemporal access to EMS at the shequ (the smallest administrative unit) level in Wuhan, China, attempting to fill a gap in literature by considering and comparing both trips in the evaluation of EMS access. Two spatiotemporal access measures are adopted here: the proximity-based travel time obtained from online map services and the enhanced two-step floating catchment area (E-2SFCA) which is a gravity-based model. First, the travel time is calculated for the two trips involved in one EMS journey: one is from the nearest EMS station to the scene (i.e. scene time interval (STI)) and the other is from the scene to the nearest hospital (i.e. transport time interval (TTI)). Then, the predicted travel time is incorporated into the E-2SFCA model to calculate the access measure considering the availability of the service provider as well as the population in need. For both access measures, the calculation is implemented for peak hours and off-peak hours. Both methods showed a marked decrease in EMS access during peak traffic hours, and differences in spatial patterns of ambulance and hospital access. About 73.9% of shequs can receive an ambulance or get to the nearest hospital within 10 min during off-peak periods, and this proportion decreases to about 45.5% for peak periods. Most shequs with good ambulance access but poor hospital access are in the south of the study area. In general, the central areas have better ambulance, hospital and overall access than peripheral areas, particularly during off-peak periods. In addition to the impact of peak traffic periods on EMS access, we found that good ambulance access does not necessarily guarantee good hospital access nor the overall access, and vice versa.


Effectiveness, safety and acceptability of medical abortion at home versus in the clinic: a systematic review and meta-analysis in response to COVID-19.
Increased access to home-based medical abortion may offer women a convenient, safe and effective abortion method, reduce burdens on healthcare systems and support social distancing during the COVID-19 pandemic. Home-based medical abortion is defined as any abortion where mifepristone, misoprostol or both medications are taken at home. A systematic review and meta-analysis of randomised controlled trials (RCTs) and non-randomised studies (NRSs) were conducted. We searched databases from inception to 10 July 2019 and 14 June 2020. Successful abortion was the main outcome of interest. Eligible studies were RCTs and NRSs studies with a concurrent comparison group comparing home versus clinic-based medical abortion. Risk ratios (RRs) and their 95% CIs were calculated. Estimates were calculated using a random-effects model. We used the Grading of Recommendations Assessment, Development and Evaluation approach to assess risk of bias by outcome and to evaluate the overall quality of the evidence. We identified 6277 potentially eligible published studies. Nineteen studies (3 RCTs and 16 NRSs) were included with 11 576 women seeking abortion up to 9 weeks gestation. Neither the RCTs nor the NRS found any difference between home-based and clinic-based administration of medical abortion in having a successful abortion (RR 0.99, 95% CI 0.98 to 1.01, I2=0%; RR 0.99, 95% CI 0.97 to 1.01, I2=52%, respectively). The certainty of the evidence for the 16 NRSs was downgraded from low to very low due to high risk of bias and publication bias. The certainty of the evidence for the three RCTs was downgraded from high to moderate by one level for high risk of bias. Home-based medical abortion is effective, safe and acceptable to women. This evidence should be used to expand women's abortion options and ensure access to abortion for women during COVID-19 and beyond. CRD42020183171.


Repetitive-DNA-element PCR fingerprinting and antibiotic resistance of pan-European multi-resistant Acinetobacter baumannii clone III strains.
In the present study, it was shown that repetitive-DNA-element PCR fingerprinting using the (GTG)5 primer [(GTG)5-PCR] is a rapid and reliable tool to genotypically differentiate members of the recently described pan-European multi-resistant Acinetobacter baumannii (MAB) clone III from the known MAB clones I and II. The identification of four new representatives of the MAB clone III dating from 1991 to 1993 by (GTG)5-PCR indicates that this clone has persisted in European hospitals since the beginning of the 1990s. Tetracycline (TET) resistance was found to be common among clone III strains, including one strain that also displayed resistance to minocycline. The TET-resistance phenotype in this MAB clone appeared to be strongly associated with the presence of the efflux-type gene tet(A), but the fact that some members lack this gene or have acquired an additional tet gene [i.e. tet(M)] suggests that the tet gene carriage in the pan-European clone III population may have diversified in time and space. In contrast, all clone III strains shared the previously described aminoglycoside resistotype encoded by the aminoglycoside-modifying genes aphA6 and the class 1 integron-associated aadB, which may point to the fact that these genes probably are more stably inherited in MAB clone III compared to tet genes.


Longitudinal comparison of the periodontal status of patients with moderate to severe periodontal disease receiving no treatment, non-surgical treatment, and surgical treatment utilizing individual sites for analysis.
The progression of periodontal disease without treatment and the response of existing periodontal disease to various types of treatment have been studied extensively. Many past studies have used the mean of the patient's probing depths or attachment levels to evaluate disease progression as opposed to following changes in individual sites or teeth. The purpose of the current study was to evaluate the response of individual teeth to treatment or non-treatment. The records from a private periodontal practice were reviewed to find patients with complete periodontal examinations that were recorded at least 1 year apart. Patients who fit these criteria were divided into those who had none of the recommended treatment (untreated, n = 30); those who had only non-surgical treatment (partially treated, n = 20); and a control group who had completed all recommended treatment (surgically treated, n = 41). The data for each tooth of each patient were placed in a database and analyzed using the method of generalized estimating equations (GEE) to test for associations between increase or decrease in probing depths and various initial clinical parameters while adjusting for significant confounders. Teeth that received no treatment or non-surgical treatment showed significant increases in probing depths, worsening of prognosis, worsening of furcation involvement, and increases in mobility when compared to surgically treated teeth. Teeth that received surgical treatment showed significant decreases in probing depths. No significant difference was noted between teeth that had no treatment and teeth that had non-surgical treatment. When individual teeth are used as the basis for analysis, teeth that receive no treatment or non-surgical treatment show a significant worsening of probing depths, furcations, mobility, and prognosis when compared to teeth that receive surgical treatment, while surgically treated teeth show significant improvement in probing depths.


Support for children identified with acute flaccid paralysis under the global polio eradication programme in Uttar Pradesh, India: a qualitative study.
Cases of polio in India declined after the implementation of the polio eradication programme especially in these recent years. The programme includes surveillance of acute flaccid paralysis (AFP) to detect and diagnose cases of polio at early stage. Under this surveillance, over 40,000 cases of AFP are reported annually since 2007 regardless of the number of actual polio cases. Yet, not much is known about these children. We conducted a qualitative research to explore care and support for children with AFP after their diagnosis. The research was conducted in a district of western Uttar Pradesh classified as high-risk area for polio. In-depth interviews with parents of children with polio (17), with non-polio AFP (9), healthcare providers (40), and key informants from community including international and government officers, religious leaders, community leaders, journalists, and academics (21) were performed. Minimal medicine and attention were provided at government hospitals. Therefore, most parents preferred private-practice doctors for their children with AFP. Many were visited at homes to have stool samples collected by authorities. Some were visited repetitively following the sample collection, but had difficulty in understanding the reasons for these visits that pertained no treatment. Financial burden was a common concern among all families. Many parents expressed resentment for their children's disease, notably have been affected despite receiving multiple doses of polio vaccine. Both parents and healthcare providers lacked information and knowledge, furthermore poverty minimised the access to available healthcare services. Medicines, education, and transportation means were identified as foremost needs for children with AFP and residual paralysis. Despite the high number of children diagnosed with AFP as part of the global polio eradication programme, we found they were not provided with sufficient medical support following their diagnosis. Improvement in the quality and sufficiency of the healthcare system together with integration of AFP surveillance with other services in these underprivileged areas may serve as a key solution.


Impact of pharmaceutical intervention on quality of life and coping strategies in patients with haematological malignancies.
We conducted a prospective study approved by the local ethics committee to determine the impact of a pharmaceutical intervention (PI) on pain, fatigue, quality of life (QoL) and coping strategies in patients with HMs starting chemotherapy sessions. Patients received either usual care (UC)+PI (PI group) or UC alone (UC group). They had to complete 2 questionnaires, QLQ-C30 and MAC 21, at 3 different time points: before starting the 1st chemotherapy session (T1), during the intercure (T2) and the day before starting the 2nd chemotherapy session (T3). To determine predictive factors of pain, fatigue, QoL and coping scores at T3, a multivariate ANOVA was used. QoL and coping scores were analysed longitudinally using a linear mixed model. Sixty-eight patients were included in the PI (n=34) or UC groups (n=34). Ninety-two percent of the patients returned all the questionnaires. At inclusion, QoL was significantly better in the PI group (P=0.047). At T3, the group had no influence on pain, fatigue, nor coping scores but a trend towards a better QoL was observed in the PI group (P=0.090). Longitudinally, the PI group did not present significantly better scores on pain, fatigue but both a trend toward better Qol scores and lower anxious preoccupations scores. A PI at the beginning of chemotherapy sessions did not have any significant impact on pain and fatigue but a trend towards better Qol scores and lower anxious preoccupations scores.


Anesthesia considerations for patients with epilepsy: Findings of a qualitative study in the Palestinian practice.
This qualitative exploratory study was conducted to explore how anesthesiologists in Palestine provide perioperative care for patients with epilepsy and how they account for the unique challenges relevant to epilepsy while planning perioperative care for patients with epilepsy. This study was conducted in an explorative qualitative design. Purposive and snowball sampling approaches were used to recruit the study participants. Qualitative semi-structured in-depth interviews were conducted with anesthesiologists (n = 10) and a neurologist (n = 1). The qualitative data collected in this study were thematically analyzed using the interpretive description methodology to generate themes, subthemes, and patterns. Three major themes emerged from the collected qualitative data with a total of 18 subthemes. The 3 themes were: 1) considerations/challenges while assessing patients, 2) anesthetic considerations, and 3) recovery considerations. Lack of epilepsy-specific assessment and anesthesia protocols, underuse of neurology referral services, and lack of neuromonitoring were identified. Findings of this study highlighted the need to develop specific anesthesia protocols for patients with epilepsy. Anesthesiologists and planners of perioperative care should improve collection of patient information and assessment methods, ensure control over seizures, reduce triggers of seizures, and improve patient monitoring approaches. Findings of this study might be used to inform anesthesiologists and decision makers in professional groups, patient advocacy groups, and healthcare authorities to benchmark and improve anesthesia care and services offered to patients with epilepsy. More studies are still needed to quantitatively assess the quality of anesthesia care and services provided to patients with epilepsy.


Liver Cancer Working Group report.
Hepatocellular carcinoma is a highly prevalent disease in many Asian countries, accounting for 75-80% of victims worldwide. The incidence of hepatocellular carcinoma varies enormously across Asia, but tends to follow the incidences of hepatitis B infection and liver cirrhosis. The incidence and etiology of hepatocellular carcinoma in Japan are different from the rest of Asia, but similar to that in Western countries because hepatitis C infection is the main etiological factor in Japan. Hepatitis B virus vaccination programs are showing great success in reducing hepatitis B virus-related hepatocellular carcinoma. Screening program improves detection of early hepatocellular carcinoma and has some positive impact on survival, but the majority of hepatocellular carcinoma patients in Asia still present with advanced hepatocellular carcinoma. Long-term outcomes following treatment of even early/intermediate or advanced disease are often unsatisfactory because of a lack of effective adjuvant and systemic therapies. Various clinical practice guidelines for hepatocellular carcinoma have been established and are in use. Clinical diagnosis of hepatocellular carcinoma by imaging diagnosis is replacing diagnosis of hepatocellular carcinoma by pathological confirmation. New imaging and treatment techniques are continuously being developed and guidelines should be updated every 3 or 4 years, incorporating new evidence. New molecularly targeted therapies hold great promise. Sorafenib is the first systemic therapy to demonstrate prolonged survival vs. the placebo in patients with advanced hepatocellular carcinoma. Various other new molecularly targeted agents are currently under investigation.


Consumption of trans-fatty acid and its association with colorectal adenomas.
trans-Fatty acid consumption is known to have detrimental effects on cardiovascular health, but little is known about its role in digestive tract neoplasia. To investigate the association between colorectal adenomas and trans-fatty acid consumption, the authors utilized data from a cross-sectional study of 622 individuals who underwent complete colonoscopy between 2001 and 2002 at the University of North Carolina Hospitals. Participants were interviewed about demographic, lifestyle, and dietary factors thought to be related to colorectal cancer. trans-Fatty acid consumption, energy adjusted by the residual method, was categorized into quartiles based on its distribution in controls. Compared with participants in the lowest quartile of consumption, those in the highest quartile had an increased prevalence of colorectal adenomas, with an adjusted prevalence odds ratio of 1.86 (95% confidence interval: 1.04, 3.33). The authors further investigated the relation between trans-fatty acid consumption and colorectal neoplasia by examining the adenoma characteristics, with the adjusted prevalence odds ratios showing little or no difference by adenoma location, size, or number. These results suggest that consumption of high amounts of trans-fatty acid may increase the risk of colorectal neoplasia, and they provide additional support to recommendations to limit trans-fatty acid consumption.


Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
The Third International Consensus Definitions Task Force defined sepsis as "life-threatening organ dysfunction due to a dysregulated host response to infection." The performance of clinical criteria for this sepsis definition is unknown. To evaluate the validity of clinical criteria to identify patients with suspected infection who are at risk of sepsis. Among 1.3 million electronic health record encounters from January 1, 2010, to December 31, 2012, at 12 hospitals in southwestern Pennsylvania, we identified those with suspected infection in whom to compare criteria. Confirmatory analyses were performed in 4 data sets of 706,399 out-of-hospital and hospital encounters at 165 US and non-US hospitals ranging from January 1, 2008, until December 31, 2013. Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, systemic inflammatory response syndrome (SIRS) criteria, Logistic Organ Dysfunction System (LODS) score, and a new model derived using multivariable logistic regression in a split sample, the quick Sequential [Sepsis-related] Organ Failure Assessment (qSOFA) score (range, 0-3 points, with 1 point each for systolic hypotension [≤100 mm Hg], tachypnea [≥22/min], or altered mentation). For construct validity, pairwise agreement was assessed. For predictive validity, the discrimination for outcomes (primary: in-hospital mortality; secondary: in-hospital mortality or intensive care unit [ICU] length of stay ≥3 days) more common in sepsis than uncomplicated infection was determined. Results were expressed as the fold change in outcome over deciles of baseline risk of death and area under the receiver operating characteristic curve (AUROC). In the primary cohort, 148,907 encounters had suspected infection (n = 74,453 derivation; n = 74,454 validation), of whom 6347 (4%) died. Among ICU encounters in the validation cohort (n = 7932 with suspected infection, of whom 1289 [16%] died), the predictive validity for in-hospital mortality was lower for SIRS (AUROC = 0.64; 95% CI, 0.62-0.66) and qSOFA (AUROC = 0.66; 95% CI, 0.64-0.68) vs SOFA (AUROC = 0.74; 95% CI, 0.73-0.76; P < .001 for both) or LODS (AUROC = 0.75; 95% CI, 0.73-0.76; P < .001 for both). Among non-ICU encounters in the validation cohort (n = 66 522 with suspected infection, of whom 1886 [3%] died), qSOFA had predictive validity (AUROC = 0.81; 95% CI, 0.80-0.82) that was greater than SOFA (AUROC = 0.79; 95% CI, 0.78-0.80; P < .001) and SIRS (AUROC = 0.76; 95% CI, 0.75-0.77; P < .001). Relative to qSOFA scores lower than 2, encounters with qSOFA scores of 2 or higher had a 3- to 14-fold increase in hospital mortality across baseline risk deciles. Findings were similar in external data sets and for the secondary outcome. Among ICU encounters with suspected infection, the predictive validity for in-hospital mortality of SOFA was not significantly different than the more complex LODS but was statistically greater than SIRS and qSOFA, supporting its use in clinical criteria for sepsis. Among encounters with suspected infection outside of the ICU, the predictive validity for in-hospital mortality of qSOFA was statistically greater than SOFA and SIRS, supporting its use as a prompt to consider possible sepsis.


Differences in relatives' and patients' illness perceptions in functional neurological symptom disorders compared with neurological diseases.
The illness perceptions of the relatives of patients with functional neurological symptom disorders (FNSDs) and their relation to the illness perceptions of the patients have been little studied. We aimed to compare illness perceptions of relatives of patients with FNSDs with those held by patients themselves. We used control pairs with neurological diseases (NDs) to examine the specificity of the findings to FNSDs. Patients with FNSDs (functional limb weakness and psychogenic nonepileptic seizures) and patients with NDs causing limb weakness and epilepsy, as well as their relatives, completed adapted versions of the Illness Perception Questionnaire - Revised (IPQ-R). We included 112 pairs of patients with FNSDs and their relatives and 60 pairs of patients with NDs and their relatives. Relatives of patients with FNSDs were more likely to endorse psychological explanations and, in particular, stress as causal factors than patients with FNSDs (p<.001). Relatives of patients with FNSDs were also more pessimistic about the expected duration of the disorder and perceived a greater emotional impact compared with patients themselves (p<.001). However, the latter two differences between patients and relatives were also found in pairs of patients with NDs and their relatives. The main difference in illness perceptions between relatives and patients that appeared specific to FNSDs was a tendency for relatives to see psychological factors as more relevant compared with patients. Some other differences were observed between pairs of patients with FNSDs and their relatives, but the same differences were also seen in pairs of patients with NDs and their relatives. These other differences were, therefore, not specific to FNSDs. Discussion about possibly relevant psychological factors with patients suffering from FNSDs may be helped by including relatives.


Regulation of GATA-binding protein 2 levels via ubiquitin-dependent degradation by Fbw7: involvement of cyclin B-cyclin-dependent kinase 1-mediated phosphorylation of THR176 in GATA-binding protein 2.
A GATA family transcription factor, GATA-binding protein 2 (GATA2), participates in cell growth and differentiation of various cells, such as hematopoietic stem cells. Although its expression level is controlled by transcriptional induction and proteolytic degradation, the responsible E3 ligase has not been identified. Here, we demonstrate that F-box/WD repeat-containing protein 7 (Fbw7/Fbxw7), a component of Skp1, Cullin 1, F-box-containing complex (SCF)-type E3 ligase, is an E3 ligase for GATA2. GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1). Moreover, depletion of endogenous Fbw7 stabilized endogenous GATA2 in K562 cells. Conditional Fbw7 depletion in mice increased GATA2 levels in hematopoietic stem cells and myeloid progenitors at the early stage. Increased GATA2 levels in Fbw7-conditional knock-out mice were correlated with a decrease in a c-Kit high expressing population of myeloid progenitor cells. Our results suggest that Fbw7 is a bona fide E3 ubiquitin ligase for GATA2 in vivo.


Tailored dendritic core-multishell nanocarriers for efficient dermal drug delivery: A systematic top-down approach from synthesis to preclinical testing.
Drug loaded dendritic core-multishell (CMS) nanocarriers are of especial interest for the treatment of skin diseases, owing to their striking dermal delivery efficiencies following topical applications. CMS nanocarriers are composed of a polyglycerol core, connected by amide-bonds to an inner alkyl shell and an outer methoxy poly(ethylene glycol) shell. Since topically applied nanocarriers are subjected to biodegradation, the application of conventional amide-based CMS nanocarriers (10-A-18-350) has been limited by the potential production of toxic polyglycerol amines. To circumvent this issue, three tailored ester-based CMS nanocarriers (10-E-12-350, 10-E-15-350, 10-E-18-350) of varying inner alkyl chain length were synthesized and comprehensively characterized in terms of particle size, drug loading, biodegradation and dermal drug delivery efficiency. Dexamethasone (DXM), a potent drug widely used for the treatment of inflammatory skin diseases, was chosen as a therapeutically relevant test compound for the present study. Ester- and amide-based CMS nanocarriers delivered DXM more efficiently into human skin than a commercially available DXM cream. Subsequent in vitro and in vivo toxicity studies identified CMS (10-E-15-350) as the most biocompatible carrier system. The anti-inflammatory potency of DXM-loaded CMS (10-E-15-350) nanocarriers was assessed in TNFα supplemented skin models, where a significant reduction of the pro-inflammatory cytokine IL-8 was seen, with markedly greater efficacy than commercial DXM cream. In summary, we report the rational design and characterization of tailored, biodegradable, ester-based CMS nanocarriers, and their subsequent stepwise screening for biocompatibility, dermal delivery efficiency and therapeutic efficacy in a top-down approach yielding the best carrier system for topical applications.


Multi-channel microfluidic biosensor platform applied for online monitoring and screening of biofilm formation and activity.
Bacterial colonization of surfaces and interfaces has a major impact on various areas including biotechnology, medicine, food industries, and water technologies. In most of these areas biofilm development has a strong impact on hygiene situations, product quality, and process efficacies. In consequence, biofilm manipulation and prevention is a fundamental issue to avoid adverse impacts. For such scenario online, non-destructive biofilm monitoring systems become important in many technical and industrial applications. This study reports such a system in form of a microfluidic sensor platform based on the combination of electrical impedance spectroscopy and amperometric current measurement, which allows sensitive online measurement of biofilm formation and activity. A total number of 12 parallel fluidic channels enable real-time online screening of various biofilms formed by different Pseudomonas aeruginosa and Stenotrophomonas maltophilia strains and complex mixed population biofilms. Experiments using disinfectant and antibiofilm reagents demonstrate that the biofilm sensor is able to discriminate between inactivation/killing of bacteria and destabilization of biofilm structures. The impedance and amperometric sensor data demonstrated the high dynamics of biofilms as a consequence of distinct responses to chemical treatment strategies. Gene expression of flagellar and fimbrial genes of biofilms grown inside the microfluidic system supported the detected biofilm growth kinetics. Thus, the presented biosensor platform is a qualified tool for assessing biofilm formation in specific environments and for evaluating the effectiveness of antibiofilm treatment strategies.


Use of contact lenses by firefighters. Part 1: Questionnaire data.
The use of contact lenses by firefighters is currently prohibited. However, many firefighters may benefit from this form of visual correction, without predisposing themselves to additional risk. Visual benefits gained by contact lens wear may increase a firefighter's safety. To determine if it is safe to allow firefighters to use contact lenses 29 were fitted with soft contact lenses and 21 with rigid gas permeable contact lenses. Questionnaires were completed prior to fitting, after 1, 4 and 10 months of contact lens wear. Both soft contact lens (SCL) wearers, and rigid gas permeable contact lens (RGPCL) wearers showed a statistically significantly reduction in the frequency with which they experience irritable foreign bodies and irritant fumes in the eyes, compared to not wearing contact lenses. Firefighters felt that their performance on the fireground had been improved by the use of contact lenses. SCL wearers also benefited from a reduction in the frequency with which they experienced watery eyes and ocular discomfort. There were significantly fewer problems encountered with SCL wearers than RGPCL wearers. The frequency with which firefighters experienced lenses falling out, lens displacement, watery eyes, ocular discomfort, and operational difficulties was significantly less for the SCL group than the RGPCL group. SCL appear to offer considerable benefits for firefighters with refractive error, but their use cannot be sanctioned without assessment of their effect on the ocular adnexa.


Underscreening in concentrated electrolytes.
Screening of a surface charge by an electrolyte and the resulting interaction energy between charged objects is of fundamental importance in scenarios from bio-molecular interactions to energy storage. The conventional wisdom is that the interaction energy decays exponentially with object separation and the decay length is a decreasing function of ion concentration; the interaction is thus negligible in a concentrated electrolyte. Contrary to this conventional wisdom, we have shown by surface force measurements that the decay length is an increasing function of ion concentration and Bjerrum length for concentrated electrolytes. In this paper we report surface force measurements to test directly the scaling of the screening length with Bjerrum length. Furthermore, we identify a relationship between the concentration dependence of this screening length and empirical measurements of activity coefficient and differential capacitance. The dependence of the screening length on the ion concentration and the Bjerrum length can be explained by a simple scaling conjecture based on the physical intuition that solvent molecules, rather than ions, are charge carriers in a concentrated electrolyte.


Metabolomic profile of glycolysis and the pentose phosphate pathway identifies the central role of glucose-6-phosphate dehydrogenase in clear cell-renal cell carcinoma.
The analysis of cancer metabolome has shown that proliferating tumor cells require a large quantities of different nutrients in order to support their high rate of proliferation. In this study we analyzed the metabolic profile of glycolysis and the pentose phosphate pathway (PPP) in human clear cell-renal cell carcinoma (ccRCC) and evaluate the role of these pathways in sustaining cell proliferation, maintenance of NADPH levels, and production of reactive oxygen species (ROS). Metabolomic analysis showed a clear signature of increased glucose uptake and utilization in ccRCC tumor samples. Elevated levels of glucose-6-phosphate dehydrogenase (G6PDH) in association with higher levels of PPP-derived metabolites, suggested a prominent role of this pathway in RCC-associated metabolic alterations. G6PDH inhibition, caused a significant decrease in cancer cell survival, a decrease in NADPH levels, and an increased production of ROS, suggesting that the PPP plays an important role in the regulation of ccRCC redox homeostasis. Patients with high levels of glycolytic enzymes had reduced progression-free and cancer-specific survivals as compared to subjects with low levels. Our data suggest that oncogenic signaling pathways may promote ccRCC through rerouting the sugar metabolism. Blocking the flux through this pathway may serve as a novel therapeutic target.


Development of a simple, sensitive and selective colorimetric aptasensor for the detection of cancer-derived exosomes.
There is a growing need for cancerous exosome detection towards potential non-invasive cancer diagnosis. This study aims to develop a reliable colorimetric aptasensor for sensitive and specific detection of circulating cancer-derived exosomes. In this design, target exosomes were firstly captured by latex beads via aldimine condensation, followed by bio-recognition using a specific CD63 aptamer, which was conjugated to horseradish peroxidase (HRP) through biotin-streptavidin binding. Colorimetric detection was achieved in 10 min via enzymatic catalysis to produce dark coloured polydopamine (PDA) from colourless substrate dopamine (DA) in especially prepared H2O2 reaction solution. The sensitivity was enhanced by in situ deposition of PDA around exosome particles to strengthen the developed colorimetric signal, which could be directly observed by naked eye. Signal quantification was carried out by absorbance measurement. The colour intensity correlates to the CD63 amount and the limit of detection can be as low as 7.7 × 103 particle/mL, improved by 3-5 orders of magnitude from conventional Dot-blot methods. The aptasensor showed specificity to HER2 and integrin αvβ6 positive, cell culture-derived, breast and pancreatic cancer-derived exosomes, respectively, when the correct aptamer sequence was used. Overall, a sensitive and selective colorimetric aptasensor was successfully developed for detecting cancer-derived exosomes facilitated by HRP-accelerated DA polymerization and in situ PDA deposition. This versatile aptasensor holds great potential for future development of point-of-care detection kits for cancer diagnosis in a clinical setting.


Orphan legume crops enter the genomics era!
Many of the world's most important food legumes are grown in arid and semi-arid regions of Africa and Asia, where crop productivity is hampered by biotic and abiotic stresses. Until recently, these crops have also suffered from a dearth of genomic and molecular-genetic resources and thus were 'orphans' of the genome revolution. However, the community of legume researchers has begun a concerted effort to change this situation. The driving force is a series of international collaborations that benefit from recent advances in genome sequencing and genotyping technologies. The focus of these activities is the development of genome-scale data sets that can be used in high-throughput approaches to facilitate genomics-assisted breeding in these legumes.


Characterization of vascular endothelial progenitor cells from chicken bone marrow.
Endothelial progenitor cells (EPC) are a type of stem cell used in the treatment of atherosclerosis, vascular injury and regeneration. At present, most of the EPCs studied are from human and mouse, whereas the study of poultry-derived EPCs has rarely been reported. In the present study, chicken bone marrow-derived EPCs were isolated and studied at the cellular level using immunofluorescence and RT-PCR. We found that the majority of chicken EPCs were spindle shaped. The growth-curves of chicken EPCs at passages (P) 1, -5 and -9 were typically "S"-shaped. The viability of chicken EPCs, before and after cryopreservation was 92.2% and 81.1%, respectively. Thus, cryopreservation had no obvious effects on the viability of chicken EPCs. Dil-ac-LDL and FITC-UAE-1 uptake assays and immunofluorescent detection of the cell surface markers CD34, CD133, VEGFR-2 confirmed that the cells obtained in vitro were EPCs. Observation of endothelial-specific Weibel-Palade bodies using transmission electron microscopy further confirmed that the cells were of endothelial lineage. In addition, chicken EPCs differentiated into endothelial cells and smooth muscle cells upon induction with VEGF and PDGF-BB, respectively, suggesting that the chicken EPCs retained multipotency in vitro. These results suggest that chicken EPCs not only have strong self-renewal capacity, but also the potential to differentiate into endothelial and smooth muscle cells. This research provides theoretical basis and experimental evidence for potential therapeutic application of endothelial progenitor cells in the treatment of atherosclerosis, vascular injury and diabetic complications.


Picosecond multistage interconnection network architecture for optical computing.
We use nonlinear optical bistable devices to design a prototype of a building block for an all-optical multistage interconnection network architecture. This architecture is flexible in the sense that it can be used for either circuit-switched interconnection networks or packet-switched interconnection networks, depending on the user's applications and type of network architecture. Therefore this is a generalpurpose all-optical switch that is applicable to almost all types of network such as omega, banyan, perfect shuffle, etc. The system consists of several design units, each of which is described separately, and then all are synthesized together to form the complete system. When used with the packet-switched networks, the system is capable of buffering information optically with no need for electronic backup. The main functions of the architecture are achieved by the use of a nonlinear optical bistable device, namely, the interference filter (with the addition of mirrors and beam splitters). These optical c mponents are commercially available. They can also be integrated for future mass production. Therefore we anticipate that the implementation of this architecture is feasible.


Pertussis toxin-sensitive cholinergic inhibition of somatostatin release from canine D-cells.
Development of an enriched cultured cell system allowed us to investigate the mechanism of cholinergic inhibition of somatostatin release stimulated by adenosine 3',5'-cyclic monophosphate (cAMP) and Ca2+-protein kinase C-dependent pathways of cell activation. After a 24-h culture on rat tail collagen, D-cells, quantified by immunohistochemistry, were 18-fold enriched compared with unelutriated dispersed cells. Somatostatin release from cultured cells was expressed as a percent of the somatostatin released by a specific stimulus in control cells. Under basal conditions release of somatostatin was 2.3 +/- 0.6% of the total cell content. Epinephrine (1 microM) and cholecystokinin octapeptide (10 nM) increased somatostatin release to 6.98 +/- 1.25 and 10.72 +/- 1.64%, respectively. Carbachol (1 microM) completely inhibited somatostatin release stimulated by epinephrine and reduced cholecystokinin octapeptide-stimulated release to 75% of control levels. Carbachol inhibition of the response to both epinephrine and cholecystokinin octapeptide was totally prevented by 5 h of treatment of the cells with pertussis toxin (300 ng/ml). Somatostatin release in response to the diterpene forskolin (10 microM), dibutyryl cAMP (300 microM), the phorbol ester beta-phorbol 12-myristate 13-acetate (0.1 microM), and the calcium ionophore A23187 (1 microM) was also inhibited by carbachol and prevented by pertussis toxin pretreatment. The ADP-ribosylase inhibitor isonicotinamide (1 mM) selectively blocked the effect of pertussis toxin without altering other stimulatory or inhibitory responses. These data are consistent with the view that carbachol inhibits somatostatin release at guanyl nucleotide-binding protein and/or another pertussis toxin-sensitive site.


The treatment of hepatic encephalopathy in the cirrhotic patient.
Cirrhosis of the liver is a rising epidemic in the United States, affecting 2 out of every 1,000 adults. It is responsible for the deaths of more than 27,000 people each year. The primary diseases that underlie cirrhosis include viral hepatitis, alcoholic liver disease, and nonalcoholic fatty liver disease. Monitoring the extent of fibrosis and aggressively treating the underlying disease is essential for maintaining quality of life and preventing the complications of cirrhosis. As patients progress toward end-stage liver disease, the most common complications include portal hypertension, the development of esophageal varices, and hepatic encephalopathy. Esophageal varices can lead to hemorrhaging, a dangerous complication that is fatal in 30-50% of patients during the first occurrence. Hepatic encephalopathy is another serious complication of end-stage liver disease, as it significantly reduces patient quality of life and places heavy economic and caregiving burdens upon the patient's family. In this clinical roundtable monograph, the latest advances in the monitoring of liver disease and the management of portal hypertension and hepatic encephalopathy are discussed.


Comparison of fine-needle aspiration and fine-needle biopsy devices for endoscopic ultrasound-guided sampling of solid lesions: a systemic review and meta-analysis.
Endoscopic ultrasound (EUS)-guided tissue acquisition is extensively used, but the optimal sampling device is still a matter of debate. We performed meta-analyses on studies comparing fine-needle aspiration (FNA) with fine-needle biopsy (FNB) needles, and studies comparing different FNB needles. Online databases were searched for randomized controlled trials (RCTs) of at least 50 cases with a suspected solid pancreatic or nonpancreatic lesion that compared FNA with FNB needles. Outcome measures included diagnostic accuracy, adequacy, number of passes, presence of tissue cores, and adverse events. We also performed meta-regression analysis on the effect of FNB design on diagnostic accuracy. Quality was assessed using the QUADAS-2 tool. 18 RCTs comparing FNA with FNB needles were included. FNB provided a higher pooled diagnostic accuracy (87 % vs. 80 %; P = 0.02) and tissue core rate (80 % vs. 62 %; P = 0.002), and allowed diagnosis with fewer passes (P = 0.03), in both pancreatic and nonpancreatic lesions. A total of 93 studies were included comparing different FNB devices. Pooled diagnostic accuracy was higher for forward-facing bevel needles than for the reverse bevel needle. In this analysis, study quality was low and heterogeneity was high (I2 = 80 %). FNB outperformed FNA when sampling pancreatic and nonpancreatic lesions. Forward-facing bevel FNB needles seemed to outperform the reverse bevel FNB needle, but the low quality of evidence prevents us from making strong recommendations on the optimal FNB design.


The cognitive phenotype in Klinefelter syndrome: a review of the literature including genetic and hormonal factors.
Klinefelter syndrome (KS) or 47,XXY occurs in approximately 1 in 650 males. Individuals with KS often present with physical characteristics including tall stature, hypogonadism, and fertility problems. In addition to medical findings, the presence of the extra X chromosome can lead to characteristic cognitive and language deficits of varying severity. While a small, but significant downward shift in mean overall IQ has been reported, the general cognitive abilities of patients with KS are not typically in the intellectual disability range. Most studies support that males with KS have an increased risk of language disorders and reading disabilities. Results of other studies investigating the relationship between verbal and nonverbal/spatial cognitive abilities have been mixed, with differing results based on the age and ascertainment method of the cohort studied. Executive function deficits have been identified in children and adults with KS, however, the research in this area is limited and further investigation of the neuropsychological profile is needed. In this article, we review the strengths and weaknesses of previous cognitive and neuropsychological studies in males with KS in childhood and adulthood, provide historical perspective of these studies, and review what is known about how hormonal and genetic factors influence cognitive features in 47,XXY/KS.


Administration of hydrogen-rich saline protects mice from lethal acute graft-versus-host disease (aGVHD).
Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant and nonmalignant hematologic diseases. However, acute graft-versus-host disease (aGVHD) is a lethal complication of hematopoietic stem cell transplantation, which limits its application. Cytokines such as tumor necrosis factor-α and interleukin-6 play an extremely important role in the formation and development of aGVHD. Reactive oxygen species, such as hydroxyl radicals, also play an important role in the formation and development of aGVHD. In recent years, hydrogen was reported to have an ability to inhibit the levels of cytokines, such as tumor necrosis factor and interleukin-6 in vivo, and it also has a strong selective free radical-scavenging ability. Therefore, we hypothesized that hydrogen may have therapeutic effects on aGVHD. To determine whether hydrogen could protect mice from lethal GVHD in a major histocompatibility complex-incompatible murine bone marrow transplantation (BMT) model, survival rates of mice were calculated and leukocyte counts were also determined after BMT. We also examined serum cytokine levels and scored clinical signs of GVHD mice after BMT. This article demonstrated that the administration of hydrogen-rich saline increased the survival rate and clinical score of aGVHD mice. Administration of hydrogen-rich saline after transplantation also promoted the recovery of white blood cells of aGVHD mice. However, there was no report on the therapeutic effects of hydrogen on aGVHD. It is suggested that hydrogen has a potential as an effective and safe therapeutic agent on aGVHD.


Synovial chondromatosis of the elbow.
Synovial chondromatosis (SC) is a rare, mostly benign proliferation of the synovium of the joint, tendon or bursa which results in the formation of loose bodies. It can appear in one of 33 described localisations, but it is most common in the knee. In our study we gathered a group of 7 patients (6 male and 1 female) with SC of the elbow, which underwent arthroscopic surgery of the elbow, performing both removal of the loose bodies and complete synovectomy. Mayo Elbow Performance Score (MEPS) was used to evaluate and compare the patients' condition before the operation and at the final follow-up, 31 months, on average, after the operation (range 18-56 months). All patients had poor MEPS before the operation, with an average of 40.7 (range 15-50 points). At the final follow-up, 6 patients had a good or excellent MEPS, while a poor MEPS was present in a single patient. The average MEPS was 85 (range 45-100 points). The one patient who's MEPS remained poor developed heterotopic ossification in the same elbow shortly after arthroscopic surgery. This patient was reoperated 8 months later using an open technique. No other complications occurred in the rest of the operated patients and no recurrence of SC occurred in any of the operated patients. Our results confirm that arthroscopic removal of loose bodies and complete synovectomy should be the treatment of choice for SC of the elbow.


Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression.
Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.