Discrimination Ability of Patient Reported Outcome Measurement Information System Pediatric Domains Compared With Scoliosis Research Society-22r and Legacy Patient Reported Outcome Measures in Juvenile and Adolescent Idiopathic Scoliosis.
Comparative cohort study. To compare patient reported outcome measures (PROMs) in children and adolescents with varying extent of spinal deformity. Several PROMs have been proposed to help assess health-related quality-of-life (HRQoL) in pediatric spinal deformity surgery and research, but it is unclear which are sensitive to deformity severity. Pediatric patients diagnosed with spinal asymmetry or juvenile/adolescent idiopathic scoliosis completed the patient-reported outcomes management information system (PROMIS) pediatric computer adaptive test bank (Domains: Mobility, Pain Interference, Physical Activity, Physical Stress Experiences, Psychological Stress Experiences), Scoliosis Research Society-22r (SRS-22r), Hospital for Special Surgery Pediatric Functional Activity Brief Scale (HSS Pedi-FABS) activity scale, and Trunk Appearance Perception Scale. Patients were grouped as spinal asymmetry, mild deformity, and substantial deformity by major Cobb angle measuring less than 10°, between 10° and 40°, and greater than 40° respectively. One-way analysis of variance with a Tukey post-hoc correction was used to determine score differences between groups. Final analyses included 206 patients, of which 135 (66%) were female. The mean age was 13.0 ± 2.2 years, and the mean major Cobb angle was 20.1 ± 14.1° (range: 0-74.2°). Compared with both spinal asymmetry and mild deformity patients, patients with substantial deformity reported worse outcomes, including lower function, more pain, and decreased psychological health by legacy PROMs and PROMIS. PROMIS Physical Activity and Psychological Stress Experiences did not capture any significant differences between all groups. There were no significant differences in outcomes between the spinal asymmetry and mild deformity groups for all PROMs measured. Patients with substantial spinal deformity reported lower activity and function, more pain, and greater physical and psychological stress compared with patients without clinical spinal deformity by legacy PROMs and several PROMIS domains. As PROMIS Physical Activity and Psychological Stress Experiences did not capture these differences, these PROMs may measure different constructs than the legacy PROMs as they relate to spinal curvature and may be less relevant to measure HRQoL in this population.Level of Evidence 3.


Transforming growth factor beta in human milk and allergic outcomes in children: A systematic review.
Human milk (HM) transforming growth factor beta (TGF-β) is critical for inflammation regulation and oral tolerance promotion. Previous reports suggested that variations in HM TGF-β levels are associated with allergic outcomes. We undertook a systematic review (PROSPERO 2017 CRD42017069920) to reassess the evidence on the relationships between HM TGF-β and allergic outcomes in children. Electronic bibliographic databases (MEDLINE, EMBASE and Cochrane Library) were systematically searched. Two independent reviewers screened reference lists, extracted the data and assessed risk of bias using the National Institute for Clinical Excellence methodological checklist. A total of 21 studies were identified. Sixteen studies assessed relationships between HM TGF-β and risk of eczema; 14, allergic sensitization; nine, wheezing/asthma; six, food allergy; three, allergic rhinitis/conjunctivitis. Five cohorts (5/18, 28%) reported a protective effect of TGF-β1, while 3 (3/10, 30%) suggested increased risk of allergic outcomes development and 1 (1/10, 10%), a protective effect of TGF-β2 on eczema. Meta-analysis was not possible due to significant heterogeneity in methodology, age of outcome assessment and differing statistical approaches. 71% (15/21) of studies carried a high risk of bias. In contrast with previous findings, we did not find strong evidence of associations between HM TGF-β and allergic outcomes. Differences in studies' methodology and outcomes do not allow unconditional rejection or acceptance of the hypothesis that HM TGF-β influences the risk of allergy development. Future studies on diverse populations employing standardized methods, accurate phenotyping of outcomes and evaluation of the effect of TGF-β in combination with other HM immune markers, microbiome and oligosaccharides are required.


Real-time PCR assay provides reliable assessment of intrapartum carriage of group B Streptococcus.
The objective of this study was to determine the reliability of the real-time PCR assay for determining the group B Streptococcus (GBS) status of women in labor. In this prospective study we compared the results of culture and PCR testing of vaginal and rectal samples collected by nursing staff when women were in labor. Patients' charts were also reviewed to obtain relevant information about pregnancy risk factors. Our results demonstrated a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 90.5%, 96.1%, 86.4%, and 97.4%, respectively, for rapid PCR. Of the 196 women evaluated, 29 (14.8%) presented with unknown GBS status, 11 (37.9%) of whom received unnecessary intrapartum antibiotics. The rapid real-time PCR test was robust and was able to reliably detect the presence of GBS in women in labor within 1 h of specimen submission to the laboratory. We recommend that the rapid PCR test be targeted to women who present in labor with unknown GBS status. In cases where the laboratory does not offer 24-h availability of testing, sample collection followed by PCR testing the next morning is still valuable and provides reliable results 24 to 48 h faster than culture and will aid appropriate decision-making regarding continuing or stopping antibiotics for neonates of women with unknown GBS status.


Inducible Membrane Permeabilization by Attenuated Lytic Peptides: A New Concept for Accessing Cell Interiors through Ruffled Membranes.
A variety of mid-sized and large biomolecules have been used as tools to explore fundamental biological questions. However, such molecules are often cell-impermeable and thus unable to attain sufficient access to the cell interior. This inhibits their ability to yield analytical data about the cell interior or modify the cellular events. We have recently developed a peptide, engineered from a natural hemolytic peptide, named L17E. Substantial cytosolic delivery of biomacromolecules, including antibodies, was attained in the presence of this peptide. In this study, detailed analysis of the modes of action of L17E was conducted, elucidating that a large fraction of the cytosolic translocation of biomacromolecules is accomplished in the presence of L17E within 5 min. L17E stimulates actin polymerization and induces a dynamic structural alteration of cell membranes, resulting in a ruffled appearance. Studies using macropinocytosis inhibitors and proteins that control endosome maturation raise the possibility that the transient permeabilization of ruffled cell membranes, rather than the rupture of endosomal membranes, is the crucial mechanism for facile cytosolic translocation of biomacromolecules in the presence of L17E. Our results provide a distinct concept of intracellular delivery, different from direct translocation through cell membranes or endocytic uptake followed by endosomal escape. This method of permeabilization via membrane ruffling provides a novel concept in intracellular delivery.


Multiple scales and phases in discrete chains with application to folded proteins.
Chiral heteropolymers such as large globular proteins can simultaneously support multiple length scales. The interplay between the different scales brings about conformational diversity, determines the phase properties of the polymer chain, and governs the structure of the energy landscape. Most importantly, multiple scales produce complex dynamics that enable proteins to sustain live matter. However, at the moment there is incomplete understanding of how to identify and distinguish the various scales that determine the structure and dynamics of a complex protein. Here we address this impending problem. We develop a methodology with the potential to systematically identify different length scales, in the general case of a linear polymer chain. For this we introduce and analyze the properties of an order parameter that can both reveal the presence of different length scales and can also probe the phase structure. We first develop our concepts in the case of chiral homopolymers. We introduce a variant of Kadanoff's block-spin transformation to coarse grain piecewise linear chains, such as the Cα backbone of a protein. We derive analytically, and then verify numerically, a number of properties that the order parameter can display, in the case of a chiral polymer chain. In particular, we propose that in the case of a chiral heteropolymer the order parameter can reveal traits of several different phases, contingent on the length scale at which it is scrutinized. We confirm that this is the case with crystallographic protein structures in the Protein Data Bank. Thus our results suggest relations between the scales, the phases, and the complexity of folding pathways.


At the brink of eusociality: transcriptomic correlates of worker behaviour in a small carpenter bee.
There is great interest in understanding the genomic underpinnings of social evolution, in particular, the evolution of eusociality (caste-containing societies with non-reproductives that care for siblings). Subsociality is a key precursor for the evolution of eusociality and characterized by prolonged parental care and parent-offspring interaction. Here, we provide the first transcriptomic data for the small carpenter bee, Ceratina calcarata. This species is of special interest because it is subsocial and in the same family as the highly eusocial honey bee, Apis mellifera. In addition, some C. calcarata females demonstrate alloparental care without reproduction, which provides a unique opportunity to study worker behaviour in a non-eusocial species. We uncovered similar gene expression patterns related to maternal care and sibling care in different groups of females. This agrees with the maternal heterochrony hypothesis, specifically, that changes in timing of offspring care gene expression are related to worker behaviour in incipient insect societies. In addition, we also detected some similarity to caste-related gene expression patterns in highly eusocial honey bees, and uncovered large lifetime changes in gene expression that accompany shifts in reproductive and maternal care behaviour. For Ceratina calcarata, we found that transcript expression profiles were most similar between sibling care and maternal care females. The maternal care behaviour exhibited post-reproductively by Ceratina mothers is concordant in terms of transcript expression with the alloparental care exhibited by workers. In line with theoretical predictions, our data are consistent with the maternal heterochrony hypothesis for the evolutionary development of worker behaviour in subsocial bees.


Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing.
To prospectively determine the diagnostic accuracy of massively parallel sequencing to detect whole chromosome fetal aneuploidy from maternal plasma. Blood samples were collected in a prospective, blinded study from 2,882 women undergoing prenatal diagnostic procedures at 60 U.S. sites. An independent biostatistician selected all singleton pregnancies with any abnormal karyotype and a balanced number of randomly selected pregnancies with euploid karyotypes. Chromosome classifications were made for each sample by massively parallel sequencing and compared with fetal karyotype. Within an analysis cohort of 532 samples, the following were classified correctly: 89 of 89 trisomy 21 cases (sensitivity 100%, 95% [confidence interval] CI 95.9-100), 35 of 36 trisomy 18 cases (sensitivity 97.2%, 95% CI 85.5-99.9), 11 of 14 trisomy 13 cases (sensitivity 78.6%, 95% CI 49.2-95.3), [corrected] 232 of 233 females (sensitivity 99.6%, 95% CI 97.6 to more than 99.9), 184 of 184 males (sensitivity 100%, 95% CI 98.0-100), and 15 of 16 monosomy X cases (sensitivity 93.8%, 95% CI 69.8-99.8). There were no false-positive results for autosomal aneuploidies (100% specificity, 95% CI more than 98.5 to 100). In addition, fetuses with mosaicism for trisomy 21 (3/3), trisomy 18 (1/1), and monosomy X (2/7), three cases of translocation trisomy, two cases of other autosomal trisomies (20 and 16), and other sex chromosome aneuploidies (XXX, XXY, and XYY) were classified correctly. This prospective study demonstrates the efficacy of massively parallel sequencing of maternal plasma DNA to detect fetal aneuploidy for multiple chromosomes across the genome. The high sensitivity and specificity for the detection of trisomies 21, 18, 13, and monosomy X suggest that massively parallel sequencing can be incorporated into existing aneuploidy screening algorithms to reduce unnecessary invasive procedures. ClinicalTrials.gov, www.clinicaltrials.gov, NCT01122524. II.


Escherichia coli genes regulated by cell-to-cell signaling.
Utilizing the bicistronic reporter transposon mini-Tn5 lacZ-tet/1, we have identified lacZ fusions to four Escherichia coli genes/operons that are strongly activated by the accumulation of self-produced extracellular signals. These fusions were designated cma9, cma48, cma113, and cma114 for conditioned medium activated. Each of the cma fusions was expressed in a growth phase-dependent manner, and the presence of conditioned medium from a stationary phase E. coli culture resulted in the premature activation of these fusions in cells at early to mid-logarithmic phase. The cma48 and cma114 fusions were dependent on RpoS for growth phase expression and response to extracellular factors. The extracellular factors that activated the cma9, cma48, and cma114 fusions were produced in both rich complex and defined minimal media. The cma fusions were shown to be within the cysK (cma9), astD (cma48), tnaB (cma113), and gabT (cma114) genes. These genes function in the uptake, synthesis, or degradation of amino acids that yield pyruvate and succinate.


Influence of dye molecules on the birefringence of liquid crystal mixtures at near infrared frequencies.
The optical properties of nematic liquid crystals have been extensively exploited in the production of devices working in the visible range of the spectrum. These same properties can be employed to make devices that function in the near infrared as required for telecommunications applications. However, it is generally observed that the birefringence of liquid crystal mixtures decreases with increasing wavelength, making it important to identify new materials, optimized for use in the near infrared region. One route to high birefringence is to operate close to an absorption band edge, which in the present context implies choosing highly conjugated materials which are potentially colored and, thus, not suited to traditional display applications. In this paper we explore the usefulness of dye molecules as birefringence enhancers in mixtures with conventional nematic liquid crystals. The optical properties, in particular, the absorption edge, polarizability, and birefringence, of families of known dyes are calculated at optical (589 nm) and infrared (1550 nm) wavelengths, using electronic density functional theory. We demonstrate the expected correlation between the proximity of the absorption edge and the magnitude of the birefringence, and estimate the birefringence enhancement occurring when each dye is incorporated in a guest-host system.


Experiences in applying skills learned in a Mental Health First Aid training course: a qualitative study of participants' stories.
Given the high prevalence of mental disorders and the comparatively low rate of professional help-seeking, it is useful for members of the public to have some skills in how to assist people developing mental disorders. A Mental Health First Aid course has been developed to provide these skills. Two randomized controlled trials of this course have shown positive effects on participants' knowledge, attitudes and behavior. However, these trials have provided limited data on participants' subsequent experiences in providing first aid. To remedy this, a study was carried out gathering stories from participants in one of the trials, 19-21 months post-training. Former course participants were contacted and sent a questionnaire either by post or via the internet. Responses were received from 94 out of the 131 trainees who were contacted. The questionnaire asked about whether the participant had experienced a post-training situation where someone appeared to have a mental health problem and, if so, asked questions about that experience. Post-training experiences were reported by 78% of respondents. Five key points emerged from the qualitative data: (1) the majority of respondents had had some direct experience of a situation where mental health issues were salient and the course enabled them to take steps that led to better effects than otherwise might have been the case; (2) positive effects were experienced in terms of increased empathy and confidence, as well as being better able to handle crises; (3) the positive effects were experienced by a wide range of people with varied expectations and needs; (4) there was no evidence of people over-reaching themselves because of over-confidence and (5) those who attended were able to identify quite specific benefits and many thought the course not only very useful, but were keen to see it repeated and extended. The qualitative data confirm that most members of the public who receive Mental Health First Aid training subsequently provide support to people with mental health problems and that this support generally has positive effects.


Relative bioavailability and pharmacokinetics of a new sibutramine formulation in healthy male subjects: a randomized, open-label, two-period, comparative crossover study.
Sibutramine is an orally administered, centrally acting antiobesity drug. Sibutramine hydrochloride monohydrate is the conventional formulation, whereas sibutramine mesylate hemihydrate is a newly developed formulation. Drugs formed from different salts may differ in their solubility profiles and dissolution rates, which may affect their rate of absorption and thus their onset, duration, and intensity of effect. This study was conducted to compare the relative bioavailability and pharmacokinetics of the new sibutramine formulation (test) with those of the conventional formulation (reference). : This was a single-center, randomized, open-label, 2-period, comparative crossover study in healthy male subjects. All subjects received a single 15-mg oral dose of sibutramine hydrochloride monohydrate (reference) and a single 17.3-mg oral dose of sibutramine mesylate hemihydrate (test), both containing 12.55 mg sibutramine base. The 2 doses were separated by a 2-week washout period. Blood samples for pharmacokinetic analysis were collected during a 72-hour period after treatment. Safety parameters were assessed, including adverse events, hematology and biochemistry, urinalysis, and electrocardiography. Plasma concentrations of the active metabolites of sibutramine (desmethylsibutramine [M1] and didesmethylsibutramine [M2]) were determined, and the pharmacokinetic characteristics of the 2 formulations were compared using noncompartmental analysis. Sixteen subjects (mean [SD] age, 24.3 [2.3] years [range, 20-25 years]; mean [SD] body weight, 66.1 [5.1] kg [range, 57-77 kg]) were enrolled in and completed the study. The plasma concentration-time profiles of M1 and M2 were similar after administration of both formulations. The reference and test formulations showed pharmacokinetic equivalence with respect to M1 and M2. The relative bioavailability of the test drug was 117.6% for M1 and 102.4% for M2. The 90% Cls for the ratios of the log-transformed C(max) and AUC values were within the predetermined equivalence range of 80% to 125%. There were no significant changes in physical, biochemical, hematologic, or urinalysis variables during the study. Neither formulation was associated with any serious adverse events. In this study in healthy male subjects, the 2 sibutramine formulations were pharmacokinetically equivalent, and the newly developed formulation had a safety profile comparable to that of the conventional formulation.


[Benign liver tumours - current diagnostics and therapeutic modalities].
The most common benign liver tumours are haemangiomas, focal nodular hyperplasia and hepatocellular adenoma. We perform a review of the literature and show the current diagnostic and therapeutic modalities based on the EASL Clinical Practice Guideline. With the widespread use of ultrasound, the detection of liver lesions is increased. They are usually found in women of childbearing age with atypical abdominal pain or incidentally. Contrast-enhanced US, CT or MRI are usually necessary for differential diagnosis. In atypical appearance or in malignancy suspect cases biopsy could be performed. For symptomatic patients conservative therapy can be sufficient. In haemorrhagic cases transarterial embolisation can be useful, also for tumour size decreasing before surgery. In patients with persisting symptoms, with vessel or soft tissue compression effect or in malignancy suspect cases definitive surgical treatment is advised. In men with hepatocellular adenoma primary resection is appropriate because of the higher risk for malignant transformation. As alternative treatment options radiofrequency ablation, irradiation, chemotherapy, monoclonal antibody therapy or liver transplantation are published.


The Effect of OnabotulinumtoxinA on Aura Frequency and Severity in Patients With Hemiplegic Migraine: Case Series of 11 Patients.
OnabotulinumtoxinA has been demonstrated to be effective for the preventive treatment of headache in individuals with chronic migraine and has been approved and recommended for this patient population. While the therapeutic effect of onabotulinumtoxinA on migraine headache is well documented, there is limited information on the effect of onabotulinumtoxinA on migraine aura. Given the prolonged and often debilitating nature of aura in patients with hemiplegic migraine, our group sought to examine the effect of onabotulinumtoxinA on aura frequency and severity in this specific subset of migraine patients. All clinical notes from July 1, 1994 to December 1, 2017 at our institution were retrospectively reviewed to identify patients diagnosed with hemiplegic migraine who received at least one set of onabotulinumtoxinA injections. Thirty-four patients were identified; and of those, 23 were excluded due to incomplete documentation regarding aura symptoms at follow-up visits. The clinical notes of the remaining 11 patients (4 with familial hemiplegic migraine [FHM] and 7 with sporadic hemiplegic migraine [SHM]) were reviewed, and the frequency and description of their headaches and aura before and after receiving onabotulinumtoxinA were recorded. Nine of the 11 patients in our series noted a decrease in the frequency, severity, and/or duration of their aura after receiving onabotulinumtoxinA. Of the 2 non-responders, one was FHM and one was SHM. Of the 9 that noticed improved aura symptoms, 6 described a "wearing off" effect of onabotulinumtoxinA around week 9 or 10 of the 12-week cycle, with subsequent improvement after the next round. For 9 of 11 patients with hemiplegic migraine, onabotulinumtoxinA was helpful not only in reducing the frequency and severity of headaches but also in reducing the frequency and severity of the aura. In this manuscript, we speculate on potential pathophysiologic mechanisms that could have contributed to this effect.


Seasonal variation in molecular and physiological stress markers in Asian elephants.
Free-living species exhibit seasonal variation in various life history traits, including vital rates such as birth and death patterns. Different physiological mechanisms are thought to underlie the expression of life history traits that contribute to lifetime fitness. However, although the broad impacts of seasonality on life history traits and trade-offs is well established in many systems, the exact physiological mechanisms responsible for driving differences within and between individuals are poorly understood. Among them, molecular and physiological stress pathways, such as stress hypothalamic-pituitary-adrenal axis and oxidative stress, have potential to mediate relationships between individual survival, reproduction and environmental seasonality. Here, we determine how different physiological markers of stress including faecal cortisol metabolites (FCMs), heterophils/lymphocytes (H/L) ratio, two markers indicating oxidative balance including a marker of oxidative damage (reactive oxygen metabolites, ROM) and a marker of antioxidant defences (superoxide dismutase, SOD) and body weight vary in a large semi-captive population of Asian elephants (Elephas maximus) exposed to extreme seasonality (e.g. elevated temperatures). Individuals showed higher FCM levels and H/L ratios during cold season, indicating increased stress, and the lowest FCM levels during monsoon season and H/L ratios during hot and dry season, but we found no pattern in oxidative stress (ROM and SOD) levels. Hot season also associated with a decline in body weight. The present study shows how different physiological parameters (FCM levels and H/L ratio), molecular (oxidative stress) and body condition vary with seasonal changes, and how these parameters might allow individuals to adapt to such variations. Our results on an endangered long-lived species are crucial in indicating the most productive timing for conservation efforts, predicting how individuals cope with environmental changes, and allow for a more accurate representation of how animal physiology operates in nature.


Psychometric properties of the Inventory of Interpersonal Problems (IIP-C) used with a clinical sample of adolescents: a preliminary study.
Interpersonal problems are consistently identified with psychopathology that often has its onset in adolescence. Most of the commonly used instruments in child and adolescent psychiatry target non-interpersonal problems. The Inventory of Interpersonal Problems (IIP) is a widely studied and utilized instrument in the adult mental health field. This study aimed to examine the psychometric properties of the IIP (circumplex version) used with a clinical adolescent population. Method: Sixty-two adolescents (13-17 years) who received treatment in a child and adolescent mental health clinic (CAMHS) were included in the study. To establish reliability and validity, we conducted confirmatory factor analyses, internal consistency, and validity analyses. Confirmatory analyses did not show optimal model fit. However, other indices like CFI and TLI were promising. The reliability of the eight scales was in the same range as previous studies and acceptable. There were expected significant correlations between IIP-C scales and the broadband scales of Youth Self-report (YSR). The pioneer nature and its clinical focus are strengths however, there is a need for more research. The promising results are encouraging, and future research could also explore how best to bring the instrument into the digital age.


Case report and review of literature: Resection of a huge mediastinal low-grade fibromyxoid sarcoma with neck, axillary, and lung involvement.
Low-grade fibromyxoid sarcoma is an extremely rare malignant neoplasm, with an incidence of 0.18 per million, and comprises 0.6% of all soft tissue sarcomas. It has a high recurrence rate and late metastatic spread and is chemotherapy and radiotherapy insensitive. This paper reports a case of an unusually large mediastinal low-grade fibromyxoid sarcoma in a 55-year-old patient. The tumor was engulfing the main blood vessels of the mediastinum, involving the lung, and extending beyond the chest cavity to involve the cervical and axillary regions. The patient has a 21-year history of frequent surgical resections for lesions that were repeatedly misdiagnosed as neurofibroma. The tumor was successfully resected by a challenging operation that involved mediastinal mass resection, chest wall mass resection, and wedge resection of the left upper lobe of the lung. The deceivingly benign-looking histology of this tumor makes it a commonly misdiagnosed one, requiring careful assessment by pathologists to reach the right diagnosis. Surgical resection with clear margins remains the treatment of choice for these lesions. Due to the behavior of this tumor, once detected and managed, extensive long-term follow-up is always recommended.


Reporting morbidity associated with pediatric brain tumor surgery: are the available scoring systems sufficient?
Complications in pediatric neurooncology surgery are seldom and inconsistently reported. This study quantifies surgical morbidity after pediatric brain tumor surgery from the last decade in a single center, using existing morbidity and outcome measures. The authors identified all pediatric patients undergoing surgery for an intracranial tumor in a single tertiary pediatric neurosurgery center between January 2008 and December 2018. Complications between postoperative days 0 and 30 that had been recorded prospectively were graded using appropriate existing morbidity scales, i.e., the Clavien-Dindo (CD), Landriel, and Drake scales. The result of surgery with respect to the predetermined surgical aim was also recorded. There were 477 cases (364 craniotomies and 113 biopsies) performed on 335 patients (188 males, median age 9 years). The overall 30-day mortality rate was 1.26% (n = 6), and no deaths were a direct result of surgical complication. Morbidity on the CD scale was 0 in 55.14%, 1 in 10.69%, 2 in 18.66%, 3A in 1.47%, 3B in 11.74%, and 4 in 1.05% of cases. Morbidity using the Drake classification was observed in 139 cases (29.14%). Neurological deficit that remained at 30 days was noted in 8.39%; 78% of the returns to the operative theater were for CSF diversion. To the authors' knowledge, this is the largest series presenting outcomes and morbidity from pediatric brain tumor surgery. The mortality rate and morbidity on the Drake classification were comparable to those of published series. An improved tool to quantify morbidity from pediatric neurooncology surgery is necessary.


HIV reverse transcriptase gene mutations in anti-retroviral treatment naïve rural people living with HIV/AIDS.
This study is designed to find out the mutational variations of reverse transcriptase (RT) gene of HIV, after the traditional drug usage among anti-retroviral therapy naïve rural people living with HIV/AIDS. HIV Reactive patients, who were exposed for indigenous medicines such as Siddha, Ayurveda etc., for a minimum period of 6 months were taken for this study. Among 40 patients, two samples (5.55%) demonstrated high-level mutational resistance variations for nucleoside RT inhibitor (NRTI) and non-NRTI. The predominant polymorphisms detected were K122E (91.7%), V60I (91.7%), V35T (89%), Q207E (89%), D177E (89%), T200A (86.1%), S48T (83.33%), K173A (80.6%).


Fasinumab (REGN475), an antinerve growth factor monoclonal antibody, for the treatment of acute sciatic pain: results of a proof-of-concept study.
To evaluate the efficacy and safety of subcutaneously administered fasinumab (REGN475), a nerve growth factor-neutralizing antibody, in patients with acute sciatic pain receiving standard of care therapy. This was a double-blind, parallel-group, proof-of-concept study. Patients with unilateral, moderate-to-severe sciatic pain of 2-16 weeks' duration were randomized to a subcutaneous dose of placebo (n=51), fasinumab 0.1 mg/kg (n=53), or 0.3 mg/kg (n=53); follow-up was 12 weeks. Pain was assessed in a daily diary using a numerical rating scale (NRS) (0= no pain, 10= worst pain) for average and worst leg and back pain. The primary efficacy end point was the area under the curve of NRS scores for average leg pain from baseline to week 4. Key secondary end points included changes in average and worst leg and back pain from baseline to the end of week 4 and to each weekly study visit. Patient functioning (Oswestry Disability Index) and concomitant analgesic use were also assessed. Safety and tolerability were evaluated by treatment-emergent adverse events (TEAEs). Demographic and clinical characteristics were similar among the treatment groups; 141 (88.7%) patients completed the study. For the primary end point, mean ± standard deviation area under the curve values from baseline to week 4 were not significantly different between placebo (96.8±6.0) and fasinumab 0.1 mg/kg (112.7±58.3; P=0.0610) or fasinumab 0.3 mg/kg (112.4±55.8; P=0.0923). All secondary efficacy end points of changes in pain and function demonstrated responses that were similar between placebo and fasinumab groups. Incidence of TEAEs was 45.1%, 50.9%, and 64.8% in the placebo, fasinumab 0.1mg/kg, and fasinumab 0.3 mg/kg groups, respectively. The most commonly reported TEAEs included paresthesia, arthralgia, pain in extremity, and headache. Administration of fasinumab provided no significant clinical benefit compared with placebo for the pain or functional limitations associated with acute sciatica. Fasinumab was generally well tolerated and incidence of TEAEs appeared to be dose related.


Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide.
Recent evidence indicates a key role for the neuropeptide calcitonin gene-related peptide (CGRP) in migraine pain, as demonstrated by the strong analgesic action of CGRP receptor antagonists, although the mechanisms of this effect remain unclear. Most trigeminal nociceptive neurons releasing CGRP also express ATP-activated purinergic P2X3 receptors to transduce pain. To understand whether the CGRP action involves P2X3 receptor modulation, the model of trigeminal nociceptive neurons in culture was used to examine the long-term action of this peptide. Although 79% of CGRP-binding neurons expressed P2X3 receptors, acute application of CGRP did not change P2X3 receptor function. Nevertheless, after 1 h of CGRP treatment, strong enhancement of the amplitude of P2X3 receptor currents was observed together with accelerated recovery from desensitization. Receptor upregulation persisted up to 10 h (despite CGRP washout), was accompanied by increased P2X3 gene transcription, and was fully prevented by the CGRP antagonist CGRP(8-37). Surface biotinylation showed CGRP augmented P2X3 receptor expression, consistent with confocal microscopy data indicating enhanced P2X3 immunoreactivity beneath the neuronal membrane. These results suggest that CGRP stimulated trafficking of P2X3 receptors to the cell-surface membrane. Using pharmacological tools, we demonstrated that this effect of CGRP was dependent on protein kinase A and PKC activation and was prevented by the trafficking inhibitor brefeldin A. Capsaicin-sensitive TRPV1 vanilloid receptors were not upregulated. The present data demonstrate a new form of selective, slow upregulation of nociceptive P2X3 receptors on trigeminal neurons by CGRP. This mechanism might contribute to pain sensitization and represents a model of neuronal plasticity in response to a migraine mediator.


Development of a self-report instrument for measuring in-class student engagement reveals that pretending to engage is a significant unrecognized problem.
Student engagement during classes includes behavioural, cognitive and emotional components, and is a pre-requisite for successful active learning environments. A novel approach to measuring student engagement was developed, involving triangulation of real-time student-self report, observation by trained observers and heart rate measurement. The self-report instrument was evaluated in four separate cohorts (n = 123) at Monash University and the University of North Carolina. The six item self-report demonstrated good reliability (Cronbach's alpha values ranged from 0.7-0.81). The self-report showed predictive validity in that small group activities were rated as significantly more engaging than didactic lecturing. Additionally, there was significant inter-instructor variability and within-class variability, indicating good discrimination between classroom activities. This self-report may prove useful to academic teaching staff in evaluating and refining their active learning activities. Independent observation was not found to correlate with student self-report, due in part to students who were pretending to engage being rated as engaged by an observer. Strikingly, students reported that they were pretending to engage for 23% of class time, even for highly regarded instructors. Individual participants were rated as engaged for 42 of the 46 intervals for which they reported that they had "pretended to engage", indicating that the two observers were unable to detect disengagement during periods in which students pretended to engage. Instructors should be aware that student cues such as eye contact and nodding may indicate pretending to engage. One particular self-report item; "I tried a new approach or way of thinking about the content", correlated positively with heart rates, and a controlled study reproduced this finding during two activities that required students to try a new approach to understanding a concept. Agreement with this item also correlated with superior performance on two in-class written assessment tasks (n = 101, p<0.01). Further use of this tool and related educational research may be useful to identify in-class activities that are engaging and likely to lead to improved student attainment of learning outcomes.


Can the critically ill patient generate sufficient energy to facilitate exercise in the ICU?
Trials of physical rehabilitation post critical illness have yet to deliver improved health-related quality of life in critical illness survivors. Muscle mass and strength are lost rapidly in critical illness and a proportion of patients continue to do so resulting in increased mortality and functional disability. Addressing this issue is therefore fundamental for recovery from critical illness. Altered mitochondrial function occurs in the critically ill and is likely to result in decreased adenosine tri-phosphate (ATP) production. Muscle contraction is a process that requires ATP. The metabolic demands of exercise are poorly understood in the ICU setting. Recent research has highlighted that there is significant heterogeneity in energy requirements between critically ill individuals undertaking the same functional activities, such as sit-to-stand. Nutrition in the critically ill is currently thought of in terms of carbohydrates, fat and protein. It may be that we need to consider nutrition in a more contextual manner such as energy generation or management of protein homeostasis. Current nutritional support practices in critically ill patients do not lead to improvements in physical and functional outcomes, and it may be that alternative methods of delivery or substrates are needed.


Chemical mapping of individual semiconductor nanostructures.
We demonstrate experimentally the power of a novel analytical tool for X-ray spectromicroscopy. This provides a minimally intrusive elemental mapping of surfaces at the nanoscale and holds the promise of remarkable versatility. We have applied our procedure to the characterization of Ge(Si) islands on Si(111) substrates, with the aim of investigating the surface stoichiometry gradients and gaining insight into the intermixing dynamics. By identifying Si-richer edges with respect to the centers, we are able to associate alloying in these islands to surface transport processes.


Novel Cysteine-Sparing Hypomorphic NOTCH3 A1604T Mutation Observed in a Family With Migraine and White Matter Lesions.
To conduct a clinical study of a family with neurologic symptoms and findings carrying a novel NOTCH3 mutation and to analyze the molecular consequences of the mutation. We analyzed a family with complex neurologic symptoms by MRI and neurologic examinations. Exome sequencing of the NOTCH3 locus was conducted, and whole-genome sequencing was performed to identify COL4A1, COL4A2, and HTRA1 mutations. Cell lines expressing the normal or NOTCH3A1604T receptors were analyzed to assess proteolytic processing, cell morphology, receptor routing, and receptor signaling. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease (SVD) and caused by mutations in the NOTCH3 gene. Most CADASIL mutations alter the number of cysteine residues in the extracellular domain of the NOTCH3 receptor, but in this article, we describe a family in which some members carry a novel cysteine-sparing NOTCH3 mutation (c.4810 G>A, p.Ala1604Thr). Two of 3 siblings heterozygous for the NOTCH3A1604T mutation presented with migraine and white matter lesions (WMLs), the latter of a type related to but distinct from what is normally observed in CADASIL. Two other members instead carried a novel COL4A1 missense mutation (c.4795 G>A; p.(Ala1599Thr)). The NOTCH3A1604T receptor was aberrantly processed, showed reduced presence at the cell surface, and less efficiently activated Notch downstream target genes. We identify a family with migraine and WML in which some members carry a cysteine-sparing hypomorphic NOTCH3 mutation. Although a causal relationship is not established, we believe that the observations contribute to the discussion on dysregulated Notch signaling in cerebral SVDs.


A pivotal heme-transfer reaction intermediate in cytochrome c biogenesis.
c-Type cytochromes are widespread proteins, fundamental for respiration or photosynthesis in most cells. They contain heme covalently bound to protein in a highly conserved, highly stereospecific post-translational modification. In many bacteria, mitochondria, and archaea this heme attachment is catalyzed by the cytochrome c maturation (Ccm) proteins. Here we identify and characterize a covalent, ternary complex between the heme chaperone CcmE, heme, and cytochrome c. Formation of the complex from holo-CcmE occurs in vivo and in vitro and involves the specific heme-binding residues of both CcmE and apocytochrome c. The enhancement and attenuation of the amounts of this complex correlates completely with known consequences of mutations in genes for other Ccm proteins. We propose the complex is a trapped catalytic intermediate in the cytochrome c biogenesis process, at the point of heme transfer from CcmE to the cytochrome, the key step in the maturation pathway.


Eyelid Changes Related to Meibomian Gland Dysfunction in Early Middle-Aged Patients Using Topical Glaucoma Medications.
To investigate the relationship between topical glaucoma medications and meibomian gland dysfunction (MGD) in early middle-aged patients with glaucoma. In this cross-sectional study, 50 patients with glaucoma younger than 50 years who had used topical glaucoma medications for more than 6 months and 40 normal controls of similar age were included. Patients in each group were graded for MGD (0-4) using slit-lamp microscopy. Tear film breakup time (BUT), ocular surface staining, and Marx line scores were also evaluated. Differences between both groups were analyzed statistically. The prevalence of MGD was 82% in the group using topical glaucoma medications and 52.5% in the control group. The average period of topical glaucoma medication use was 27.4 months. There were significant differences in the breakup time and Marx line score according to the presence of MGD. Although the duration of topical glaucoma medication use and the severity of MGD did not show a significant correlation, the degree of MGD and the Marx line score were significantly correlated. Glaucoma eye drops may be one factor affecting the eyelid changes associated with MGD. The Marx line score may be used as an index to evaluate MGD in patients with glaucoma.


EVALUATION OF THE RELATIONSHIP OF MPV, RDW AND PVI PARAMETERS WITH DISEASE SEVERITY IN COVID-19 PATIENTS.
Coronavirus was first detected in three severe pneumonia cases in Wuhan, China, in December 2019. Studies on red cell distribution width (RDW-CV) and mean platelet volume (MPV) laboratory parameters, which can be examined in complete blood count in COVID-19 patients, are still very limited. However, to the best of our knowledge, there are no studies examining the relationship between platelet volume index (PVI) and disease severity in COVID-19 patients, which was evaluated in this study. The aim of this study was to evaluate the relationship of disease severity in COVID-19 patients with their MPV, RDW, and PVI parameters. The study included 92 COVID-19 patients as a study group and 84 healthy individuals as control group. All laboratory data and radiological images were scanned retrospectively from patient files and hospital information system. Evaluation of the RDW-CV and MPV blood parameters, and PVI measured in COVID-19 patients yielded statistically significant differences according to the disease severity. We suggest that RDW-CV and PVI, evaluated within the scope of the study, may be the parameters that should be considered in the early diagnosis of the disease, from the initial stages of COVID-19. In addition, we think that the RDW-CV and MPV laboratory parameters, as well as PVI, which all are simple, inexpensive and widely used hematologic tests, can be used as important biomarkers in determining COVID-19 severity and mortality.


Effect of strength training on functional outcomes and strength in patients with polyneuropathy: A scoping review.
Introduction: Polyneuropathy (PNP) is a chronic progressive disease that over time can lead to damage of sensory, motor and/or autonomic peripheral nerves. Symptoms vary from predominantly sensory to severe sensorimotor affection both proximally and distally. This can result in considerable functional impairments that affect activities of daily living. In other neurological patients, strength training has shown to improve strength and functional outcomes. Since medical treatment only exists for very few percentages of the underlying causes it is obvious to consider if strength training could be a potential treatment for functional impairments. To date little is known on the effect of strength training in patients with PNP. Aim: The aim of this scoping review was to summarize research on strength training and outcomes on physical function in patients with PNP. Methods: We systematically searched five data bases; Pubmed, Embase, Cinahl, Cochrane library and Web of science. Studies on strength training (load ≥70% of 1RM) in patients with PNP were included. The search was carried out in November 2022. Results: 362 articles were screened by title and abstract, 101 articles were full text screened. Eight studies were included. Patients with Charcot-Marie-Tooth (CMT), chronic inflammatory polyneuropathy (CIDP) and diabetic polyneuropathy (DPN) were represented in the studies (five RCTs, two case-series, and one cross-over trial). The methodological quality ranged from fair-poor in seven studies, one study reached good quality. Results from the studies indicated that strength training in CMT, CIDP and DPN may improve strength. However, various outcomes were used to evaluate strength training, so direct comparisons were difficult. Discussion: In this scoping review we summarized research on strength training and outcomes evaluated in interventions in patients with PNP. Eight studies were included, they indicated that strength training may be beneficial for patients with PNP. However, due to low methodological strength of most studies a recommendation for patients with PNP cannot be made. Thus, the low number of studies with relatively low quality, where various functional outcomes were used, underscores the importance of future studies to evaluate the effect of strength training on relevant functional outcomes and strength in patients with PNP.


Presence of parabens, phenols and phthalates in paired maternal serum, urine and amniotic fluid.
To examine whether selected endocrine disrupting chemicals were present in pregnant women and passed through the placental barrier to amniotic fluid, potentially exposing the developing fetus. Paired samples of maternal serum, urine and amniotic fluid were concurrently collected (<1 h) from 200 pregnant women (age >18 years) with a singleton pregnancy and undergoing amniocentesis between gestational weeks 12 - 36. The concentration of six different parabens, seven phenols, 31 metabolites from 15 phthalate diesters and the polychlorinated substance triclocarban were analyzed by isotope diluted TurboFlow-liquid chromatography-tandem mass spectrometry. Concentrations of all included compounds were highest in maternal urine followed by serum, and lowest in amniotic fluid. Of the six parabens measured in amniotic fluid, methylparaben (MeP) and ethylparaben (EtP) were detectable most often (87% and 33% of the samples, respectively). Of the seven phenols measured, three (2,4-dichlorphenol, 2,5-dichlorphenol, 2-propylphenol) were detectable in the range of 14-21% of the amniotic fluid samples, at low concentrations (<0.12 ng/ml). Two secondary phthalates metabolites, mono-(2-carboxymethyl-hexyl) phthalate and mono-carboxy-iso-octyl phthalate were each present in ≤15% of the amniotic fluid samples at concentrations 2-5 times lower than in maternal serum and 20-100 times lower than in maternal urine. A modest statistically significant correlation between the levels of MeP and EtP was detected in paired maternal urine-amniotic fluid samples was detected (Spearman rMeP: 0.246; rEtP: 0.364). Likewise, the concentration of mono-ethyl phthalate (MEP) in paired maternal urine and amniotic fluid samples indicated a modest statistically significant correlation (Spearman rMEP: 0.264), driven by detectable levels of MEP in only 3% of the amniotic fluid samples. In general, the included parabens, phenols and phthalates were effectively metabolized and excreted via the urine, which was the matrix that reflected the highest detectable levels. The detectable levels of several included parabens and phthalates in human amniotic fluid calls for further investigations of the toxicokinetic and potential endocrine disrupting properties of individual and multiple endocrine disruptors in order to better assess the risk to the developing fetus.


Computer-Aided Nodule Assessment and Risk Yield (CANARY) may facilitate non-invasive prediction of EGFR mutation status in lung adenocarcinomas.
Computer-Aided Nodule Assessment and Risk Yield (CANARY) is quantitative imaging analysis software that predicts the histopathological classification and post-treatment disease-free survival of patients with adenocarcinoma of the lung. CANARY characterizes nodules by the distribution of nine color-coded texture-based exemplars. We hypothesize that quantitative computed tomography (CT) analysis of the tumor and tumor-free surrounding lung facilitates non-invasive identification of clinically-relevant mutations in lung adenocarcinoma. Comprehensive analysis of targetable mutations (50-gene-panel) and CANARY analysis of the preoperative (≤3 months) high resolution CT (HRCT) was performed for 118 pulmonary nodules of the adenocarcinoma spectrum surgically resected between 2006-2010. Logistic regression with stepwise variable selection was used to determine predictors of mutations. We identified 140 mutations in 106 of 118 nodules. TP53 (n = 48), KRAS (n = 47) and EGFR (n = 15) were the most prevalent. The combination of Y (Yellow) and G (Green) exemplars, fibrosis within the surrounding lung and smoking status were the best discriminators for an EGFR mutation (AUC 0.77 and 0.87, respectively). None of the EGFR mutants expressing TP53 (n = 5) had a good prognosis based on CANARY features. No quantitative features were significantly associated with KRAS mutations. Our exploratory analysis indicates that quantitative CT analysis of a nodule and surrounding lung may noninvasively predict the presence of EGFR mutations in pulmonary nodules of the adenocarcinoma spectrum.


Pertussis booster vaccination and immediate hypersensitivity.
Twelve non-atopic and 27 atopic preschool children were studied to determine the effect of pertussis booster vaccination on cutaneous histamine sensitivity and IgE antibody response to the naturally-occurring ragweed aeroallergen. Prick tests of histamine and ragweed extract, as well as ragweed-RAST, were performed prior to, and after, their booster injections. Ragweed skin tests and RAST were not repeated until 2 weeks after the end of ragweed pollination. None of the parameters changed significantly in either group regardless of the type of immunization administered.


Identification of protein antigens of group B streptococci, with special reference to the Ibc antigens.
The protein antigens of prototypes of five types of group B streptococcal strains were extracted with HCl or Triton X-100, separated by sodium dodecyl sulfate polyacrylamide electrophoresis, transferred to nitrocellulose, and examined by immunochemical staining. The Ibc proteins are shown to consist of at least two distinct protein antigens and their breakdown products. One antigen, the "beta" antigen, exists primarily as a 130,000 mol wt protein that is also able to bind human IgA. The "alpha" antigen, which has no known function, appears as a number of proteins of various molecular weights from 20,000 to 120,000. Another set of antigens, the R protein antigens of type III strains, has been identified as a group of acid-labile proteins varying in molecular weight from 100,000 to 130,000. In addition, two previously undescribed antigens have been found that are common to all five group B types.


Using a life course approach to explore how the use of AAC impacts on adult sibling relationships.
A life-course methodology was used to explore the relationship between four adults with moderate/severe cerebral palsy with complex communication needs who used AAC, and six of their non-disabled siblings. In-depth interview data were analyzed using a constructivist grounded-theory approach. Elder's life-course paradigm illuminated the importance of historical timing, social time, linked lives, and human agency to the development of communication strategies between siblings. Taking a life-course approach to studying issues related to individuals who use AAC assists understanding of how their family experiences and relationships change over time. This understanding is important, given the strong commitment by family members demonstrated in this study to supporting individuals who use AAC.


Dictionary-based fiber orientation estimation with improved spatial consistency.
Diffusion magnetic resonance imaging (dMRI) has enabled in vivo investigation of white matter tracts. Fiber orientation (FO) estimation is a key step in tract reconstruction and has been a popular research topic in dMRI analysis. In particular, the sparsity assumption has been used in conjunction with a dictionary-based framework to achieve reliable FO estimation with a reduced number of gradient directions. Because image noise can have a deleterious effect on the accuracy of FO estimation, previous works have incorporated spatial consistency of FOs in the dictionary-based framework to improve the estimation. However, because FOs are only indirectly determined from the mixture fractions of dictionary atoms and not modeled as variables in the objective function, these methods do not incorporate FO smoothness directly, and their ability to produce smooth FOs could be limited. In this work, we propose an improvement to Fiber Orientation Reconstruction using Neighborhood Information (FORNI), which we call FORNI+; this method estimates FOs in a dictionary-based framework where FO smoothness is better enforced than in FORNI alone. We describe an objective function that explicitly models the actual FOs and the mixture fractions of dictionary atoms. Specifically, it consists of data fidelity between the observed signals and the signals represented by the dictionary, pairwise FO dissimilarity that encourages FO smoothness, and weighted ℓ1-norm terms that ensure the consistency between the actual FOs and the FO configuration suggested by the dictionary representation. The FOs and mixture fractions are then jointly estimated by minimizing the objective function using an iterative alternating optimization strategy. FORNI+ was evaluated on a simulation phantom, a physical phantom, and real brain dMRI data. In particular, in the real brain dMRI experiment, we have qualitatively and quantitatively evaluated the reproducibility of the proposed method. Results demonstrate that FORNI+ produces FOs with better quality compared with competing methods.


Molecular targets of arsenic trioxide in malignant cells.
Arsenic trioxide (As2O3; ATO) has considerable efficacy in the treatment of relapsed acute promyelocytic leukemia (APL), inducing partial differentiation and promoting apoptosis of malignant promyelocytes. Although initial studies focused on the role of the characteristic APL fusion protein, PML-RARalpha, in mediating response to ATO, subsequent investigations have revealed that ATO acts on numerous intracellular targets. ATO broadly affects signal transduction pathways and causes a wide range of alterations leading to apoptosis. Key mediators of sensitivity to ATO-induced apoptosis include intracellular glutathione and hydrogen peroxide (H2O2). The loss of inner mitochondrial membrane potential is also an important step in ATO-mediated cell killing. Cellular and physiologic pathways affected by ATO provide some clues as to the mechanisms for the biologic effects of ATO. Recent research has shown that hematologic cancers other than APL and solid tumors derived from several tissue types may be responsive to monotherapy or combination therapy with ATO. A better understanding of the mechanisms of action of ATO may help guide the use of ATO for the treatment of a wide variety of malignancies and allow its potential in cancer therapy to be fully realized.


Genotype-environment interactions and the estimation of the genomic mutation rate in Drosophila melanogaster.
We have studied the relative fitnesses of three genotypes of Drosophila melanogaster in 50 environments. Two genotypes, the MA lines, had accumulated mutations in the absence of natural selection over 62 generations. The third was a related strain where selection had continued to act. The environments differed in three factors: parental density, dilution of the medium, and the temperature régime and medium composition. Our measure of fitness assessed fecundity and viability relative to a reference genotype. Both MA lines always had lower fitnesses than the selected line, but the difference increased dramatically with dilution of the medium and, especially, crowding. Under the most severe conditions, the performance of the MA lines approached 0. This increased difference in harsh conditions may be caused both by a uniform increase in the magnitude of deleterious effects of all mutations and by the exposure of mutations which are essentially neutral under benign conditions. If the second cause is important, previous experiments are likely to have underestimated the genomic deleterious mutation rate in Drosophila melanogaster more than previously thought.


Characterization of Escherichia coli from Edible Insect Species: Detection of Shiga Toxin-Producing Isolate.
Insects as novel foods are gaining popularity in Europe. Regulation (EU) 2015/2283 laid the framework for the application process to market food insects in member states, but potential hazards are still being evaluated. The aim of this study was to investigate samples of edible insect species for the presence of antimicrobial-resistant and Shiga toxin-producing Escherichia coli (STEC). Twenty-one E. coli isolates, recovered from samples of five different edible insect species, were subjected to antimicrobial susceptibility testing, PCR-based phylotyping, and macrorestriction analysis. The presence of genes associated with antimicrobial resistance or virulence, including stx1, stx2, and eae, was investigated by PCR. All isolates were subjected to genome sequencing, multilocus sequence typing, and serotype prediction. The isolates belonged either to phylogenetic group A, comprising mostly commensal E. coli, or group B1. One O178:H7 isolate, recovered from a Zophobas atratus sample, was identified as a STEC. A single isolate was resistant to tetracyclines and carried the tet(B) gene. Overall, this study shows that STEC can be present in edible insects, representing a potential health hazard. In contrast, the low resistance rate among the isolates indicates a low risk for the transmission of antimicrobial-resistant E. coli to consumers.


Fourier transform light scattering of inhomogeneous and dynamic structures.
Fourier transform light scattering (FTLS) is a novel experimental approach that combines optical microscopy, holography, and light scattering for studying inhomogeneous and dynamic media. In FTLS the optical phase and amplitude of a coherent image field are quantified and propagated numerically to the scattering plane. Because it detects all the scattered angles (spatial frequencies) simultaneously in each point of the image, FTLS can be regarded as the spatial equivalent of Fourier transform infrared spectroscopy, where all the temporal frequencies are detected at each moment in time.


Validation of the 70-gene signature test (MammaPrint) to identify patients with breast cancer aged ≥ 70 years with ultralow risk of distant recurrence: A population-based cohort study.
When risk estimation in older patients with hormone receptor positive breast cancer (HR + BC) is based on the same factors as in younger patients, age-related factors regarding recurrence risk and other-cause mortality are not considered. Genomic risk assessment could help identify patients with ultralow risk BC who can forgo adjuvant treatment. However, assessment tools should be validated specifically for older patients. This study aims to determine whether the 70-gene signature test (MammaPrint) can identify patients with HR + BC aged ≥70 years with ultralow risk for distant recurrence. Inclusion criteria: ≥70 years; invasive HR + BC; T1-2N0-3M0. HER2 + BC; neoadjuvant therapy. MammaPrint assays were performed following standardized protocols. Clinical risk was determined with St. Gallen risk classification. Primary endpoint was 10-year cumulative incidence rate of distant recurrence in relation to genomic risk. Subdistribution hazard ratios (sHR) were estimated from Fine and Gray analyses. Multivariate analyses were adjusted for adjuvant endocrine therapy and clinical risk. This study included 418 patients, median age 78 years (interquartile range [IQR] 73-83). Sixty percent of patients were treated with endocrine therapy. MammaPrint classified 50 patients as MammaPrint-ultralow, 224 patients as MammaPrint-low, and 144 patients as MammaPrint-high risk. Regarding clinical risk, 50 patients were classified low, 237 intermediate, and 131 high. Discordance was observed between clinical and genomic risk in 14 MammaPrint-ultralow risk patients who were high clinical risk, and 84 patients who were MammaPrint-high risk, but low or intermediate clinical risk. Median follow-up was 9.2 years (IQR 7.9-10.5). The 10-year distant recurrence rate was 17% (95% confidence interval [CI] 11-23) in MammaPrint-high risk patients, 8% (4-12) in MammaPrint-low (HR 0.46; 95%CI 0.25-0.84), and 2% (0-6) in MammaPrint-ultralow risk patients (HR 0.11; 95%CI 0.02-0.81). After adjustment for clinical risk and endocrine therapy, MammaPrint-high risk patients still had significantly higher 10-year distant recurrence rate than MammaPrint-low (sHR 0.49; 95%CI 0.26-0.90) and MammaPrint-ultralow patients (sHR 0.12; 95%CI 0.02-0.85). Of the 14 MammaPrint-ultralow, high clinical risk patients none developed a distant recurrence. These data add to the evidence validating MammaPrint's ultralow risk threshold. Even in high clinical risk patients, MammaPrint-ultralow risk patients remained recurrence-free ten years after diagnosis. These findings justify future studies into using MammaPrint to individualize adjuvant treatment in older patients.


Nucleolin Is a Functional Binding Protein for Salinomycin in Neuroblastoma Stem Cells.
The aim of this study is to illuminate a novel therapeutic approach by identifying a functional binding target of salinomycin, an emerging anticancer stem cell (CSC) agent, and to help dissect the underlying action mechanisms. By utilizing integrated strategies, we identify that nucleolin (NCL) is likely a salinomycin-binding target and a critical regulator involved in human neuroblastoma (NB) CSC activity. Salinomycin markedly suppresses NB CD34 expression and reduces CD34+ cell population in an NCL-dependent manner via disruption of the interaction of NCL with CD34 promoter. The elevated levels of NCL expression in NB tumors are associated with poor patient survival. Altogether, these results indicate that NCL is likely a novel functional salinomycin-binding target that exhibits the potential to be a prognostic marker for NB therapy.


Proteome Profile of Myelin in the Zebrafish Brain.
The velocity of nerve conduction along vertebrate axons depends on their ensheathment with myelin. Myelin membranes comprise specialized proteins well characterized in mice. Much less is known about the protein composition of myelin in non-mammalian species. Here, we assess the proteome of myelin biochemically purified from the brains of adult zebrafish (Danio rerio), considering its increasing popularity as model organism for myelin biology. Combining gel-based and gel-free proteomic approaches, we identified > 1,000 proteins in purified zebrafish myelin, including all known constituents. By mass spectrometric quantification, the predominant Ig-CAM myelin protein zero (MPZ/P0), myelin basic protein (MBP), and the short-chain dehydrogenase 36K constitute 12%, 8%, and 6% of the total myelin protein, respectively. Comparison with previously established mRNA-abundance profiles shows that expression of many myelin-related transcripts coincides with the maturation of zebrafish oligodendrocytes. Zebrafish myelin comprises several proteins that are not present in mice, including 36K, CLDNK, and ZWI. However, a surprisingly large number of ortholog proteins is present in myelin of both species, indicating partial evolutionary preservation of its constituents. Yet, the relative abundance of CNS myelin proteins can differ markedly as exemplified by the complement inhibitor CD59 that constitutes 5% of the total zebrafish myelin protein but is a low-abundant myelin component in mice. Using novel transgenic reporter constructs and cryo-immuno electron microscopy, we confirm the incorporation of CD59 into myelin sheaths. These data provide the first proteome resource of zebrafish CNS myelin and demonstrate both similarities and heterogeneity of myelin composition between teleost fish and rodents.


Computational investigation of actuation mechanisms of droplets on porous air-permeable substrates.
We study the actuation of droplets on porous substrates by air that permeates through pores. Air pockets are created between the droplets and the substrate which, eventually, incite the droplets to a quasi-moving state. We observe this mechanism computationally and verify it experimentally, using various case studies involving water droplets of different volume that are initially pinned on a porous substrate which has been set to different inclination levels and start to slide down when actuated by permeating air. The computational model employs the continuity equation and the equations of momentum transfer that are coupled with the Volume of Fluid (VOF) method, to track the shape of the droplet. We identify two dominant actuation mechanisms - seen in computations and experiments - that are given the names 'donut' and 'tunnel'. Both of them are characterized by the formation of small air pockets between the droplet and the substrate that coalesce into larger ones that finally escape the droplet, by collapsing its free surface. The two mechanisms differ in the way that the free surface of the droplet collapses. The donut mechanism has the free surface collapsing at its center, thus forming a hole in the middle of the droplet (hence the name, donut), whereas the tunnel mechanism has the free surface collapsing at its rear side, forming a horizontal hole that resembles a tunnel (hence the name). We compare each mechanism in terms of the event (mechanism) occurrence frequency and droplet displacement, and also provide the dependence of the droplet speed with respect to the flow rate of permeating air, substrate inclination and droplet volume.


Organization of cortico-cortical pathways supporting memory retrieval across subregions of the left ventrolateral prefrontal cortex.
Functional magnetic resonance imaging (fMRI) evidence indicates that different subregions of ventrolateral prefrontal cortex (VLPFC) participate in distinct cortical networks. These networks have been shown to support separable cognitive functions: anterior VLPFC [inferior frontal gyrus (IFG) pars orbitalis] functionally correlates with a ventral fronto-temporal network associated with top-down influences on memory retrieval, while mid-VLPFC (IFG pars triangularis) functionally correlates with a dorsal fronto-parietal network associated with postretrieval control processes. However, it is not known to what extent subregional differences in network affiliation and function are driven by differences in the organization of underlying white matter pathways. We used high-angular-resolution diffusion spectrum imaging and functional connectivity analysis in unanesthetized humans to address whether the organization of white matter connectivity differs between subregions of VLPFC. Our results demonstrate a ventral-dorsal division within IFG. Ventral IFG as a whole connects broadly to lateral temporal cortex. Although several different individual white matter tracts form connections between ventral IFG and lateral temporal cortex, functional connectivity analysis of fMRI data indicates that these are part of the same ventral functional network. By contrast, across subdivisions, dorsal IFG was connected with the midfrontal gyrus and correlated as a separate dorsal functional network. These qualitative differences in white matter organization within larger macroanatomical subregions of VLPFC support prior functional distinctions among these regions observed in task-based and functional connectivity fMRI studies. These results are consistent with the proposal that anatomical connectivity is a crucial determinant of systems-level functional organization of frontal cortex and the brain in general.


Sperm traits on in vitro production (IVP) of bovine embryos: Too much of anything is good for nothing.
Sperm samples used on fertilization strongly influence the in vitro production (IVP) rates. However, sperm traits behind this effect are not stated consistently until now. This study aimed to evaluate the isolated and combined effect of some sperm traits (MB: total motility before Percoll® gradient, MA: total motility after Percoll® gradient, AI: acrosome integrity, MI: membrane integrity, MP: mitochondrial membrane potential, and CR: chromatin resistance) on IVP rates. This is the first study focusing on the isolated effect of distinct traits. For this purpose, the experiment was divided in three steps. In first step, to study behavior of traits sperm samples (n = 63 batches) were analyzed and ranked based on each trait. In second step, samples ranked were selected from target ranks regions and allocated in groups of four to five batches, creating Higher and Lower groups, according to two different approaches. One aimed to form groups that differed to all sperm traits simultaneously (effect of combined traits). The other aimed to form groups that differed only to a single sperm trait while no differences were observed for the remaining traits (effect of each isolated trait). In third step, for each group successfully formed in step 2, sperm samples were individually and prospectively used for IVP. Cleavage, embryo development and blastocyst rates were recorded and compared between Higher and Lower of respective trait groups. Surprisingly, evaluation of isolated effects revealed that lower levels of MB, AI and MP resulted in higher embryo development and blastocyst rates (p<0.05), which was not observed on cleavage rate. We conclude that sperm traits strongly influence embryo development after in vitro fertilization (IVF), affecting the zygote competence to achieve blastocyst stage. Individually, levels of MB, AI or MP could be some of the key traits that may define IVP efficiency on current systems of embryo production.


Finite element analysis in asymptomatic, symptomatic, and ruptured abdominal aortic aneurysms: in search of new rupture risk predictors.
To compare biomechanical rupture risk parameters of asymptomatic, symptomatic and ruptured abdominal aortic aneurysms (AAA) using finite element analysis (FEA). Retrospective biomechanical single center analysis of asymptomatic, symptomatic, and ruptured AAAs. Comparison of biomechanical parameters from FEA. From 2011 to 2013 computed tomography angiography (CTA) data from 30 asymptomatic, 15 symptomatic, and 15 ruptured AAAs were collected consecutively. FEA was performed according to the successive steps of AAA vessel reconstruction, segmentation and finite element computation. Biomechanical parameters Peak Wall Rupture Risk Index (PWRI), Peak Wall Stress (PWS), and Rupture Risk Equivalent Diameter (RRED) were compared among the three subgroups. PWRI differentiated between asymptomatic and symptomatic AAAs (p < .0004) better than PWS (p < .1453). PWRI-dependent RRED was higher in the symptomatic subgroup compared with the asymptomatic subgroup (p < .0004). Maximum AAA external diameters were comparable between the two groups (p < .1355). Ruptured AAAs showed the highest values for external diameter, total intraluminal thrombus volume, PWS, RRED, and PWRI compared with asymptomatic and symptomatic AAAs. In contrast with symptomatic and ruptured AAAs, none of the asymptomatic patients had a PWRI value >1.0. This threshold value might identify patients at imminent risk of rupture. From different FEA derived parameters, PWRI distinguishes most precisely between asymptomatic and symptomatic AAAs. If elevated, this value may represent a negative prognostic factor for asymptomatic AAAs.


[Tuberculous microbladder. Ileocystoplasty for enlargement].
We have had occasion to treat 8 patients suffering from tuberculous microbladder on whom we carried out augmentation plasty with a segment of ileum according to Ring-plasty technique in 6 cases, and with U-morphology in the other two, all displayed as the main symptom increase in mictional frequency. Six patients were subjected to prior tuberculostatic treatment. Mictional frequency improved in all patients. We observed morphological improvement in seven patients and functional improvement in four, there was one death, in a patients who had only been having prior tubculostatic treatment for one month. Daytime continence was achieved in al cases and there was nocturnal incontinence in five patients. U or ring ileocystoplasties are simple fast techniques displaying good capacity with low pressures and residua of less than 80 cc. No vesicourethral reflux was observed when we carried out the reimplantation.


The face of STEM: Racial phenotypic stereotypicality predicts STEM persistence by-and ability attributions about-students of color.
[Correction Notice: An Erratum for this article was reported in Vol 116(3) of Journal of Personality and Social Psychology (see record 2019-08943-003). In the article "The Face of STEM: Racial Phenotypic Stereotypicality Predicts STEM Persistence by-and Ability Attributions About-Students of Color" by Melissa J. Williams, Julia George- Jones, and Mikki Hebl (Journal of Personality and Social Psychology. Advance online publication. October 15, 2018. http://dx.doi.org/10.1037/pspi0000153), the Editor' Note acknowledging Toni Schmader as the action editor for this article was omitted. All versions of this article have been corrected.] Despite strong initial interest, college students-especially those from underrepresented minority (URM) backgrounds-leave STEM majors at high rates. Here, we explore the role of racial phenotypic stereotypicality, or how typical one's physical appearance is of one's racial group, in STEM persistence. In a longitudinal study, URM students were especially likely to leave STEM to the extent that they looked more stereotypical of their group; Asian American students were especially likely to leave STEM to the extent that they looked less stereotypical. Three experiments documented a possible mechanism; participants (Studies 2-4), including college advisors (Study 3), attributed greater STEM ability to more-stereotypical Asian Americans and to less-stereotypical Black women (not men), than to same-race peers. Study 4 showed that prejudice concerns, activated in interactions with Black men (not women), account for this gender difference; more-stereotypical Black men (like women) were negatively evaluated when prejudice concerns were not salient. This work has important implications for ongoing efforts to achieve diversity in STEM. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Intragastric nitric oxide production in humans: measurements in expelled air.
High values (800-6000 parts per billion) of nitric oxide (NO) in expelled air from the stomach were shown in humans by chemiluminescence technique. These NO values were more than 100 times higher than those found in orally exhaled air. Intragastric NO production is probably non-enzymatic, requiring an acidic environment, as NO in expelled air was reduced by 95% after pretreatment with the proton pump inhibitor omeprazole. Furthermore, large amounts of NO were formed in vitro from lettuce and saliva when placed in hydrogen chloride (pH < 2). In conclusion, large amounts of NO are formed intragastrically in humans and this source of NO may be of importance for the integrity of the gastric mucosa in health and disease. Measurements of NO in expelled air might be of value as a non-invasive method for estimation of gastric acidity.


Heritability of phenotypic udder traits to improve resilience to mastitis in Texel ewes.
There are no estimates of the heritability of phenotypic udder traits in suckler sheep, which produce meat lambs, and whether these are associated with resilience to mastitis. Mastitis is a common disease which damages the mammary gland and reduces productivity. The aims of this study were to investigate the feasibility of collecting udder phenotypes, their heritability and their association with mastitis in suckler ewes. Udder and teat conformation, teat lesions, intramammary masses (IMM) and litter size were recorded from 10 Texel flocks in Great Britain between 2012 and 2014; 968 records were collected. Pedigree data were obtained from an online pedigree recording system. Univariate quantitative genetic parameters were estimated using animal and sire models. Linear mixed models were used to analyse continuous traits and generalised linear mixed models were used to analyse binary traits. Continuous traits had higher heritabilities than binary with teat placement and teat length heritability (h 2) highest at 0.35 (SD 0.04) and 0.42 (SD 0.04), respectively. Udder width, drop and separation heritabilities were lower and varied with udder volume. The heritabilities of IMM and teat lesions (sire model) were 0.18 (SD 0.12) and 0.17 (SD 0.11), respectively. All heritabilities were sufficiently high to be in a selection programme to increase resilience to mastitis in the population of Texel sheep. Further studies are required to investigate genetic relationships between traits and to determine whether udder traits predict IMM, and the potential benefits from including traits in a selection programme to increase resilience to chronic mastitis.


Drought stress acclimation imparts tolerance to Sclerotinia sclerotiorum and Pseudomonas syringae in Nicotiana benthamiana.
Acclimation of plants with an abiotic stress can impart tolerance to some biotic stresses. Such a priming response has not been widely studied. In particular, little is known about enhanced defense capacity of drought stress acclimated plants to fungal and bacterial pathogens. Here we show that prior drought acclimation in Nicotiana benthamiana plants imparts tolerance to necrotrophic fungus, Sclerotinia sclerotiorum, and also to hemi-biotrophic bacterial pathogen, Pseudomonas syringae pv. tabaci. S. sclerotiorum inoculation on N. benthamiana plants acclimated with drought stress lead to less disease-induced cell death compared to non-acclimated plants. Furthermore, inoculation of P. syringae pv. tabaci on N. benthamiana plants acclimated to moderate drought stress showed reduced disease symptoms. The levels of reactive oxygen species (ROS) in drought acclimated plants were highly correlated with disease resistance. Further, in planta growth of GFPuv expressing P. syringae pv. tabaci on plants pre-treated with methyl viologen showed complete inhibition of bacterial growth. Taken together, these experimental results suggested a role for ROS generated during drought acclimation in imparting tolerance against S. sclerotiorum and P. syringae pv. tabaci. We speculate that the generation of ROS during drought acclimation primed a defense response in plants that subsequently caused the tolerance against the pathogens tested.


Attention modulation by proportion congruency: the asymmetrical list shifting effect.
Proportion congruency effects represent hallmark phenomena in current theorizing about cognitive control. This is based on the notion that proportion congruency determines the relative levels of attention to relevant and irrelevant information in conflict tasks. However, little empirical evidence exists that uniquely supports such an attention modulation account; moreover, a rivaling account was recently proposed that attributes the effect of proportion congruency to mere contingency learning. In the present study, the influences of shifts in list-wide (Experiment 1) or item-specific (Experiment 2) proportion congruency were investigated. As predicted by attention modulation but not by contingency learning, strong asymmetries were observed in such shifting: An increase in the proportion of congruent trials had only limited impact on the size of the congruency effect when participants were initially trained with a mostly incongruent list, but the impact was substantial for an equivalent increase of incongruent trials when participants were initially trained with a mostly congruent list. This asymmetrical list shifting effect directly supports attention modulation by proportion congruency manipulations and as such provides a novel tool for exploring cognitive control. Implications of our findings for existing theories of cognitive control are discussed.


Evidence that blue petrel, Halobaena caerulea, fledglings can detect and orient to dimethyl sulfide.
Procellariiform seabirds (the petrels, albatrosses and shearwaters) are recognized for their acute sense of smell. These pelagic seabirds forage over thousands of miles of ocean to find patchily distributed prey resources. Over the past decade, much headway has been made in unravelling the variety of olfactory foraging strategies that Antarctic species employ, and it is becoming clearer that olfaction plays a key role in foraging, particularly for burrow nesting species. Now we are beginning to explore how these behaviours develop in chicks. Procellariiform chicks fledge and survive the open seas without aid or instruction from a parent, but how they are able to accomplish this task is unknown. Here we explore whether chicks leave the nest pre-tuned to olfactory cues necessary for foraging. In this study, we tested the hypothesis that blue petrel chicks (Halobaena caerulea) are able to detect and orient to a foraging cue (dimethyl sulphide, DMS) used by adults without ever having experienced this odour at sea. We first established that chicks could detect DMS at a biologically relevant concentration that they will later naturally encounter at sea (<10 pmol l-1). We then performed preference tests in a Y-maze on a group of birds 1-6 days before they fledged. Sixteen out of 20 fledglings preferred DMS (e.g. DMS+propylene glycol) to a ;control' odour (propylene glycol alone). Our results suggest that chicks can detect and may already recognize DMS as an orientation cue even before they leave the nest to forage for the first time.


Transcriptome analysis reveals differentially expressed transcripts in rat adrenal zona glomerulosa and zona fasciculata.
In mammals, aldosterone is produced in the zona glomerulosa (zG), the outermost layer of the adrenal cortex, whereas glucocorticoids are produced in adjacent zona fasciculata (zF). However, the cellular mechanisms controlling the zonal development and the differential hormone production (i.e. functional zonation) are poorly understood. To explore the mechanisms, we defined zone-specific transcripts in this study. Eleven-week-old male rats were used and adrenal tissues were collected from zG and zF using laser-capture microdissection. RNA was isolated, biotin labeled, amplified, and hybridized to Illumina microarray chips. The microarray data were compared by fold change calculations. In zG, 235 transcripts showed more than a 2-fold up-regulation compared to zF with statistical significance. Similarly, 231 transcripts showed up-regulation in zF. The microarray findings were validated using quantitative RT-PCR and immunohistochemical staining on selected transcripts, including Cyp11b2 (zG/zF: 214.2x), Rgs4 (68.4x), Smoc2 (49.3x), and Mia1 (43.1x) in zG as well as Ddah1 (zF/zG 16.2x), Cidea (15.5x), Frzb (9.5x), and Hsd11b2 (8.3x) in zF. The lists of transcripts obtained in the current study will be an invaluable tool for the elucidation of cellular mechanisms leading to zG and zF functional zonation.


Justice at the margins: witches, poisoners, and social accountability in northern Uganda.
Recent responses to people alleged to be 'witches' or 'poisoners' among the Madi of northern Uganda are compared with those of the 1980s. The extreme violence of past incidents is set in the context of contemporary upheavals and, in effect, encouragement from Catholic and governmental attitudes and initiatives. Mob justice has subsequently become less common. From 2006, a democratic system for dealing with suspects was introduced, whereby those receiving the highest number of votes are expelled from the neighborhood or punished in other ways. These developments are assessed with reference to trends in supporting 'traditional' approaches to social accountability and social healing as alternatives to more conventional measures. Caution is required. Locally acceptable hybrid systems may emerge, but when things turn nasty, it is usually the weak and vulnerable that suffer.


Long-Term Therapeutic Effect of Microvascular Decompression for Trigeminal Neuralgia: Kaplan-Meier Analysis in a Consecutive Series of 425 Patients.
To evaluate the long-term efficacy and safety of microvascular decompression (MVD) for treating trigeminal neuralgia (TN), and identify the predictors of pain relief. A total of 425 patients who underwent surgery between 1991 and 2011 for idiopathic TN were included in this study. Pain outcome was graded using the Barrow Neurological Institute pain scale and success was defined as complete pain relief without medication. A Kaplan-Meier survival curve was generated. Univariate analysis and Cox proportional-hazards regression were performed to identify factors associated with the maintenance of long-term pain relief. The cure rate was 89.3% at 1 year, 80.5% at 3 years, 75.6% at 5 years, and 71.2% at 8 years. Typical clinical presentation, arterial vessel compression, and age ? 60 years at the time of surgery were independent predictors of an excellent outcome. Gender, side, branches involved, symptom duration, hypertension, previously failed surgery, and number of conflicted vessels had no prognostic value. A total of 36 patients (8.47%) developed permanent cranial nerve injury and general complications and the mortality rate was 0.24%. MVD has positive effects for TN treatment, with persistent pain relief achieved in 71.2% of patients 8 years after the procedure. Long-term pain remission may be related to typical clinical presentation, an arterial conflicted vessel, and age ? 60 years at the time of surgery.


Febrile-range temperature but not heat shock augments the acute phase response to interleukin-6 in human hepatoma cells.
The relationship between the stress protein response and the acute phase response (APPR) was studied in human hepatoma cells to investigate the hierarchy of regulation of these survival responses. Huh-7 cells were subjected to heat treatment (febrile-range temperature 40 degrees C or heat shock 43 degrees C) followed by recovery at 37 degrees C in the presence or absence of IL-6 given either before or after heat treatment. The effects on total, fractional, and acute phase protein synthesis were then analyzed by metabolic labeling, ELISA, real-time PCR, Northern blot analysis, and activation of an alpha(1)-antitrypsin reporter plasmid. Cell energetics were studied under the same conditions using an index of mitochondrial activity and measurement of cellular ATP levels. Febrile-range temperature (40 degrees C) augmented acute phase protein production when cells had been pretreated with IL-6. Pretreatment of cells with IL-6 also prevented heat shock-induced suppression of alpha(1)-antichymotrypsin (ACT) but not transferrin. mRNA expression of ACT and alpha(1)-antitrypsin reporter activation studies was consistent with transcriptional regulation of these proteins. Expression of mRNA transcripts for transferrin was increased despite protein expression being reduced by heat shock. The effects of heat shock on acute phase protein synthesis can be modified by preincubation with IL-6, whereas addition of this ligand after heat treatment has no effect on the suppressive effect of heat on the APPR. The mechanism of this action appears to be transcriptionally regulated in the case of ACT, but in the case of transferrin, it may be mediated by another process such as posttranslational modification.


Concerted evolution between duplicated genetic elements in Helicobacter pylori.
The Helicobacter pylori genome includes a family of outer membrane proteins (OMPs) with substantial N and C-terminal identity. To better understand their evolution, the nucleotide sequences for two members, babA and babB, were determined from a worldwide group of 23 strains. The geographic origin of each strain was found to be the major determinant of phylogenetic structure, with strains of Eastern and Western origin showing greatest divergence. For strains 96-10 (Japan) and 96-74 (USA), the 5' regions of babB are replaced with babA sequences, demonstrating that recombination occurs between the two loci. babA and babB have nearly equivalent variation in nucleotide and amino acid identity, and frequencies of synonymous and non-synonymous substitutions. Both genes have segmental conservation but within the 3' segment, substitution patterns are nearly identical. Although babA and babB 5' and midregion segment phylogenies show strong interstrain similarity, the 3' segments show strong intrastrain similarity, indicative of concerted evolution. Within these 3' segments, the lower intrastrain than interstrain frequencies of nucleotide substitutions, which are below mean background H. pylori substitution frequencies, indicate selection against intrastrain diversification. Since babA/babB gene conversions likely underlie the concerted evolution of the 3' segments, in an experimental system, we demonstrate that gene conversions can frequently (10(-3)) occur in H. pylori. That these events are recA-dependent and DNase-resistant indicates their likely cause is intragenomic recombination.


Glucocorticoids suppress growth in neonatal cardiomyocytes co-expressing AT(2) and AT(1) angiotensin receptors.
Perinatal glucocorticoid treatment is associated with hypertrophic cardiomyopathy, but the cellular mechanism is controversial. An underlying interaction between glucocorticoids and the renin-angiotensin system may be important, but whether glucocorticoids modulate angiotensin II (AngII)-dependent cardiomyocyte growth responses in the neonate has not been investigated. The major aim of this investigation was to determine whether glucocorticoids modulate the neonatal cardiomyocyte growth response to AngII. In particular we sought evidence to determine whether angiotensin II type 2 (AT(2)) receptor co-expression with angiotensin II type 1 (AT(1)) receptor is of specific importance in this modulatory function. In this study, we used AT(1) and AT(2) receptor-expressing adenoviruses (Ad-AT(1) and Ad-AT(2)) in a well-defined in vitro neonatal cardiomyocyte culture model to assess whether glucocorticoids affect cardiomyocyte growth responses (i.e. total protein content). Following addition of AngII (0.1 micromol/l) to neonatal cardiomyocytes infected with Ad-AT(1) alone, a significant growth response was measured (133.2 +/- 4.8%). Expression of Ad-AT(2) alone induced a approximately 20% increase in total cellular protein content, which was unaffected by addition of AngII. Neither corticosterone (1 micromol/l) nor dexamethasone (1 micromol/l) had any significant effect on the AT(1)- or AT(2)-mediated growth responses. In contrast, the growth response to AngII was augmented following co-expression of AT(2) and AT(1) receptors (149.2 +/- 4.2%), which was reduced by approximately 20% in the presence of either corticosterone or dexamethasone (p < 0.05). The present study provides novel evidence that glucocorticoids suppress neonatal cardiomyocyte growth responsiveness when AT(2 )and AT(1) receptor subtypes are co-expressed.


COVID-19 Severity and Thrombo-Inflammatory Response Linked to Ethnicity.
Although there is strong evidence that SARS-CoV-2 infection is associated with adverse outcomes in certain ethnic groups, the association of disease severity and risk factors such as comorbidities and biomarkers with racial disparities remains undefined. This retrospective study between March 2020 and February 2021 explores COVID-19 risk factors as predictors for patients' disease progression through country comparison. Disease severity predictors in Germany and Japan were cardiovascular-associated comorbidities, dementia, and age. We adjusted age, sex, body mass index, and history of cardiovascular disease comorbidity in the country cohorts using a propensity score matching (PSM) technique to reduce the influence of differences in sample size and the surprisingly young, lean Japanese cohort. Analysis of the 170 PSM pairs confirmed that 65.29% of German and 85.29% of Japanese patients were in the uncomplicated phase. More German than Japanese patients were admitted in the complicated and critical phase. Ethnic differences were identified in patients without cardiovascular comorbidities. Japanese patients in the uncomplicated phase presented a suppressed inflammatory response and coagulopathy with hypocoagulation. In contrast, German patients exhibited a hyperactive inflammatory response and coagulopathy with hypercoagulation. These differences were less pronounced in patients in the complicated phase or with cardiovascular diseases. Coagulation/fibrinolysis-associated biomarkers rather than inflammatory-related biomarkers predicted disease severity in patients with cardiovascular comorbidities: platelet counts were associated with severe illness in German patients. In contrast, high D-dimer and fibrinogen levels predicted disease severity in Japanese patients. Our comparative study indicates that ethnicity influences COVID-19-associated biomarker expression linked to the inflammatory and coagulation (thrombo-inflammatory) response. Future studies will be necessary to determine whether these differences contributed to the less severe disease progression observed in Japanese COVID-19 patients compared with those in Germany.


Dynamic monitoring of the effects of adherence to medication on survival in heart failure patients: A joint modeling approach exploiting time-varying covariates.
Adherence to medication is the process by which patients take their drugs as prescribed, and represents an issue in pharmacoepidemiological studies. Poor adherence is often associated with adverse health conditions and outcomes, especially in case of chronic diseases such as heart failure (HF). This turns out in an increased request for health care services, and in a greater burden for the health care system. In recent years, there has been a substantial growth in pharmacotherapy research, aimed at studying effects and consequences of proper/improper adherence to medication both for the increasing awareness of the problem and for the pervasiveness of poor adherence among patients. However, the way adherence is computed and accounted for into predictive models is far from being informative as it may be. In fact, it is usually analyzed as a fixed baseline covariate, without considering its time-varying behavior. The purpose and novelty of this study is to define a new personalized monitoring tool exploiting time-varying definition of adherence to medication, within a joint modeling approach. In doing so, we are able to capture and quantify the association between the longitudinal process of dynamic adherence to medication with the long-term survival outcome. Another novelty of this approach consists of exploiting the potential of health care administrative databases in order to reconstruct the dynamics of drugs consumption through pharmaceutical administrative registries. In particular, we analyzed administrative data provided by Regione Lombardia - Healthcare Division related to patients hospitalized for HF between 2000 and 2012.