STP4: spatio temporal path planning based on pedestrian trajectory prediction in dense crowds.
This article proposes a means of autonomous mobile robot navigation in dense crowds based on predicting pedestrians' future trajectories. The method includes a pedestrian trajectory prediction for a running mobile robot and spatiotemporal path planning for when the path crosses with pedestrians. The predicted trajectories are converted into a time series of cost maps, and the robot achieves smooth navigation without dodging to the right or left in crowds; the path planner does not require a long-term prediction. The results of an evaluation implementing this method in a real robot in a science museum show that the trajectory prediction works. Moreover, the proposed planning's arrival times is 26.4% faster than conventional 2D path planning's arrival time in a simulation of navigation in a crowd of 50 people.


Patient was wrongly diagnosed and repeatedly treated for immune thrombocytopenia for 50 years
We report on a patient with inherited macrothrombocytopenia, MYH9 related disease (MYH9-RD). The patient was wrongly diagnosed and repeatedly treated for immune thrombocytopenia (ITP) for nearly 50 years. Cases of misdiagnosed MYH9-RD and other hereditary thrombocytopenias have been described previously. Typical clinical features such as renal failure and/or progressive loss of hearing should give grounds to suspect hereditary thrombocytopenia. Initial laboratory diagnosis can start with a simple blood smear followed by immunohistochemistry and genotyping. Therapy with thrombopoietin receptor agonists may be beneficial in selected cases of MYH9-RD. ITP treatments including splenectomy are not indicated and may cause harm.


Gene copy number variation in schizophrenia.
The possibility that gene copy number variations play a role in the development of complex disorders is a topic of considerable interest. Recent reports have highlighted the large number of such variations that exist and that their occurrence varies considerably between populations. A recent report has suggested that copy number variations in four genes (GRIK3, EFNA5, AKAP5 and CACNG2) may be associated with schizophrenia. One problem with this area of study is the validation of high throughput methods such as comparative genomic hybridisation, as the latter inevitably generates false positives. We have used two contrasting methodologies to determine the validity of the findings reported above which if true would have major implications for the pathogenesis of schizophrenia. Samples from a UK population were tested using a method of allele quantification by DNA pooling and samples from Belgium and northern Sweden were tested using Multiplex Amplicon Quantification (MAQ). Both methods were used to test DNA samples used in the original investigation. No copy number variations were found for any of the genes in any samples. Our data suggests that more reliable methods need to be used to validate the existence of CNVs before full scale association studies are carried out.


The Association between Female Genital Cutting and Spousal HCV Infection in Egypt.
Objective. To identify the risk factors for HCV infection within married couples in Egypt. Methods. In 2008 Egypt conducted its first nationally representative survey of HCV prevalence. 11126 of the 12780 individuals aged 15-59 year who were sampled agreed to participate and provided information via a questionnaire about demographic and behavioural characteristics and blood for HCV antibody and RNA analysis. We assessed the risk factors for HCV infection in a subsample of 5182 married individuals via multivariate logistic regression. Results. Overall HCV antibody prevalence in the married couples was 18.2% (95% CI, 16.8-19.6). HCV antibody prevalence was higher in the husbands (23.7%) than the wives (12.1%; P < 0.001). Having a spouse who was infected with HCV was an independent risk factor for HCV infection with odds ratios of 2.1 (95% CI, 1.6-2.9) and 2.2 (95% CI, 1.6-3.1) for women and men, respectively. Husbands whose wives had experienced female genital cutting (FGC) had a higher prevalence of HCV and this relationship was driven by a strong association in urban areas. Amongst the women there was no association between FGC and HCV overall but in urban areas only women who had experienced FGC were HCV infected. Conclusions. This study provides additional evidence of the importance of intrafamilial transmission of HCV in Egypt.


Biosafety and Proteome Profiles of Different Heat Inactivation Methods for Mycobacterium tuberculosis.
Studies involving the pathogenic organism Mycobacterium tuberculosis routinely require advanced biosafety laboratory facilities, which might not be readily available in rural areas where tuberculosis burdens are high. Attempts to adapt heat inactivation techniques have led to inconsistent conclusions, and the risk of protein denaturation due to extensive heating is impractical for subsequent mass spectrometry (MS)-based protein analyses. In this study, 240 specimens with one or two loops of M. tuberculosis strain H37Rv biomass and specific inactivated solutions were proportionally assigned to six heat inactivation methods in a thermal block at 80°C and 95°C for 20, 30, and 90 min. Twenty untreated specimens served as a positive control, and bacterial growth was followed up for 12 weeks. Our results showed that 90 min of heat inactivation was necessary for samples with two loops of biomass. Further protein extraction and a matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) MS assay demonstrated adequate scores for bacterial identification (≥1.7), with the highest score achieved in the 80°C/90 min and 95°C/30 min treatment groups. A proteomics study also confidently identified 648 proteins with ∼93% to 96% consistent protein abundances following heating at 95°C for 20, 30, and 90 min. Heat inactivation at 95°C for 90 min yielded the most quantifiable proteins, and a functional analysis revealed proteins located in the ribosomal subunit. In summary, we proposed a heat inactivation method for the M. tuberculosis strain H37Rv and studied the preservation of protein components for subsequent bacterial identification and protein-related assays. IMPORTANCE Inactivation of Mycobacterium tuberculosis is an important step to guarantee biosafety for subsequent M. tuberculosis identification and related research, notably in areas of endemicity with minimal resources. However, certain biomolecules might be denatured or hydrolyzed because of the harsh inactivation process, and a standardized protocol is yet to be determined. We evaluated distinct heating conditions to report the inactivation efficiency and performed downstream mass spectrometry-based M. tuberculosis identification and proteomics study. The results are important and useful for both basic and clinical M. tuberculosis studies.


NAA10 p.(D10G) and NAA10 p.(L11R) Variants Hamper Formation of the NatA N-Terminal Acetyltransferase Complex.
The majority of the human proteome is subjected to N-terminal (Nt) acetylation catalysed by N-terminal acetyltransferases (NATs). The NatA complex is composed of two core subunits-the catalytic subunit NAA10 and the ribosomal anchor NAA15. Furthermore, NAA10 may also have catalytic and non-catalytic roles independent of NatA. Several inherited and de novo NAA10 variants have been associated with genetic disease in humans. In this study, we present a functional analysis of two de novo NAA10 variants, c.29A>G p.(D10G) and c.32T>G p.(L11R), previously identified in a male and a female, respectively. Both of these neighbouring amino acids are highly conserved in NAA10. Immunoprecipitation experiments revealed that both variants hamper complex formation with NAA15 and are thus likely to impair NatA-mediated Nt-acetylation in vivo. Despite their common impact on NatA formation, in vitro Nt-acetylation assays showed that the variants had opposing impacts on NAA10 catalytic activity. While NAA10 c.29A>G p.(D10G) exhibits normal intrinsic NatA activity and reduced monomeric NAA10 NAT activity, NAA10 c.32T>G p.(L11R) displays reduced NatA activity and normal NAA10 NAT activity. This study expands the scope of research into the functional consequences of NAA10 variants and underlines the importance of understanding the diverse cellular roles of NAA10 in disease mechanisms.


[Translated article] The configuration of the screws in the osteosynthesis of fractures of the femoral neck does not influence the functional or mechanical outcomes.
Synthesis with cannulated screws is one of the accepted methods in femoral neck fractures, although its optimal configuration is a subject in continuous debate. The main objective was to compare the results of the patient with a femoral neck fracture fixed with three screws in triangle and inverted triangle configuration in the frontal plane. Retrospective and comparative study of 53 patients with femoral neck fracture, operated between 2015 and 2022 with fixation with three cannulated screws, 22 with a triangle configuration (triangle group) and 31 in an inverted triangle (inverted triangle group). Functionality was evaluated using the modified Merlé d'Aubigné scale, walking ability using the Koval scale, as well as postoperative complications. On the Merlé d'Aubigné scale, the mean score was 16.7 in the triangle group and 16.1 in the inverted triangle group (p=.259). On the Koval scale, a significant decrease was observed, going from 1.6 preoperative mean to 2.2 after surgery (p=.000), finding no differences between groups. There were six postoperative complications in the triangle group and three in the inverted triangle group (p=.140). The configuration of the screws in the femoral neck, both in the form of a triangle and an inverted triangle, did not influence the functional or mechanical outcomes of the patients with a femoral neck fracture fixed with three cannulated screws.


An inverse stage-shift model to estimate the excess mortality and health economic impact of delayed access to cancer services due to the COVID-19 pandemic.
Decreased cancer incidence and reported changes to clinical management indicate that the COVID-19 pandemic has delayed cancer diagnosis and treatment. This study aimed to develop and apply a flexible model to estimate the impact of delayed diagnosis and treatment on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation. A model was developed and made publicly available to estimate population-level health economic outcomes by extrapolating and weighing stage-specific outcomes by the distribution of stages at treatment initiation. It was applied to estimate the impact of 3- and 6-month delays based on Australian data for stage I breast cancer, colorectal cancer, and lung cancer patients, and for T1 melanoma. Two approaches were explored to estimate stage shifts following a delay: (a) based on the relation between time to treatment initiation and overall survival (breast, colorectal, and lung cancer), and (b) based on the tumor growth rate (melanoma). Using a conservative once-off 3-month delay and considering only shifts from stage I/T1 to stage II/T2, 88 excess deaths and $12 million excess healthcare costs were predicted in Australia over 5 years for all patients diagnosed in 2020. For a 6-month delay, excess mortality and healthcare costs were 349 deaths and $46 million over 5 years. The health and economic impacts of delays in treatment initiation cause an imminent policy concern. More accurate individual patient data on shifts in stage of disease during and after the COVID-19 pandemic are critical for further analyses.


Frequency specificity and left-ear advantage of medial olivocochlear efferent modulation: a study based on stimulus frequency otoacoustic emission.
The medial olivocochlear (MOC) bundle is an auditory nucleus that projects efferent nerve fibers to the outer hair cells (OHCs) for synaptic innervation. The aim of the present study was to investigate the possible existence of frequency and ear specificity in MOC efferent modulation, as well as how MOC activation influences cochlear tuning. Stimulus frequency otoacoustic emissions (SFOAEs) were used to study MOC efferent modulation. Therefore, the current experiment was designed to compare the degree of SFOAE suppression in the both ears of 20 individuals at 1, 2, 4, and 8 kHz. We also compared changes in Q10 values of SFOAE suppression tuning curves at 1, 2, and 4 kHz under contralateral acoustic stimulation (CAS) and no-CAS conditions. We observed a significant reduction in SFOAE magnitude in the CAS condition compared with the no-CAS condition at 1 and 2 kHz in the left ear. A significant difference in CAS suppression was also found between the left and right ears at 1 and 2 kHz, with larger CAS suppression in the left ear. CAS further produced a statistically significant increase in the Q10 value at 1 kHz and a significant reduction in Q10 values at 2 and 4 kHz. These findings suggest a left-ear advantage in terms of CAS-induced MOC efferent SFOAE suppression, with larger MOC efferent modulation for lower frequencies, and cochlear tuning was sharpened by means of MOC activation at lower frequencies and broadened at higher frequencies.


Oxidative stability of soy proteins: From ground soybeans to structured products.
The production of soy protein-based foods requires multiple-step, intensive processing and storage of soy ingredients, which can increase the product's susceptibility to oxidation. Therefore, we investigated the oxidative stability of soy protein-based products subjected to different relevant conditions or treatments: over storage of soy flours, over fractionation to yield soy protein isolate (SPI), and over subsequent thermomechanical processing to yield a model structured product. Soy flours were stable to lipid and protein oxidation over 250 days storage in chilled or ambient conditions. The fractionation process applied to make SPI did not increase substantially protein carbonylation, but increased surface-exposed hydrophobicity and decreased free thiols, compared to the starting defatted flour. Subsequent processing of hydrated SPI powder at 140 °C further increased protein carbonylation to a high extent. Therefore, we conclude that soy flours can be stable over long storage times, but processing to yield structured foods products promote protein oxidation.


Musculoskeletal pain profile of obese individuals attending a multidisciplinary weight management service.
Obesity is associated with numerous chronic diseases, including musculoskeletal (MSK) pain, which affects on quality of life (QoL). There is, however, limited research providing a comprehensive MSK pain profile of an obese cohort. This retrospective study used a patient database at a national weight management service. After ethical approval, anonymized patient data were statistically analyzed to develop a pain profile, investigate relationships between pain, sleep, and function, and explore variables associated with having low back pain (LBP) and knee pain. Overall, 915 individuals attended the weight management service from January 2011 to September 2015 [male, 35% (n = 318; confidence interval [CI] = 32-38); female, 65% (n = 597; CI = 62-68); mean age 44.6]. Mean body mass index was 50.7 kg/m [class III obese (body mass index ≥40 kg/m), 92% (n = 835; CI = 91-94)]. Approximately 91% reported MSK pain: LBP, 69% (n = 539; CI = 65-72) [mean Numeric Rating Scale 7.4]; knee pain, 58% (n = 447; CI = 55-61) [mean Numeric Rating Scale 6.8]. Class III obese and multisite pain patients had lower QoL and physical activity levels, reduced sleep, and poorer physical function than less obese patients and those without pain (P < 0.05). Relationships were found between demographic, pain, self-report, psychological, and functional measures (P < 0.05). Patients who slept fewer hours and had poorer functional outcomes were more likely to have LBP; patients who were divorced, had lower QoL, and more frequent nocturia were more likely to have knee pain (P < 0.05). Multisite MSK pain is prevalent and severe in obese patients and is negatively associated with most self-report and functional outcomes. This high prevalence suggests that pain management strategies must be considered when treating obesity.


Early experience with the use of an interlocking nail for the repair of canine femoral shaft fractures.
Static locked nailing was used to repair fractures of the femoral diaphysis in 15 dogs. The implant consists of a 5, 6, or 7 mm diameter stainless steel rod made up of two parts: the body of the nail, in which there are 13 threaded holes, and a piece without holes that contains a slot for anchoring the jig. Good limb function was obtained after less than 3 weeks in 12 dogs and these dogs remained sound throughout the study. Radiographic examination revealed fracture healing in 11 of the dogs, between 8 and 16 weeks after surgery. One dog was not returned for follow-up evaluation until 22 weeks after surgery; complete healing was apparent from radiographic examination. The remaining three dogs had to have additional operations, one because of lameness caused by excessive length of the distal screws, one because of a nonunion, and the third because of a sequestrum. Fracture healing in these dogs was observed at 18, 21, and 24 weeks respectively. Loosening of one screw and angulation of the bone occurred in one dog. These complications had no adverse effects on clinical outcome.


A previously unrecognized influenza B virus glycoprotein from a bicistronic mRNA that also encodes the viral neuraminidase.
RNA segment 6 of the influenza B virus genome codes for a previously unidentified polypeptide designated NB. The reading frame for this polypeptide begins with the first AUG codon on the mRNA and overlaps the reading frame for the viral neuraminidase by 292 nucleotides. The amino acid sequence of polypeptide NB deduced from the nucleotide sequence of the B/Lee/40 strain consists of 100 amino acids with a molecular weight of 11,242. The sequence contains four potential glycosylation sites, and the protein has been found to be glycosylated in infected cells. NB has not been found in virions. Sucrose gradient sedimentation and analysis of the structure of the mRNA by nuclease S1 mapping and sequence analysis by the primer extension method indicated that polypeptide NB and the neuraminidase are translated from a single bicistronic mRNA. A protein analogous to NB has not been found with influenza A virus, and this represents a major difference between the two virus types.


Cholesterol: Bioactivities, Structural Modification, Mechanisms of Action, and Structure-Activity Relationships.
Cholesterol, steroid alcohol, was discovered by M.E. Chevreul in 1815. Cholesterol and its derivatives showed a large variety of biological properties such as anticancer activity, anticardiac activity, anti-inflammatory activity, antimicrobial activity, anti-psychotic activity, antioxidant activity, drug-loaded activity, etc. In this mini-review, the advances of structural modification of cholesterol from 2014 to 2020 are summarized. In addition, the bioactivities, mechanisms of action and structureactivity relationships of cholesterol and its related derivatives are also discussed.


Dietary omega 3 polyunsaturated fatty acids and Alzheimer's disease: interaction with apolipoprotein E genotype.
Epidemiological studies suggest a protective role of omega-3 poly-unsaturated fatty acids (n-3 PUFA) against Alzheimer's disease (AD). However, most intervention studies of supplementation with n-3 PUFA have yielded disappointing results. One reason for such discordant results may result from inadequate targeting of individuals who might benefit from the supplementation, in particular because of their genetic susceptibility to AD. The ε4 allele of the apolipoprotein E gene (ApoE) is a genetic risk factor for late-onset AD. ApoE plays a key role in the transport of cholesterol and other lipids involved in brain composition and functioning. The action of n-3 PUFA on the aging brain might therefore differ according to ApoE polymorphism. The aim of this review is to examine the interaction between dietary fatty acids and ApoE genotype on the risk for AD. Carriers of the ε4 allele tend to be the most responsive to changes in dietary fat and cholesterol. Conversely, several epidemiological studies suggest a protective effect of long-chain n-3 PUFA on cognitive decline only in those who do not carry ε4 but with inconsistent results. An intervention study showed that only non-carriers had increased concentrations of long-chain n-3 PUFA in response to supplementation. The mechanisms underlying this gene-by-diet interaction on AD risk may involve impaired fatty acids and cholesterol transport, altered metabolism of n-3 PUFA, glucose or ketones, or modification of other risk factors of AD in ε4 carriers. Further research is needed to explain the differential effect of n-3 PUFA on AD according to ApoE genotype.


A WASN-Based Suburban Dataset for Anomalous Noise Event Detection on Dynamic Road-Traffic Noise Mapping.
Traffic noise is presently considered one of the main pollutants in urban and suburban areas. Several recent technological advances have allowed a step forward in the dynamic computation of road-traffic noise levels by means of a Wireless Acoustic Sensor Network (WASN) through the collection of measurements in real-operation environments. In the framework of the LIFE DYNAMAP project, two WASNs have been deployed in two pilot areas: one in the city of Milan, as an urban environment, and another around the city of Rome in a suburban location. For a correct evaluation of the noise level generated by road infrastructures, all Anomalous Noise Events (ANE) unrelated to regular road-traffic noise (e.g., sirens, horns, speech, etc.) should be removed before updating corresponding noise maps. This work presents the production and analysis of a real-operation environmental audio database collected through the 19-node WASN of a suburban area. A total of 156 h and 20 min of labeled audio data has been obtained differentiating among road-traffic noise and ANEs (classified in 16 subcategories). After delimiting their boundaries manually, the acoustic salience of the ANE samples is automatically computed as a contextual Signal-to-Noise Ratio (SNR) together with its impact on the A-weighted equivalent level ( Δ L A e q ). The analysis of the real-operation WASN-based environmental database is evaluated with these metrics, and we conclude that the 19 locations of the network present substantial differences in the occurrences of the subcategories of ANE, with a clear predominance of the noise of sirens, trains, and thunder.


Detection of pancreatic neuroendocrine tumors (PNET) using semi-quantitative [68Ga]DOTATOC PET in combination with multiphase contrast-enhanced CT.
Pancreatic neuroendocrine tumors (PNETs) pose a diagnostic challenge with respect to the physiologic somatostatin receptor expression in the uncinate process representing a potential pitfall for receptor imaging with PET/CT. We identified 49 PNETs from a total of 316 consecutive [68Ga]DOTATOC PET/CT examinations for whom the detections rates of PET and multiphase contrast enhanced (CE-) CT could be retrospectively compared and 38 PNETs for which SUVmax and SUVmax target-to-liver ratios could be calculated for the tumors and the uncinate process. The detection rate of PET (83.7%) was higher than of the different CT phases (arterial: 59.2%, P=0.017; portal-venous: 38.8%, P<0.001; venous: 46.9%, P=0.001; multiphase: 71.4%, P=0.286). Compared to the other method PET revealed 28.6% additional lesions and multiphase CE-CT 16.3%. The portal-venous phase revealed only lesions that were also detected in the arterial or venous phase. The detection rate for PNETs in the uncinate process (N.=9) was 66.7% for PET versus 55.6% for multiphase CE-CT. SUVmax and SUVmax target-to-liver ratios differed significantly (P<0.001) for PNETs (mean, range: SUVmax, 14.6, 1.4-69.3; SUVmax target-to-liver ratio, 3.2, 0.69-23.1) and uncinate process (4.32, 0.8-13.5; 0.94, 0.51-1.56), however with a wide overlap. Patients with PNETs should undergo [68Ga]DOTATOC PET/CT with at least an arterial and venous phase CT scan. SUVmax and SUVmax target-to-liver ratios provide additional information but do no reliably separate PNETs from normal tracer uptake in the uncinate process.


Overexpression of MUC1 and Genomic Alterations in Its Network Associate with Prostate Cancer Progression.
We investigate the association of MUC1 with castration-resistant prostate cancer (CRPC), bone metastasis, and PC recurrence. MUC1 expression was studied in patient-derived bone metastasis and CRPCs produced by prostate-specific PTEN-/- mice and LNCaP xenografts. Elevations in MUC1 expression occur in CRPC. Among nine patients with hormone-naïve bone metastasis, eight express MUC1 in 61% to 100% of PC cells. Utilizing cBioPortal PC genomic data, we organized a training (n=300), testing (n=185), and validation (n=194) cohort. Using the Cox model, a nine-gene signature was derived, including eight genes from a MUC1-related network (APC, CTNNB1/β-catenin, GALNT10, GRB2, LYN, SIGLEC1, SOS1, and ZAP70) and FAM84B. Genomic alterations in these genes reduce disease-free survival (DFS) in the training (P=.00161), testing (P=.00699), entire (training+testing, P=5.557e-5), and a validation cohort (P=3.326e-5). The signature independently predicts PC recurrence [hazard ratio (HR)=1.731; 95% confidence interval (CI): 1.104-2.712; P=.0167] after adjusting for known clinical factors and stratifies patients with high risk of PC recurrence using the median (HR 2.072; 95% CI: 1.245-3.450, P=.0051) and quartile 3 (HR 3.707, 95% CI: 1.949-7.052, P=6.51e-5) scores. Several novel β-catenin mutants are identified in PCs leading to a rapid onset of death and recurrence. Genomic alterations in APC and CTNNB1/β-catenin reduce DFS in two independent PC cohorts (n=485, P=.0369; n=84, P=.0437). The nine-gene signature also associates with reductions in overall survival (P=.0458) and DFS (P=.0163) in melanoma patients (n=367). MUC1 upregulation is associated with CRPC and bone metastasis. A nine-gene signature derived from a MUC1 network predicts PC recurrence.


Absence of carbon transfer between Medicago truncatula plants linked by a mycorrhizal network, demonstrated in an experimental microcosm.
Carbon transfer between plants via a common extraradical network of arbuscular mycorrhizal (AM) fungal hyphae has been investigated abundantly, but the results remain equivocal. We studied the transfer of carbon through this fungal network, from a Medicago truncatula donor plant to a receiver (1) M. truncatula plant growing under decreased light conditions and (2) M. truncatula seedling. Autotrophic plants were grown in bicompartmented Petri plates, with their root systems physically separated, but linked by the extraradical network of Glomus intraradices. A control Myc-/Nod- M. truncatula plant was inserted in the same compartment as the receiver plant. Following labeling of the donor plant with 13CO2, 13C was recovered in the donor plant shoots and roots, in the extraradical mycelium and in the receiver plant roots. Fatty acid analysis of the receiver's roots further demonstrated 13C enrichment in the fungal-specific lipids, while almost no label was detected in the plant-specific compounds. We conclude that carbon was transferred from the donor to the receiver plant via the AM fungal network, but that the transferred carbon remained within the intraradical AM fungal structures of the receiver's root and was not transferred to the receiver's plant tissues.


Novel trans-tail regulation of H2B ubiquitylation and H3K4 methylation by the N terminus of histone H2A.
Chromatin is regulated by cross talk among different histone modifications, which can occur between residues within the same tail or different tails in the nucleosome. The latter is referred to as trans-tail regulation, and the best-characterized example of this is the dependence of H3 methylation on H2B ubiquitylation. Here we describe a novel form of trans-tail regulation of histone modifications involving the N-terminal tail of histone H2A. Mutating or deleting residues in the N-terminal tail of H2A reduces H2B ubiquitylation and H3K4 methylation but does not affect the recruitment of the modifying enzymes, Rad6/Bre1 and COMPASS, to genes. The H2A tail is required for the incorporation of Cps35 into COMPASS, and increasing the level of ubiquitylated H2B in H2A tail mutants suppresses the H3K4 methylation defect, suggesting that the H2A tail regulates H2B-H3 cross talk. We mapped the region primarily responsible for this regulation to the H2A repression domain, HAR. The HAR and K123 of H2B are in close proximity to each other on the nucleosome, suggesting that they form a docking site for the ubiquitylation machinery. Interestingly, the HAR is partially occluded by nucleosomal DNA, suggesting that the function of the H2A cross talk pathway is to restrict histone modifications to nucleosomes altered by transcription.


Does conventional posterior vault remodeling alter endocranial morphology in patients with true lambdoid synostosis?
True lambdoid synostosis (TLS) produces a consistent morphology that includes occipital flattening, an ipsilateral occipitomastoid prominence, and a mild contralateral hemifacial deficiency that minimally improves with surgery. Prior studies have demonstrated that dysmorphic middle and posterior cranial fossae contribute to the craniofacial scoliosis characteristic of TLS. We hypothesize that these endocranial features remain after surgery, causing the persistent hemifacial deficiency seen in these patients. Three-dimensional anthropometric measurements were made on preoperative and postoperative CT scans of patients with TLS (n = 5). Quantitative analysis was performed on the middle cranial fossa area (MCF), anterior cranial fossa area (ACF), posterior fossa deflection angle (PFA), petrous ridge angle (PRA), temperomandibular joint (TMJ) angle, and external auditory meatus angle. The results were analyzed using a 2-tailed t test. Preoperative CT scans were obtained at a mean age of 1.05 years. Patients underwent posterior vault remodeling at a mean age of 1.33 years. Postoperative CT scans were obtained a mean age of 3.14 years. Following surgery, patients with TLS demonstrated an unchanged PFA (P = 0.76) with deviation toward the affected suture. The ACF remained symmetrical (P = 0.212), and the contralateral MCF remained enlarged relative to the ipsilateral side (P = 0.003). The contralateral middle fossa became more retrodisplaced (P = 0.021). The ipsilateral PRA remained unchanged (P = 0.95). Ear position also remained asymmetrical (P = 0.037). The position of the TMJ was not statistically different between sides before (P = 0.24) or after surgery (P = 0.07). Traditional cranioplasty effectively restores calvarial shape, but does not significantly alter the dysmorphic features seen in the endocranium of patients with TLS.


Hypertension Management in Primary Care.
To improve hypertension control, this cluster randomized trial evaluated the effectiveness of physician manager education about hypertension management. After randomization at practice level, primary care physicians of the intervention arm, whose practices collaborated with a university department, participated in a three-session education on evidence-based hypertensiology and practice implementation strategies. The primary outcome was blood pressure (BP) control (ambulatory blood pressure [ABP] <130/80 mmHg) after 5 months. Secondary outcomes were changes in BP and practice routines regarding hypertension management. Following an intention-to-treat approach, data analyses included crude and adjusted generalized mixed models and sensitivity analyses. These took into account sex, age, ≥ hypertension-related disease and resistant hypertension (RH). The analysis included 103 of 169 patients from 22 practices. Overall, BP decrease was -8.2 systolic and -4.1 mmHg diastolic. The intervention had no effect on BP control (odds ratio 0.84 [95% CI 0.29-2.43]) and BP changes (interventional effect: systolic -2.48 mmHg [95% CI -7.24 to 2.29], diastolic -0.25 mmHg [95% CI 3.31 to 2.82]). Sensitivity analysis indicated effect modification in patients with RH. Intervention practices requested educational input on difficult cases, and newly implemented 3 practice strategies (14.5±2.6 versus 11.4±2.2; P=0.005). After the short follow-up of 5 months, the intervention had no impact on BP control but improved the use of practice strategies.


Beta-adrenergic-receptor localization by light microscopic autoradiography.
beta-Receptors were identified in rat brain by a light microscopic autoradiographic technique. The procedure involved binding 3H-labeled dihydroalprenolol to beta-receptors in intact slide-mounted tissue sections and generating autoradiograms by the apposition of emulsion-coated cover slips, Biochemical analysis of the binding indicated that these conditions provided a high degree of selective labeling of beta-receptors. High densities of receptors were found in superficial layers of the cerebral cortex, throughout the caudate-putamen, in the periventricular nucleus of the thalamus, in the molecular layer of the cerebellum, and in other areas. These results are in agreement with other electrophysiological and histochemical data. This radiohistochemical approach should be an important addition to other methods for mapping functional catecholamine neuronal pathways and sites of hormonal action.


Pyrrolo[2',3':3,4]cyclohepta[1,2-d][1,2]oxazoles, a New Class of Antimitotic Agents Active against Multiple Malignant Cell Types.
A new class of pyrrolo[2',3':3,4]cyclohepta[1,2-d][1,2]oxazoles was synthesized for the treatment of hyperproliferative pathologies, including neoplasms. The new compounds were screened in the 60 human cancer cell lines of the NCI drug screen and showed potent activity with GI50 values reaching the nanomolar level, with mean graph midpoints of 0.08-0.41 μM. All compounds were further tested on six lymphoma cell lines, and eight showed potent growth inhibitory effects with IC50 values lower than 500 nM. Mechanism of action studies showed the ability of the new [1,2]oxazoles to arrest cells in the G2/M phase in a concentration dependent manner and to induce apoptosis through the mitochondrial pathway. The most active compounds inhibited tubulin polymerization, with IC50 values of 1.9-8.2 μM, and appeared to bind to the colchicine site. The G2/M arrest was accompanied by apoptosis, mitochondrial depolarization, generation of reactive oxygen species, and PARP cleavage.


How the Term 'Self-Management' is Used in HIV Research in Low- and Middle-Income Countries: A Scoping Review.
This scoping review assessed how the term 'self-management' (SM) is used in peer-reviewed literature describing HIV populations in low- and middle-income countries (LMIC). This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. OVID Medline, Embase, CAB Abstracts, and EBSCO CINAHL, Scopus, and Cochrane Library were searched up to September 2021 for articles with SM in titles, key words, or abstracts. Two team members independently screened the titles and abstracts, followed by the full-text. A data extraction tool assisted with collecting findings. A total of 103 articles were included. Since 2015, there has been a 74% increase in articles that use SM in relation to HIV in LMIC. Fifty-three articles used the term in the context of chronic disease management and described it as a complex process involving active participation from patients alongside providers. Many of the remaining 50 articles used SM as a strategy for handling one's care by oneself, with or without the help of community or family members. This demonstrates the varied conceptualizations and uses of the term in LMIC, with implications for the management of HIV in these settings. Future research should examine the applicability of SM frameworks developed in high-income settings for LMIC.


Predictors of independent walking in children with spastic diplegia.
A prospective study was carried out to identify predictors of independent walking in 31 children with either spastic diplegia or triplegia, observed from the age of 9 to 18 months (mean, 11 months) and followed for a mean period of 30 months (range, 24 to 36 months). Mean age at most recent examination was 41 months (range, 36 to 54 months). We used an 18-item scheme to chart the acquisition, from the prone position, of prelocomotor, sitting, and locomotor skills. Examinations were conducted every 6 months and videotaped according to a standardized procedure. At latest assessment 18 (58%) of the 31 children had achieved walking, 7 (23%) independently and 11 (35%) with assistance; 13 (42%) did not achieve walking. Ambulatory status was related to developmental quotient and visual acuity: all the children who became independent walkers had normal visual acuity and in 86% of cases a normal general development quotient. Moreover, we found a significant correlation between the number of gross motor skills achieved and the rate of achievement before 2 years of age and ambulatory status at 3 to 5 years of age. Ability to put weight on the hands while prone and to roll from supine to prone position by 18 months of age were significantly related to independent walking, while ability to sit without support was predictive only at around 24 months of age.


The reproduction number of COVID-19 and its correlation with public health interventions.
Throughout the past six months, no number has dominated the public media more persistently than the reproduction number of COVID-19. This powerful but simple concept is widely used by the public media, scientists, and political decision makers to explain and justify political strategies to control the COVID-19 pandemic. Here we explore the effectiveness of political interventions using the reproduction number of COVID-19 across Europe. We propose a dynamic SEIR epidemiology model with a time-varying reproduction number, which we identify using machine learning. During the early outbreak, the basic reproduction number was 4.22 ± 1.69, with maximum values of 6.33 and 5.88 in Germany and the Netherlands. By May 10, 2020, it dropped to 0.67 ± 0.18, with minimum values of 0.37 and 0.28 in Hungary and Slovakia. We found a strong correlation between passenger air travel, driving, walking, and transit mobility and the effective reproduction number with a time delay of 17.24 ± 2.00 days. Our new dynamic SEIR model provides the flexibility to simulate various outbreak control and exit strategies to inform political decision making and identify safe solutions in the benefit of global health.


Acute phase protein and protein electrophoresis values for captive Grant's zebra (Equus burchelli).
Grant's zebra (Equus burchelli) are commonly kept in zoos and are subject to routine health monitoring and research studies. Recently, assays for acute phase proteins (APP) have been described in many wildlife species, and specific assays for serum amyloid A (SAA) have been well validated and studied in horses (Equus ferus caballus), in which it serves as a major APP. In the present study, serum samples from 26 Grant's zebra were subject to analysis by using assays for SAA, haptoglobin (HP), and protein electrophoresis. Reference intervals were calculated by using the robust method: SAA 1.8-31.4 mg/L and HP 0.37-1.58 mg/ml. Significant differences in SAA and HP were observed in clinically abnormal zebra; in some cases, these differences were marked and were noted in the absence of abnormal values for protein electrophoretic fractions. These data indicate that APP may be a valuable and sensitive tool in monitoring inflammation in this species.


Attenuating illusory binding with TMS of the right parietal cortex.
A number of neuroimaging and neuropsychology studies have implicated various regions of parietal cortex as playing a critical role in the binding of color and form into conjunctions. The current study investigates the role of two such regions by examining how parietal transcranial magnetic stimulation (TMS) influences binding errors known as 'illusory conjunctions'. Participants made fewer binding errors after 1 Hz rTMS of the right intraparietal sulcus (IPS), while basic perception of features (color and shape) was unaffected. No perceptual effects were found following left IPS stimulation, or stimulation of the right angular gyrus at the junction of the transverse occipital sulcus (IPS/TOS). These results support a role for the parietal cortex in feature binding but in ways that may require rethinking.


RIG-I suppresses the migration and invasion of hepatocellular carcinoma cells by regulating MMP9.
The retinoic acid-induced protein I (Rig-I/Ddx58), (RIG-I) initiates a signaling cascade that induces innate immune defences which is associated with the production of type I interferons (IFNs) and inflammatory cytokines to establish an antiviral state. Aberrant RIG-I signaling leads to inflammation, autoimmune diseases and cancer. However, the role of RIG-I in hepatocellular carcinoma (HCC) is still unknown. Here, we observed that RIG-I expression was downregulated in HCC tissues and loss of RIG-I expression was correlated with poor clinicopathological features. Additionally, we demonstrated that patients with positive RIG-I expression had a better 3-year survival and RIG-I was an independent factor for predicting the prognosis of HCC patients. Elevated RIG-I expression inhibited the proliferation, migration, and invasion of HCC. Inhibiting RIG-I with its specific siRNA was able to attenuate the malignant behavior of HCC cells. Moreover, RIG-I inhibited the invasive behavior through downregulating matrix metalloproteinase-9 (MMP9). Mechanistically, RIG-I enhances IFN-α response by amplifying IFN-α effecter signaling via strengthening STAT1 activation. Addressing this pathway, we identified that RIG-I may serve as a prognostic marker and that MMP9 may be a potential target of RIG-I in HCC.


The regulation of Insulin/IGF-1 signaling by miR-142-3p associated with human longevity.
MicroRNAs (miRNAs) have been demonstrated to modulate life span in the invertebrates C. elegans and Drosophila by targeting conserved pathways of aging, such as insulin/IGF-1 signaling (IIS). However, a role for miRNAs in modulating human longevity has not been fully explored. Here we investigated novel roles of miRNAs as a major epigenetic component of exceptional longevity in humans. By profiling the miRNAs in B-cells from Ashkenazi Jewish centenarians and 70-year-old controls without a longevity history, we found that the majority of differentially expressed miRNAs were upregulated in centenarians and predicted to modulate the IIS pathway. Notably, decreased IIS activity was found in B cells from centenarians who harbored these upregulated miRNAs. miR-142-3p, the top upregulated miRNA, was verified to dampen the IIS pathway by targeting multiple genes including GNB2, AKT1S1, RHEB and FURIN . Overexpression of miR-142-3p improved the stress resistance under genotoxicity and induced the impairment of cell cycle progression in IMR90 cells. Furthermore, mice injected with a miR-142-3p mimic showed reduced IIS signaling and improved longevity-associated phenotypes including enhanced stress resistance, improved diet/aging-induced glucose intolerance, and longevity-associated change of metabolic profile. These data suggest that miR-142-3p is involved in human longevity through regulating IIS-mediated pro-longevity effects. This study provides strong support for the use of miR-142-3p as a novel therapeutic to promote longevity or prevent aging/aging-related diseases in human.


PCR-RFLP genotyping protocol for chicken Mx gene G/A polymorphism associated with the S631N mutation.
The Mx (myxovirus resistance) gene codes for a protein with antiviral activity. Non-synonymous G/A polymorphism at position 2032 of chicken Mx cDNA results in a change at amino acid 631 of the Mx protein. This mutation has been shown to affect the antiviral activity of the Mx molecule, although recent studies have not confirmed this effect in response to some influenza strains. Nevertheless, the G/A polymorphism could be important for the chicken's response to other viruses. A robust PCR-RFLP protocol for genotyping chicken Mx gene polymorphism associated with the S631N mutation was developed. The F primer anneals to the last intron of the Mx gene, and the R primer anneals to the last exon of the gene, with an expected PCR product of 299 bp. PCR products were digested with Hpy8I. This enzyme cuts the sequence 5'-GTN|NAC-3', 2 bp downstream of the Mx polymorphism for the G allele, whereas the fragment containing the A allele is not cleaved. One hundred and twenty-seven chickens (commercial broilers, White Leghorn and New Hampshire) were genotyped using this protocol, and genotyping data were validated by sequencing. Full identity of results between the two genotyping methods was observed for all 127 samples, proving the reliability and robustness of this PCR-RFLP protocol.


Substance Use and Adherence to HIV Pre-Exposure Prophylaxis in Studies Enrolling Men Who Have Sex with Men and Transgender Women: A Systematic Review.
Optimal adherence to pre-exposure prophylaxis (PrEP) is critical, but challenging. Men who have sex with men and transgender women have high rates of HIV incidence and substance use. Substance use is associated with reduced adherence to other medications, but associations between substance use and adherence to PrEP are less clear. Thus, the current review 1) systematically evaluates the measurement of substance use and PrEP adherence in studies examining both and 2) summarizes reported findings. Peer-reviewed articles published between 2010 - April 2021 examining associations between substance use and PrEP adherence were reviewed. Fifty studies met inclusion criteria. Assessment of substance use (i.e., mostly via self-reports at baseline) and PrEP adherence (i.e., often via tenofovir diphosphate [TFV-DP] concentration levels at follow-up) varied considerably across studies. Many studies used categorical variables (e.g., substance use: yes/no). Studies using TFV-DP levels defined adherence consistently (i.e., TFV-DP ≥ 700 fmol/punch), with slight variations. Qualitative studies (n = 10) indicated that substance use (mainly alcohol) is related to poorer PrEP adherence. While quantitative findings to date are equivocal for alcohol, there is a pattern of findings linking stimulant use with poorer PrEP adherence. This review reveals four methodological gaps, which can be addressed in future research by: 1) use of uniform benchmarks for substance use measures, 2) prospective assessment for substance use, 3) use of continuous outcome variables wherever possible, and 4) more extensive consideration of potential confounders. Addressing these methodological gaps may help us reach more definitive conclusions regarding associations between substance use and PrEP adherence.


[Use of the granulocytic myeloperoxidase release reaction to diagnose food additive allergies].
Adverse reactions to food additives are difficult to diagnose due to the diversity of mechanisms involved in their realization and to the absence of reasonably reliable methods for their determination. Eighty-three patients with allergic diseases were examined using the granulocytic myeloperoxidase release reaction (MRR) to diagnose intolerance reactions to food additives (E102, E122, E124, E132, E110, E2111). MRR revealed leukocyte hypersensitivity to tartrazine in 10.8%, sunset yellow in 4.8%, ponceau in 13.2%, indigo carmine in 8.4%, carmoisine and benzoate in 9.6%. The findings were correlated with history data and the levels of IgE antibodies to these dyes. The practical use of the proposed MRR method makes it possible to enhance the accuracy of diagnosis of allergy to food additives.


The impact of thoracic paravertebral block over post-operatory evolution in open lobectomy.
The thoracic paravertebral block (PVB), a technique of post-thoracotomy analgesia of similar effectiveness as continuous epidural analgesia (CEA) but with a better safety profile, is underutilized in current practice. This study compares the outcome of post-lobectomy patients in relation to the analgesic method used: parenteral analgesia (PA) vs. PVB + PA, and provides justification for the routine use of PVB in all patients where CEA is contraindicated. We randomized 213 consecutive patients undergoing open lobectomy to benefit from two different protocols of postoperative analgesia: PA vs. PVB +PA. We compared the frequency of cardiac hemodynamic, respiratory, pleural or surgical-related complications. After lobectomy, the PVB patients (72/213) were found to have a significantly lower frequency of congestive heart failure (7.1%vs.0.0%)(p=0.049), ischemic cardiomyopathy (10.6%vs.0.0%)(p=0.010), pulmonary atelectasis (35%vs.1.1%)(p<0.001), residual pleural space (29.8%vs.15.3%)(p=0.032) and residual intrapleural blood clots (14.9%vs.1.4%)(p=0.005). Other postoperative complications, Intensive Care stay, total hospital stay and mortality rate were less frequent in the PVB group but without reaching statistical significance. The use of SPVB is associated with significant less postoperative complications than PA only. This study suggests that the SPVB might be the ideal choice in post-thoracotomy pain management when CEA cannot be used. Open lobectomy, Post-lobectomy, Thoracic paravertebral block.


Metal-free hydroxy and aminocyanation of furanos-3-uloses.
TSAO-T and ATSAO-T analogues are molecules of interest that are able to inhibit the reverse transcriptase (RT) of HIV-1 and HCV. We also recently highlighted their antiproliferative properties. In all cases, the spiro cycle was a required group for biological activities, which led chemists to produce many derivatives, especially on this ring. These structures can be accessed through the formation of glycoaminonitriles and glycocyanhydrins using methodologies not always adapted to the synthesis of large quantities. Moreover, these latter are poorly versatile (substrate-dependent), need expensive cyanogenic agents and implies the use of a metal in non-catalytic amounts. For this reason, we report here a new metal-free methodology for the synthesis of glycoaminonitriles and glycocyanhydrins using molecular iodine (I2).


Changes of inducible protein-10 and regulated upon activation, normal T cell expressed and secreted protein in acute rejection of pancreas transplantation in rats.
To investigate the role of IFN-gamma inducible protein -10 (IP-10) and regulated upon activation, normal T cell expressed and secreted (RANTES) protein in acute pancreatic allograft rejection in rats. An experimental pancreas transplantation model was established using diabetic SD rats as the recipient, induced by applying streptozocin (STZ). Pancreas transplantation was performed with a physiologic method of portal venous and enteric drainage. Rats were divided into two groups, isograft group (group A, n = 24) and allograft group (group B, n = 24) in which either healthy SD rats or Wistar rats served as donors, respectively. Twelve diabetic or healthy SD rats were used as controls. At d 1, 4, 7, and 10 post transplantation, serum IP-10 and RANTES were assessed by ELISA and their expression in the allografts was determined by immunohistochemistry. In group B (allograft group), the development of acute rejection was significantly correlated with increased serum concentration and tissue expression of IP-10 and RANTES, with a peak level at d 7 post transplantation. In contrast, there was no obvious change before and after transplantation in group A (isograft group). Our study suggests a possible role of IP-10 and RANTES in acute rejection and early monitoring of chemokines may be helpful in predicting the outcome of pancreas transplantation.


Development and Validation of a Terbium-Sensitized LuminescenceAnalytical Method for Deferiprone.
A sensitive fluorometric method for the determination of deferiprone (DFP) based on the formation of a luminescent complex with Tb(3+) ions in aqueous solutions is reported. The maximum excitation and emission wavelengths were 295 and 545 nm, respectively. The effects of various factors on the luminescence intensity of the system were investigated and optimized, then under the optimum conditions, the method was validated. The method validation results indicated that the relative intensity at 545 nm has a linear relationship with the concentration of DFP in aqueous solutions at the range of 7.2 × 10(-9) to 1.4 × 10(-5) M, the detection and quantification limits were calculated respectively as 6.3 × 10(-9) and 2.1 × 10(-8) M, precision and accuracy of the method were lower than 5% and the recovery was between 100.1% and 102.3%. The results indicated that this method was simple, time saving, specific, accurate and precise for the determination of DFP in aqueous solutions. After optimization and validation, the method successfully applied for determination of DFP in tablet dosage forms. The stoichiometry of the Tb(3+)-DFP complex was found as 1:3 and the complex formation constant was 1.6 × 10(16).


Trends in nonindigenous aquatic species richness in the United States reveal shifting spatial and temporal patterns of species introductions.
Understanding the spatial and temporal dynamics underlying the introduction and spread of nonindigenous aquatic species (NAS) can provide important insights into the historical drivers of biological invasions and aid in forecasting future patterns of nonindigenous species arrival and spread. Increasingly, public databases of species observation records are being used to quantify changes in NAS distributions across space and time, and are becoming an important resource for researchers, managers, and policy-makers. Here we use publicly available data to describe trends in NAS introduction and spread across the conterminous United States over more than two centuries of observation records. Available data on first records of NAS reveal significant shifts in dominance of particular introduction patterns over time, both in terms of recipient regions and likely sources. These spatiotemporal trends at the continental scale may be subject to biases associated with regional variation in sampling effort, reporting, and data curation. We therefore also examined two additional metrics, the number of individual records and the spatial coverage of those records, which are likely to be more closely associated with sampling effort. Our results suggest that broad-scale patterns may mask considerable variation across regions, time periods, and even entities contributing to NAS sampling. In some cases, observed temporal shifts in species discovery may be influenced by dramatic fluctuations in the number and spatial extent of individual observations, reflecting the possibility that shifts in sampling effort may obscure underlying rates of NAS introduction.


Identification of clusters of rapid and slow decliners among subjects at risk for Alzheimer's disease.
The heterogeneity of Alzheimer's disease contributes to the high failure rate of prior clinical trials. We analyzed 5-year longitudinal outcomes and biomarker data from 562 subjects with mild cognitive impairment (MCI) from two national studies (ADNI) using a novel multilayer clustering algorithm. The algorithm identified homogenous clusters of MCI subjects with markedly different prognostic cognitive trajectories. A cluster of 240 rapid decliners had 2-fold greater atrophy and progressed to dementia at almost 5 times the rate of a cluster of 184 slow decliners. A classifier for identifying rapid decliners in one study showed high sensitivity and specificity in the second study. Characterizing subgroups of at risk subjects, with diverse prognostic outcomes, may provide novel mechanistic insights and facilitate clinical trials of drugs to delay the onset of AD.


Association of Polypharmacy and Potentially Inappropriate Medications With Physical Functional Impairments in Older Adults With Cancer.
Polypharmacy and potentially inappropriate medications (PIMs) are prevalent in older adults with cancer, but their associations with physical function are not often studied. This study examined the associations of polypharmacy and PIMs with physical function in older adults with cancer, and determined the optimal cutoff value for the number of medications most strongly associated with physical functional impairment. This cross-sectional analysis used baseline data from a randomized study enrolling patients aged ≥70 years with advanced cancer starting a new systemic cancer treatment. We categorized PIM using 2015 American Geriatrics Society Beers Criteria. Three validated physical function measures were used to assess patient-reported impairments: activities of daily living (ADL) scale, instrumental activities of daily living (IADL) scale, and the Older Americans Resources and Services Physical Health (OARS PH) survey. Optimal cutoff value for number of medications was determined by the Youden index. Separate multivariate logistic regressions were then performed to examine associations of polypharmacy and PIMs with physical function measures. Among 439 patients (mean age, 76.9 years), the Youden index identified ≥8 medications as the optimal cutoff value for polypharmacy; 43% were taking ≥8 medications and 62% were taking ≥1 PIMs. On multivariate analysis, taking ≥8 medications was associated with impairment in ADL (adjusted odds ratio [aOR], 1.64; 95% CI, 1.01-2.58) and OARS PH (aOR, 1.73; 95% CI, 1.01-2.98). PIMs were associated with impairments in IADL (aOR, 1.72; 95% CI, 1.09-2.73) and OARS PH (aOR, 1.97; 95% CI, 1.15-3.37). A cutoff of 5 medications was not associated with any of the physical function measures. Physical function, an important component of outcomes for older adults with cancer, is cross-sectionally associated with polypharmacy (defined as ≥8 medications) and with PIMs. Future studies should evaluate the association of polypharmacy with functional outcomes in this population in a longitudinal fashion.


Comparison of a nonradiometric liquid-medium method (MB REDOX) with the BACTEC system for growth and identification of mycobacteria in clinical specimens.
Early identification of tuberculosis in the clinical setting is of great importance in order for specific therapy to be swiftly initiated. MB REDOX (Heipha Diagnostika), a growth-based medium without radioactive materials, was evaluated and was compared to the BACTEC system for detection of mycobacteria, including the Mycobacterium tuberculosis complex and atypical mycobacteria. MB REDOX consists of a Kirchner medium enriched with growth-promoting additives, antibiotic compounds, and a redox indicator which can be monitored to detect growth of mycobacteria with the naked eye. MB REDOX only detects growth and cannot differentiate the M. tuberculosis complex (M. tuberculosis, M. bovis, and M. africanum) from other species of Mycobacterium. Therefore, PCR-restriction fragment length polymorphism analysis (PRA) was used in this investigation to identify to the species level organisms showing positive growth with MB REDOX. Our data demonstrate the usefulness of MB REDOX for the detection of mycobacteria in clinical specimens. The rate of detection of M. tuberculosis complex with MB REDOX (84. 3%) was higher than that with the BACTEC system (68.6%). When combined with PRA for species identification, MB REDOX is easy to perform and is suited to most clinical laboratory settings for the detection and identification of mycobacteria.


[Biliary obstruction: MR-cholangiography with a rapid gradient-echo sequence (2D CE-Fast)].
Magnetic resonance (MR) was used to delineate the biliary tree in patients with obstructive jaundice originating from various types of malignant or benign processes at different locations. With the aid of a rapid sequential gradient-echo acquisition (CE-Fast) and 3D post-processing, heavily T2-weighted images could be obtained to identify the site of obstruction in ten out of eleven patients. Slices were acquired during breath-holding periods of about 12 sec with a total examination time of 10-15 min. The three-dimensional display reliably demonstrated the dilated bile ducts in pre-stenotic areas whereas in the majority of cases post-stenotic ductal segments could not be visualised.


Association of EEG-fMRI Responses and Outcome After Epilepsy Surgery.
To assess the utility of EEG-fMRI for epilepsy surgery, we evaluated surgical outcome in relation to the resection of the most significant EEG-fMRI response. Patients with post-operative neuroimaging and follow-up of at least one year were included. In EEG-fMRI responses, we defined as "primary" the cluster with the highest absolute t-value located in the cortex, and evaluated three levels of confidence for the results. The threshold for low confidence was t ≥ 3.1 (p < 0.005); the one for medium confidence corresponded to correction for multiple comparisons with a false discovery rate of 0.05; and a result reached high confidence when the primary cluster was much more significant than the next highest cluster. Concordance with the resection was determined by comparison to post-operative neuroimaging. We evaluated 106 epilepsy surgeries in 84 patients. An increasing association between concordance and surgical outcome with higher levels of confidence was demonstrated. If the peak response was not resected, the surgical outcome was likely to be poor: for the high confidence level, no patient had a good outcome; for the medium and low levels, only 18% and 28% had a good outcome. The positive predictive value remained low for all confidence levels, indicating that removing the maximum cluster did not ensure seizure freedom. Resection of the primary EEG-fMRI cluster, especially in high confidence cases, is necessary to obtain a good outcome, but not sufficient. This study provided Class II evidence that failure to resect the primary EEG-fMRI cluster is associated with poorer epilepsy surgery outcomes.


Urban green space, tree canopy and 11-year risk of dementia in a cohort of 109,688 Australians.
Urban greening is a climate change-related policy with considerable health benefits. But do these benefits extend to prevention of dementia and, if so, which types of green space matter? Multilevel discrete time-to-event cohort study of incident Alzheimer's disease over 11 years among a baseline recruited between January 1, 2006 and December 31, 2009 (the Sax Institute's 45 and Up Study). Sampled participants for this study (N=109,688) were aged 45 years or older with no record of dementia up to 6 years before baseline, living in the cities of Sydney, Wollongong and Newcastle, Australia. Exposures were percentage total green space, tree canopy and open grass within 1.6-km road network distance buffers at baseline. Outcomes were time-to-first anti-dementia medication prescription (Department of Human Services) or dementia detected during hospitalisation or death up to 31 December 2016 (up to 11 years follow-up). Outcomes were analysed in parallel to triangulate on associations with green space, while testing for bias due to potential under-prescribing of anti-dementia medications. Models were adjusted for baseline person-level factors and area-level socioeconomic disadvantage. Dementia detection varied by case ascertainment method. 1.55% (1,703/109,688) persons were detected using prescribed anti-dementia medications. 3.32% (3,639/109,688) persons were detected during hospitalisation or death via ICD-10 codes. Dementia incidence irrespective of outcome measurement was lower among females, younger participants, those living in couples, with higher qualifications and higher incomes. Dementia risk was lower with more tree canopy when the outcome was measured using hospital and death records (≥30% vs <10% tree canopy incidence hazard ratio (IHR) = 0.86, 95%CI 0.75, 0.99), after adjusting for person-level factors. The opposite association was observed when anti-dementia medications were used to detect dementia (≥30% vs <10% tree canopy IHR = 1.33, 95%CI 1.07, 1.66). Anti-dementia medication-based detection also indicated lower dementia risk with more open grass (≥20% vs <5% IHR = 0.83, 95%CI 0.67, 1.03). Anti-dementia medication prescribing was lower in the highest vs. lowest area-level disadvantage tertile (29.8% vs. 43.7%) among people diagnosed with dementia, indicating potential bias from geographic differences in prescribing practices. Adjusting for area-level disadvantage explained associations between tree canopy, open grass and dementia when detected by anti-dementia medication, but had negligible impact on negative (i.e. potentially protective) association between tree canopy and dementia detected by hospital and death records (≥30% vs <10% tree canopy hazard ratio 0.84, 95%CI 0.72, 0.99). Increasing urban tree canopy cover may help to reduce the risk of dementia. Replication in contrasting contexts and mediation studies to assess pathways are warranted.


Inexpensive Monocular Pico-Projector-based Augmented Reality Display for Surgical Microscope.
This paper describes an inexpensive pico-projector-based augmented reality (AR) display for a surgical microscope. The system is designed for use with Micron, an active handheld surgical tool that cancels hand tremor of surgeons to improve microsurgical accuracy. Using the AR display, virtual cues can be injected into the microscope view to track the movement of the tip of Micron, show the desired position, and indicate the position error. Cues can be used to maintain high performance by helping the surgeon to avoid drifting out of the workspace of the instrument. Also, boundary information such as the view range of the cameras that record surgical procedures can be displayed to tell surgeons the operation area. Furthermore, numerical, textual, or graphical information can be displayed, showing such things as tool tip depth in the work space and on/off status of the canceling function of Micron.


High-resolution SNPs and microsatellite haplotypes point to a single, recent entry of Native American Y chromosomes into the Americas.
A total of 63 binary polymorphisms and 10 short tandem repeats (STRs) were genotyped on a sample of 2,344 Y chromosomes from 18 Native American, 28 Asian, and 5 European populations to investigate the origin(s) of Native American paternal lineages. All three of Greenberg's major linguistic divisions (including 342 Amerind speakers, 186 Na-Dene speakers, and 60 Aleut-Eskimo speakers) were represented in our sample of 588 Native Americans. Single-nucleotide polymorphism (SNP) analysis indicated that three major haplogroups, denoted as C, Q, and R, accounted for nearly 96% of Native American Y chromosomes. Haplogroups C and Q were deemed to represent early Native American founding Y chromosome lineages; however, most haplogroup R lineages present in Native Americans most likely came from recent admixture with Europeans. Although different phylogeographic and STR diversity patterns for the two major founding haplogroups previously led to the inference that they were carried from Asia to the Americas separately, the hypothesis of a single migration of a polymorphic founding population better fits our expanded database. Phylogenetic analyses of STR variation within haplogroups C and Q traced both lineages to a probable ancestral homeland in the vicinity of the Altai Mountains in Southwest Siberia. Divergence dates between the Altai plus North Asians versus the Native American population system ranged from 10,100 to 17,200 years for all lineages, precluding a very early entry into the Americas.


Mechanism of resveratrol in improving ovarian function in a rat model of premature ovarian insufficiency.
To investigate the mechanism of resveratrol treatment in chemically induced premature ovarian insufficiency (POI) in rats. Five-week-old specific pathogen-free healthy Sprague-Dawley female rats (n = 90) were randomly divided into five groups (n = 18): low-dose resveratrol (group A), moderate-dose resveratrol (group B), high-dose resveratrol (group C), model control group (group D) and blank control group (group E). POI was induced in rats from the resveratrol-treated groups and the model control group according to observed indexes using a previously established model (oral administration of tripterygium wilfordii polyglycoside tablet 50 mg/kg/day for 14 days). Western blot analysis was performed to compare levels of PI3K, p-PI3K, Akt, p-Akt, mTOR, p-mTOR, Bax, Bcl-2 and Caspase-3 in ovarian tissues of each group, and expression of p-Akt, p-mTOR, Bax, Bcl-2 and Caspase-3 was also evaluated by immunohistochemistry. Serum levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined using enzyme-linked immunosorbent assay. Compared with controls, we found that serum MDA decreased and SOD increased in resveratrol-treated groups. In addition, we found increased expression of p-PI3K, p-Akt, p-mTOR and Bcl-2, and decreased expression of Bax and Caspase-3 were observed in ovarian tissues of treated rats with POI. There was reduced ovarian function in POI rats compared with rats from the blank control group. Resveratrol reduced oxidative stress and inhibited apoptosis in granulosa cells by activating the PI3K/Akt/mTOR signaling pathway in a rat model of POI.


Strategies for tracking anastasis, a cell survival phenomenon that reverses apoptosis.
Anastasis (Greek for "rising to life") refers to the recovery of dying cells. Before these cells recover, they have passed through important checkpoints of apoptosis, including mitochondrial fragmentation, release of mitochondrial cytochrome c into the cytosol, activation of caspases, chromatin condensation, DNA damage, nuclear fragmentation, plasma membrane blebbing, cell shrinkage, cell surface exposure of phosphatidylserine, and formation of apoptotic bodies. Anastasis can occur when apoptotic stimuli are removed prior to death, thereby allowing dying cells to reverse apoptosis and potentially other death mechanisms. Therefore, anastasis appears to involve physiological healing processes that could also sustain damaged cells inappropriately. The functions and mechanisms of anastasis are still unclear, hampered in part by the limited tools for detecting past events after the recovery of apparently healthy cells. Strategies to detect anastasis will enable studies of the physiological mechanisms, the hazards of undead cells in disease pathology, and potential therapeutics to modulate anastasis. Here, we describe effective strategies using live cell microscopy and a mammalian caspase biosensor for identifying and tracking anastasis in mammalian cells.


[Strengthening interhemispheric interferential inhibition in man with diazepam].
The influence of oral diazepam administration (10 mg) on interhemispheric proactive and retroactive interferential inhibition during detection of test verbal signals was tachistoscopally studied in eight healthy right-handed subjects, in conditions of forward and backward contralateral masking according to the scheme of double blind investigations. Strengthening of effects of forward and backward contralateral masking was revealed which is considered as a testimony to participation of GABA-ergic inhibitory systems in the mechanisms of interhemispheric proactive and retroactive interferential inhibition.


The prevention of peridural adhesions. A comparative long-term histomorphometric study using a biodegradable barrier and a fat graft.
We studied peridural fibrosis in 16 dogs after laminectomies at the L2, L4 and L6 levels. They received either a free fat graft, a biodegradable mechanical barrier (polyethylene oxide (PEO)/polybutylene terephthalate (PBT) copolymer), or no treatment. The animals were killed after 4, 12, 26 and 52 weeks. Histomorphometry showed extensive and consistent peridural fibrosis in control and PEO/PBT groups. Fat grafts produced significantly less fibrous tissue, but the presence of the fat graft in the bony defect prevented closure. Degradation of the PEO/PBT barrier resulted in the formation of more fibrous tissue. We conclude that up to one year a free fat graft is effective in reducing the amount of peridural scarring.


Thumb carpometacarpal arthroplasty using an absorbable interference screw for flexor carpi radialis ligament reconstruction.
Few surgical techniques that address advanced thumb carpometacarpal osteoarthrosis specifically allow early mobilization postoperatively. After trapeziectomy, we carry out a ligament reconstruction using an absorbable interference screw to secure a flexor carpi radialis tendon autograft within the first metacarpal base. Theoretically, superior tendon graft fixation strength allows early mobilization within 2 weeks postoperatively. We have retrospectively compared our clinical results using this technique with another group of patients who underwent traditional ligament reconstruction and tendon interposition as described by Burton and Pellegrini. There were no differences in the verbal pain score, satisfaction rating, or DASH scores between groups. There was a statistically significant decrease in trapezial space ratio both at rest and with stress for the experimental group. Although the clinical significance of this finding is largely unknown, it did not correlate with clinical outcome in our patients. Although no conclusions could be drawn regarding early mobilization after thumb carpometacarpal arthroplasty, further studies are planned to investigate this intriguing aspect of postoperative care. In this article, we present the details of the surgical technique and postoperative rehabilitation.


Urban parents' perceptions of healthy infant growth.
To examine how urban parents' perceptions of healthy infant size and growth relate to objective weight-for-length percentiles of their children, parents of 222 (69% minority) 6- to 27-month-old infants were surveyed. In all, 41% of parents said growth charts had never been explained to them, and 31% were not confident they understood the meaning of chart percentiles. A total of 20% of parents preferred their child weigh ≥75th percentile, and these children had higher mean weight-for-length percentiles than their peers (P = .05). Similarly, 37% of parents agreed that "a chubby baby is a healthy baby," and these children had higher mean weight-for-length percentiles than others in the cohort ( P = .02). Additionally, 58% of parents ranked a growth curve with consistent growth at the 10th percentile as the "least healthy" of 6 infant growth curves. Growth charts are not consistently explained to or understood by urban parents, and many prefer early life growth patterns associated with later obesity.


[Orbital veins and arteries in relation to the connective tissue system of the orbit].
Our study revealed that the relationships between the vessels and the connective tissue, which forms a constant and bilateral symmetrical system of connective tissue septa bordering adipose tissue compartments, are characteristics and constant but essentially different for veins and arteries. The arteries run within the adipose tissue compartments only contacting the connective tissue septa where they perforate them. As to the veins, their relationship with the connective tissue apparatus is completely different. These vessels run within the septa firmly connected with their connective tissue fibres, forming a continuity between the adventitia of the veins and the walls of the adipose tissue compartments. This difference between arteries and veins results in a different spatial structure for the two vascular systems. The arterial system is a radiating system, whereas the venous system is an anastomosing complex of venous rings which are arranged circularly inside as well as outside the muscle cone. It seems likely that the relationships of the vessels, particularly of the veins, with the connective tissue apparatus play an important role in the well-functioning of the orbital blood-circulation.


[Transfection of Escherichia coli using bacteriophage MS2 RNA].
The authors present materials for comparison of three methods of E. coli infection by the RNA of the MS2 bacteriophage. The cells accepted the RNA at the stage of spheroplasts (obtained with the aid of a lysozyme and EDTA) with the efficacy of up to 1.5 X 10(5) IC/mug of the RNA. Diethylpyrocarbonate was used as a transfection stimulant. The product of transfection was identical to the MS2 bacteriophage. The efficacy of transfection in the calcinated system and on the frozen-defrosted bacteria was lower than on the spheroplasts (10(2) IC/mug of the RNA) which was largely associated with the formation of "latent infectious centres". Formation of latent negative colonies was characteristic of bacteriophage MS2, but formation of these colonies was intensified when calcinated cells were used for transfection.


Can managed care do it all?
The thought of turning the public health system over to managed care companies worries many public health professionals. A look at the complexities involved in treating tuberculosis may explain why.


Salvianolic acid B decreases interleukin-1β-induced colitis recurrence in mice.
Degree of mucosal recovery is an important indicator for evaluating the therapeutic effects of drugs in treatment of inflammatory bowel disease (IBD). Increasing evidences has proved that tight junction (TJ) barrier dysfunction is one of the pathological mechanisms of IBD. The aim of this study was to observe whether enhancement of TJ can decrease colitis recurrence. Eighty C57BL/6 mice were randomly divided into four groups including normal group, colitis group, sulfasalazine (SASP) treated group, and traditional Chinese drug salvianolic acid B (Sal B) treated group. Colitis was established in mice by free drinking water containing dextran sulfate sodium, after treatments by SASP and Sal B, recombinant human interleukin-1β (IL-1β) was injected intraperitoneally to induce colitis recurrence. Compared with sham control, cell apoptosis in colitis group was increased from 100.85 ± 3.46% to 162.89 ± 11.45% (P = 0.0038), and TJ dysfunction marker myosin light chain kinase (MLCK) was also significantly increased from 99.70 ± 9.29% to 296.23 ± 30.78% (P = 0.0025). The increased cell apoptosis was reversed by both SASP (125.99 ± 8.45% vs. 162.89 ± 11.45%, P = 0.0059) and Sal B (104.27 ± 6.09% vs. 162.89 ± 11.45%, P = 0.0044). High MLCK expression in colitis group was reversed by Sal B (182.44 ± 89.42% vs. 296.23 ± 30.78%, P = 0.0028) but not influenced by SASP (285.23 ± 41.04% vs. 296.23 ± 30.78%, P > 0.05). The recurrence rate induced by recombinant human IL-1β in Sal B-treated group was significantly lower than that in SASP-treated group. These results suggested a link between intestinal mucosal barrier dysfunction, especially TJ barrier dysfunction, and colitis recurrence. The TJ barrier dysfunction in remission stage of colitis increased the colitis recurrence. This study might provide potential treatment strategies for IBD recurrence.


Precision measurements of relaxation rates of degenerate 1H transitions in methyl groups of small proteins.
An NMR experiment is designed for accurate and robust measurement of transverse relaxation rates of degenerate 1H transitions in selectively 13CH3-labeled, deuterated small proteins. The measurement is based on the use of acute (<90°) angle 1H radio-frequency pulses and relies on selection of the slow- and fast-relaxing components of methyl magnetization following the relaxation period in separate experiments. The R2 decay series recorded with selection of the fast-relaxing components serves as a useful complement to the R2 series acquired with selection of the slow-relaxing part, and permits the extension of the range of relative contributions of the fast- and slow-relaxing parts to apparent signal decay. The approach is experimentally verified on 13CH3 methyl groups of the ILV-{13CH3}-labeled protein ubiquitin at 10 °C and 25 °C. The obtained methyl 1H relaxation rates are in remarkably good agreement with the values obtained from well-established NMR techniques.


beta-Conglycinins among sources of bioactives in hydrolysates of different soybean varieties that inhibit leukemia cells in vitro.
Soybean is a complex matrix containing several potentially bioactive components. The objective was to develop a statistical model to predict the in vitro anticancer potential of soybean varieties based on the correlation between protein composition and bioactive components after simulated gastrointestinal enzyme digestion with their effect on leukemia mouse cells. The IC 50 values of the hydrolysates of soy genotypes (NB1-NB7) on L1210 leukemia cells ranged from 3.5 to 6.2 mg/mL. Depending on genotype, each gram of soy hydrolysates contained 2.7-6.6 micromol of total daidzein, 3.0-4.7 micromol of total genistein, 0.5-1.3 micromol of glycitein, 2.1-2.8 micromol of total saponins, 0.1-0.2 micromol of lunasin, and 0.1-0.6 micromol of Bowman-Birk inhibitor (BBI). The IC 50 values calculated from a partial least-squares (PLS) analysis model correlated well with experimental data ( R (2) = 0.99). Isoflavones and beta-conglycinin positively contributed to the cytotoxicity of soy on L1210 leukemia cells. Lunasin and BBI were potent L1210 cell inhibitors (IC 50 = 13.9 and 22.5 microM, respectively), but made modest contributions to the activity of defatted soy flour hydrolysates due to their relatively low concentrations. In conclusion, the data demonstrated that beta-conglycinins are among the major protein components that inhibit leukemia cell growth in vitro. Furthermore, it was feasible to differentiate soybean varieties on the basis of the biological effect of their components using a statistical model and a cell-based assay.


Production cost structure in US outpatient physical therapy health care.
This paper investigates the technology cost structure in US physical therapy care. We exploit formal economic theories and a rich national data of providers to tease out implications for operational cost efficiencies. The 2008-2009 dataset comprising over 19 000 bi-weekly, site-specific physical therapy center observations across 28 US states and Occupational Employment Statistics data (Bureau of Labor Statistics) includes measures of output, three labor types (clinical, support, and administrative), and facilities (capital). We discuss findings from the iterative seemingly unrelated regression estimation system model. The generalized translog cost estimates indicate a well-behaved underlying technology structure. We also find the following: (i) factor demands are downwardly sloped; (ii) pair-wise factor relationships largely reflect substitutions; (iii) factor demand for physical therapists is more inelastic compared with that for administrative staff; and (iv) diminishing scale economies exist at the 25%, 50%, and 75% output (patient visits) levels. Our findings advance the timely economic understanding of operations in an increasingly important segment of the medical care sector that has, up-to-now (because of data paucity), been missing from healthcare efficiency analysis. Our work further provides baseline estimates for comparing operational efficiencies in physical therapy care after implementations of the 2010 US healthcare reforms.


Central and peripheral mechanism of MOTS-c attenuates pain hypersensitivity in a mice model of inflammatory pain.
Inflammatory pain is caused by damaged tissue or noxious stimuli, accompanied by the release of inflammatory mediators that often leads to severe hyperalgesia and allodynia with limited therapy options. Recently, a novel mitochondrial-derived peptide (named MOTS-c) was reported to regulate obesity, metabolic homeostasis and inflammatory response. The aim of this study was to investigate the effects of MOTS-c and its related regulatory mechanisms involved in inflammatory pain. Male Kunming mice (8-10 weeks-old) were intraplantar injected with formalin, capsaicin, λ-Carrageenan and complete Freund adjuvant (CFA) to establish acute and chronic inflammatory pain. The effects of MOTS-c on the above inflammatory pain mice and its underlying mechanisms were examined by behavioral tests, quantitative polymerase chain reaction (qPCR), western blotting, enzyme linked immunosorbent assay (ELISA), immunohistochemistry (IHC) and immunofluorescence (IF). Behavioral experiments investigated the potential beneficial effects of MOTS-c on multiple acute and chronic inflammatory pain in mice. The results showed that MOTS-c treatment produced potent anti-allodynic effects in formalin-induced acute inflammatory pain, capsaicin-induced nocifensive behaviors and λ-Carrageenan/CFA-induced chronic inflammatory pain model. Further mechanistic studies revealed that central MOTS-c treatment significantly ameliorated CFA-evoked the release of inflammatory factors and activation of glial cells and neurons in the spinal dorsal horn. Moreover, peripheral MOTS-c treatment reduced CFA-evoked inflammatory responses in the surface structure of hindpaw skin, accompanied by inhibiting excitation of peripheral calcitonin gene-related peptide (CGRP) and P2X3 nociceptive neurons. The present study indicates that MOTS-c may serve as a promising therapeutic target for inflammatory pain.


The Chiari malformations: a constellation of anomalies.
The Chiari malformations form a group of abnormalities that are pathogenetically interrelated. The most important member of the group is the Chiari type II malformation, known as the Arnold-Chiari malformation. Its cardinal features are the myelomeningocele in the thoraco-lumbar spine, the venting of the intracranial cerebrospinal fluid through the central canal, the hypoplasia of the posterior fossa, the herniation of hindbrain into the cervical spinal canal, and the compressive damage to cranial nerves. Some of the abnormalities are progressive, and thus treatable. Limitation of progression may improve outcomes. The challenges to our treatment programs involve early diagnosis, delivery by Caesarean section, emergent closure of the neural plaque and prophylaxis of hydrocephalus, anticipatory prevention of the neurological compression syndromes, multidisciplinary teams, and age-appropriate interventions.


Blood-feeding patterns of native mosquitoes and insights into their potential role as pathogen vectors in the Thames estuary region of the United Kingdom.
The range of vertebrate hosts on which species of mosquito blood-feed is an important parameter for identifying potential vectors and in assessing the risk of incursion and establishment of vector-borne pathogens. In the United Kingdom, studies of mosquito host range have collected relatively few specimens and used techniques that could only broadly identify host species. This study conducted intensive collection and analysis of mosquitoes from a grazing marsh environment in southeast England. This site provides extensive wetland habitat for resident and migratory birds and has abundant human nuisance biting mosquitoes. The aim was to identify the blood-feeding patterns of mosquito species present at the site which could contribute to the transmission of pathogens. Twice-weekly collections of mosquitoes were made from Elmley Nature Reserve, Kent, between June and October 2014. Mosquitoes were collected using resting boxes, by aspiration from man-made structures and using a Mosquito Magnet Pro baited with 1-octen-3-ol. Blood-fed specimens were classified according to the degree of blood meal digestion using the Sella scale and vertebrate origin determined using sequencing of a fragment of the mitochondrial cytochrome C oxidase subunit I gene. Mosquitoes that were morphologically cryptic were identified to species level using multiplex PCR and sequencing methods. A total of 20,666 mosquitoes of 11 species were collected, and 2,159 (10.4%) were blood-fed (Sella scale II-VI); of these 1,341 blood-fed specimens were selected for blood meal analysis. Vertebrate origin was successfully identified in 964 specimens (72%). Collections of blood-fed individuals were dominated by Anopheles maculipennis complex (73.5%), Culiseta annulata (21.2%) and Culex pipiens form pipiens (10.4%). Nineteen vertebrate hosts comprising five mammals and 14 birds were identified as hosts for mosquitoes, including two migratory bird species. Feeding on birds by Culex modestus and Anopheles atroparvus populations in England was demonstrated. This study expands the vertebrate host range of mosquitoes in the Thames estuary region of the UK. Feeding on both resident and migratory bird species by potential arbovirus vectors including Cx. pipiens f. pipiens and Cx. modestus indicates the potential for enzootic transmission of an introduced arbovirus between migratory and local bird species by native mosquito species.


Cardiovascular risk factors, monitoring, and therapy for HIV-infected patients.
Cardiovascular complications are important contributors to morbidity and mortality in HIV-infected patients. These complications can usually be detected at subclinical levels with monitoring, which can help guide targeted interventions. This article reviews available data on types and frequency of cardiovascular manifestations in HIV-infected patients and proposes monitoring strategies aimed at early subclinical detection. In particular, we recommend routine echocardiography for HIV-infected patients, even those with no evidence of cardiovascular disease. We also review preventive and therapeutic cardiovascular interventions. For procedures that have not been studied in HIV-infected patients, we extrapolate from evidence-based guidelines for the general population.


Analysis of RNA from brush cytology detects changes in B2M, CYP1B1 and KRT17 levels with OSCC in tobacco users.
RNA expression analysis of oral keratinocytes can be used to detect early oral cancer, but a limitation is the inability to obtain high quality RNA from oral tissue without using biopsies. While oral cytology cell samples can be obtained from patients in a minimally invasive manner, they have not been validated for quantitative analysis of RNA expression. Earlier we showed RNA from brush cytology of hamster Oral Squamous Cell Carcinoma (OSCC) demonstrated differential expression of B2M and CYP1B1 using real time RT-PCR in a dibenz[a,I]pyrene, tobacco carcinogen, induced model of this disease. Here we show reproducibility of this approach to measuring gene expression in humans. Cytology brush samples from 12 tobacco and betel related OSCC and 17 nonmalignant oral lesions revealed B2M mRNA was enriched in tumor samples while CYP1B1 mRNA was reduced, similar to what was seen in the model system. Additionally, we showed that KRT17 mRNA, a gene linked to OSCC in another brush cytology study, was also enriched in OSCC versus nonmalignant lesions, again supporting the promise of using RNA from brush oral cytology to reproducibly monitor oral gene expression.


Effect of quantitative nuclear image features on recurrence of Ductal Carcinoma In Situ (DCIS) of the breast.
Nuclear grade has been associated with breast DCIS recurrence and progression to invasive carcinoma; however, our previous study of a cohort of patients with breast DCIS did not find such an association with outcome. Fifty percent of patients had heterogeneous DCIS with more than one nuclear grade. The aim of the current study was to investigate the effect of quantitative nuclear features assessed with digital image analysis on ipsilateral DCIS recurrence. Hematoxylin and eosin stained slides for a cohort of 80 patients with primary breast DCIS were reviewed and two fields with representative grade (or grades) were identified by a Pathologist and simultaneously used for acquisition of digital images for each field. Van Nuys worst nuclear grade was assigned, as was predominant grade, and heterogeneous grading when present. Patients were grouped by heterogeneity of their nuclear grade: Group A: nuclear grade 1 only, nuclear grades 1 and 2, or nuclear grade 2 only (32 patients), Group B: nuclear grades 1, 2 and 3, or nuclear grades 2 and 3 (31 patients), Group 3: nuclear grade 3 only (17 patients). Nuclear fine structure was assessed by software which captured thirty-nine nuclear feature values describing nuclear morphometry, densitometry, and texture. Step-wise forward Cox regressions were performed with previous clinical and pathologic factors, and the new image analysis features. Duplicate measurements were similar for 89.7% to 97.4% of assessed image features. The rate of correct classification of nuclear grading with digital image analysis features was similar in the two fields, and pooled assessment across both fields. In the pooled assessment, a discriminant function with one nuclear morphometric and one texture feature was significantly (p = 0.001) associated with nuclear grading, and provided correct jackknifed classification of a patient's nuclear grade for Group A (78.1%), Group B (48.4%), and Group C (70.6%). The factors significantly associated with DCIS recurrence were those previously found, type of initial presentation (p = 0.03) and amount of parenchymal involvement (p = 0.05), along with the morphometry image feature of ellipticity (p = 0.04). Analysis of nuclear features measured by image cytometry may contribute to the classification and prognosis of breast DCIS patients with more than one nuclear grade.


Repetitive Transcranial Magnetic Stimulation Improves Neuropathy and Oxidative Stress Levels in Rats with Experimental Cerebral Infarction through the Nrf2 Signaling Pathway.
Ischemic stroke poses a serious threat to human health. Its high morbidity, disability, and lethality rates have led to it being a research hotspot. Cerebral ischemia reperfusion injury is a difficult point in the treatment of ischemic stroke. In recent years, studies have shown that repeated transcranial magnetic stimulation (rTMS) can enhance cerebral ischemic tolerance and have a significant protective effect on reperfusion injury after ischemia, but its specific mechanism is unknown. The Nrf2/pathway plays a vital role in ischemia-reperfusion injury in the body environment. Therefore, in this experiment, the middle cerebral artery occlusion (MCAO) reperfusion model of SD rats was made to simulate the occurrence of experimental cerebral infarction by the suture method. After treatment with rTMS, it was studied whether it can regulate the expression of Nrf2 and HO-1, affect the content of MDA and SOD activity, and then activate the Nrf2 pathway to exert its brain protection. The results showed that after MCAO reperfusion, the neurological deficit score of rats increased, and the time to remove the bilateral stickers and the time to cross the balance beam increased, suggesting the successful establishment of the experimental cerebral infarction model. Detecting the brain tissue of experimental cerebral infarction rats found that the expression of Nrf2 and HO-1 decreased, the content of MDA increased, and the activity of SOD decreased. After rTMS treatment, the neuromotor function of experimental cerebral infarction rats improved, the expression of Nrf2 and HO-1 in the brain tissue gradually increased, the content of MDA decreased, and the activity of SOD increased. It indicates that the expression of Nrf2 and HO-1 in experimental cerebral infarction rats is reduced. After treatment with rTMS, it can improve the neuromotor function damage of the rats and reduce the level of oxidative stress. The mechanism may be through promoting the activation of the Nrf2 signaling pathway, acting on the expression of antioxidant proteins, such as HO-1 and SOD1, reducing oxidative stress damage, and playing a protective effect on brain tissue.


Ceramide metabolism analysis in a model of binge drinking reveals both neuroprotective and toxic effects of ethanol.
Binge drinking is a common form of alcohol abuse that involves repeated rounds of intoxication followed by withdrawal. The episodic effects of binge drinking and withdrawal on brain resident cells are thought to contribute to neural remodeling and neurological damage. However, the molecular mechanisms for these neurodegenerative effects are not understood. Ethanol (EtOH) regulates the metabolism of ceramide, a highly bioactive lipid that is enriched in brain. We used a mouse model of binge drinking to determine the effects of EtOH intoxication and withdrawal on brain ceramide metabolism. Intoxication and acute alcohol withdrawal were each associated with distinct changes in ceramide regulatory genes and metabolic products. EtOH intoxication was accompanied by decreased concentrations of multiple ceramides, coincident with reductions in the expression of enzymes involved in the production of ceramides, and increased expression of ceramide-degrading enzymes. EtOH withdrawal was associated with specific increases in ceramide C16:0, C18:0, and C20:0 and increased expression of enzymes involved with ceramide production. These data suggest that EtOH intoxication may evoke a ceramide phenotype that is neuroprotective, whereas EtOH withdrawal results in a metabolic shift that increases the production of potentially toxic ceramide species.


Extended hindfoot fusions and pantalar fusions. History, biomechanics, and clinical results.
Contemporary techniques of hindfoot and ankle arthrodesis can result in a high rate of osseous union, pain relief, and patient satisfaction. Methods range from open approaches to fully arthroscopic surgical techniques. Arthrodesis should be limited to the joints involved with the arthritic, deforming, or neuromuscular process because the rate and severity of progressive adjacent joint degeneration appear related to the number of joints fused initially. Appropriate joint position, maintained with stable internal fixation applied in compression and augmented with bone-graft material when necessary, should be considered the gold standard for most hindfoot and ankle arthrodeses. External fixation may be used in the revision or salvage setting if needed or when soft tissues or bone stock do not permit stable internal fixation. Meticulous attention must be given to the handling of soft and hard tissues as well as to correction of the underlying deformity and to appropriate positioning of the joints in question. Newer techniques, such as intramedullary fixation, arthroscopic or arthroscopically assisted ankle arthrodesis, and total ankle arthroplasty, have shown some promise and warrant more extensive study.