Perivascular tumor-associated macrophages and their role in cancer progression.
Perivascular (Pv) tumor-associated macrophages (TAMs) are a highly specialized stromal subset within the tumor microenvironment (TME) that are defined by their spatial proximity, within one cell thickness, to blood vasculature. PvTAMs have been demonstrated to support a variety of pro-tumoral functions including angiogenesis, metastasis, and modulating the immune and stromal landscape. Furthermore, PvTAMs can also limit the response of anti-cancer and anti-angiogenic therapies and support tumor recurrence post-treatment. However, their role may not exclusively be pro-tumoral as PvTAMs can also have immune-stimulatory capabilities. PvTAMs are derived from a monocyte progenitor that develop and localize to the Pv niche as part of a multistep process which relies on a series of signals from tumor, endothelial and Pv mesenchymal cell populations. These cellular communications and signals create a highly specialized TAM subset that can also form CCR5-dependent multicellular 'nest' structures in the Pv niche. This review considers our current understanding of the role of PvTAMs, their markers for identification, development, and function in cancer. The role of PvTAMs in supporting disease progression and modulating the outcome from anti-cancer therapies highlight these cells as a therapeutic target. However, their resistance to pan-TAM targeting therapies, such as those targeting the colony stimulating factor-1 (CSF1)-CSF1 receptor axis, prompts the need for more targeted therapeutic approaches to be considered for this subset. This review highlights potential therapeutic strategies to target and modulate PvTAM development and function in the TME.


Urgent management of a giant scrotal hernia.
An unusual case of giant scrotal hernia is presented. Hernias of this magnitude are extremely rare, even in underdeveloped countries, and their repair is challenging to the surgeon and stressful to the patient. Only a few case reports on the use of pneumoperitoneum prior to herniorrhaphy have been published; however, our patient's accompanying complications of diabetes mellitus and gastrointestinal symptoms precluded the use of pneumoperitoneum. The emergency management, including the expansion of the abdominal cavity with prosthesis, the ensuing postoperative complications, and the patient outcome, are discussed.


Units of Language Mixing: A Cross-Linguistic Perspective.
Language mixing is a ubiquitous phenomenon characterizing bilingual speakers. A frequent context where two languages are mixed is the word-internal level, demonstrating how tightly integrated the two grammars are in the mind of a speaker and how they adapt to each other. This raises the question of what the minimal unit of language mixing is, and whether or not this unit differs depending on what the languages are. Some scholars have argued that an uncategorized root serves as a unit, others argue that the unit needs to have been categorized prior to mixing. We will discuss the question of what the relevant unit for language mixing is by studying word-internal mixing in Cypriot Greek-English, English-Norwegian, Greek-English, Greek-German, and Spanish-German varieties that have been reported in the literature based on data from judgment experiments and spoken corpora. By understanding and modeling the units of language mixing across languages, we will gain insight into how languages adapt to each other word-internally, and what some possible outcomes of language contact are in the minds of speakers.


Osteoporosis in end-state renal disease.
Maintaining the intricate bone mineral homeostasis in patients with chronic renal failure and renal osteodystrophy is a complex and challenging process. In addition to the well described high-turnover bone disease caused by secondary hyperparathyroidism and low-turnover disease in the form of osteomalacia (either from aluminum or a dynamic bone disease) osteopenia also is present in end-stage renal disease patients. In contrast to abnormalities in the ability of bone to remodel, osteopenia is a deficiency in bone mass or volume. The prevalence of fractures in dialysis patients, regardless of histomorphometry appears to exceed that observed in elderly women. This osteopenia that occurs in chronic renal failure patients secondary to multiple factors that include hypogonadism, medications (such as corticosteroids), immobilization, and the typical osteopenia associated with aging. All of these factors amplify the risk of fracture in dialysis patients.


Prehospital haemostatic dressings for trauma: a systematic review.
Haemorrhage is a major cause of mortality and morbidity following both military and civilian trauma. Haemostatic dressings may offer effective haemorrhage control as part of prehospital treatment. To conduct a systematic review of the clinical literature to assess the prehospital use of haemostatic dressings in controlling traumatic haemorrhage, and determine whether any haemostatic dressings are clinically superior. MEDLINE and EMBASE databases were searched using predetermined criteria. The reference lists of all returned review articles were screened for eligible studies. Two authors independently undertook the search, performed data extraction, and risk of bias and Grading of Recommendations, Assessment, Development and Evaluation quality assessments. Meta-analysis could not be undertaken due to study and clinical heterogeneity. Our search yielded 470 studies, of which 17 met eligibility criteria, and included 809 patients (469 military and 340 civilian). There were 15 observational studies, 1 case report and 1 randomised controlled trial. Indications for prehospital haemostatic dressing use, wound location, mechanism of injury, and source of bleeding were variable. Seven different haemostatic dressings were reported with QuikClot Combat Gauze being the most frequently applied (420 applications). Cessation of bleeding ranged from 67% to 100%, with a median of 90.5%. Adverse events were only reported with QuikClot granules, resulting in burns. No adverse events were reported with QuikClot Combat Gauze use in three studies. Seven of the 17 studies did not report safety data. All studies were at risk of bias and assessed of 'very low' to 'moderate' quality. Haemostatic dressings offer effective prehospital treatment for traumatic haemorrhage. QuikClot Combat Gauze may be justified as the optimal agent due to the volume of clinical data and its safety profile, but there is a lack of high-quality clinical evidence, and randomised controlled trials are warranted. Systematic review, level IV.


[The morphofunctional changes in the periodontal tissues in cardiovascular pathology].
Five rheoparodontographic curve types were distinguished, characterizing the severity of periodontal condition and the underlying disease. Morphologic examinations have revealed specific features of involvement of the periodontal regional hemomicrocirculation bed, leading to disorders in energy metabolism and development of circulatory and tissue hypoxia. The detected changes result in rapid progress of the pathologic process in periodontal tissues and should be paid special attention to when planning the treatment strategy.


rs1501299 Polymorphism in the Adiponectin Gene and Their Association with Total Adiponectin Levels, Insulin Resistance and Metabolic Syndrome in Obese Subjects.
The aim of this study was to determine the association of single nucleotide polymorphism rs1501299 in the ADIPOQ gene with body weight, insulin resistance, serum adipokine levels and metabolic syndrome (MetS). The study involved a population of 1,007 adult obese subjects. Parameters like body weight, fat mass, waist circumferences, blood pressure, fasting blood glucose, C-reactive protein, insulin concentration, homeostasis model assessment for insulin resistance (HOMA-IR), lipid profile and adipocytokines levels (leptin, adiponectin and resistin) were all measured. The genotype of ADIPOQ gene polymorphism (rs1501299) was evaluated. Insulin levels (GG: 13.6 ± 5.1 mUI/l vs. GT: 14.1 ± 5.2 mUI/l vs. TT: 16.6 ± 5.2 mUI/l; p < 0.05) and HOMA-IR (GG: 3.3 ± 1.5 units vs. GT: 4.1 ± 1.1 units vs. TT: 4.5 ± 1.3 units; p < 0.05) were higher in T-allele carriers than they were in non-T-allele carriers. Total adiponectin levels (GG: 20.2 ± 2.4 ng/dl vs. GT: 15.8 ± 3.4 ng/dl vs. TT: 13.7 ± 1.4 ng/dl; p < 0.05) were lower in T-allele carriers than they were in non-T-allele carriers. Logistic regression analysis indicated that subjects with T allele were associated with an increased risk of MetS (OR 1.15, 95% CI 1.08-1.25, p = 0.033) and an increased risk of hyperglycemia (OR 1.99, 95% CI 1.37-2.55, p = 0.028) after adjusting by age and gender. These data suggest an important role of this ADIPOQ variant at position +276 on insulin resistance, total adiponectin levels and MetS.


Age moderates the short-term effects of transdermal 17beta-estradiol on endothelium-dependent vascular function in postmenopausal women.
We evaluated age and coronary heart disease (CHD) as potential moderators of the effects of 17beta-estradiol on vascular endothelial function in postmenopausal women. In a double-blind crossover design, 100 postmenopausal women aged 50 to 80 years were randomized to each of 3 transdermal patches, releasing 17beta-estradiol (0.05 mg/d), 17beta-estradiol (0.05 mg/d) + norethindrone acetate (NETA, 0.14 mg/d), and placebo. Flow-mediated dilation (FMD) and response to 400 microg sublingual glyceryl trinitrate (GTN-D) were assessed approximately 18 hours after patch placement. Age, but not CHD, moderated the FMD response to treatment (P=0.01). For women in their fifties, the estradiol patch was associated with improved FMD (7.69+/-4.79%) compared with placebo (4.81+/-5.97%, P<0.05), but the estradiol+norethindrone patch response (5.81+/-4.85%) was not significantly different from placebo. Women in their sixties and seventies showed no alterations in FMD response to either active patch. GTN-D response declined with advancing age (P<0.01), with women in their seventies exhibiting blunted GTN-D response compared with younger women. The cardiovascular benefits of natural estrogen supplementation on vascular endothelial function may be dependent on postmenopausal age, with improved vascular function evident only in the early postmenopausal years. Short-term FMD response to estradiol might help stratify individual differences in risks versus benefits of HRT.


An Approach Based on Preference Learning for Identifying Experts Reasoning in Antibiotic Treatment.
Clinical Practice Guidelines (CPGs) aim at improving the quality of health care by providing standardized best practices for diagnosis and treatment. However, physicians have difficulties to understand the (often implicit) rationale underlying expert recommendations. The aim of this paper is to propose an approach based on preference learning for building a model that is closest to the reasoning of experts to provide recommendations. We apply this method to antibiotherapy in primary care. The preference model was learned from the recommendations and from a database describing the domain.


Ravitch versus Nuss procedure for pectus excavatum: systematic review and meta-analysis.
Pectus excavatum is the most common congenital chest wall deformity. The two most common surgical techniques for its correction are the modified Ravitch technique and the minimally invasive Nuss technique. Despite both procedures being used widely, data comparing them are scarce. We conducted a systematic review and meta-analysis of comparative studies to evaluate these procedures. A systematic search of the literature was performed from six electronic databases. Pooled meta-analysis was conducted using odds ratio (OR) and weighted mean difference (WMD). A total of 13 studies comprising 1,432 pediatric (79.3%) and adult (20.7%) patients were identified, including 912 patients undergoing the Nuss procedure compared to 520 patients undergoing the Ravitch procedure. There was no significant difference found between the Nuss group versus Ravitch group in pediatric patients with regard to overall complications (OR =1.16; 95% CI: 0.61-2.19; I2=56%; P=0.65), reoperations (6.1% vs. 6.4%; OR =1.00; 95% CI: 0.40-2.50; I2=0%; P=1.00), wound infections (OR =0.58; 95% CI: 0.23-1.46; I2=0%; P=0.25), hemothorax (1.6% vs. 1.3%; OR =0.74; 95% CI: 0.21-2.65; I2=12%; P=0.64), pneumothorax (3.4% vs. 1.5%; OR =1.11; 95% CI: 0.42-2.93; I2=0%; P=0.83) or pneumonia (OR =0.15; 95% CI: 0.02-1.48; I2=0%; P=0.10). Adult patients undergoing the Nuss procedure had a higher incidence of overall complications (OR =3.26; 95% CI: 1.01-10.46; I2=0%; P=0.05), though there were far fewer studies that reported data. These results suggest no difference between the Nuss and Ravitch procedures for pediatric patients, while in adults the Ravitch procedure resulted in fewer complications.


[Chemical diagnosis of carbamazepine intoxication and its usefulness in toxicological jurisprudence].
Intoxication with carbamazepine (Amizepine, Tegretol) represents a significant problem of clinical and forensic toxicology which frequently develops independently of the commonly used monitored therapy. In the study a technique of qualitative and quantitative analysis applied to carbamazepine (CBZ) as well as its metabolites carbamazepine 10, 11-epoxide (CBZ-E) and 10, 11-dihydroxycarbamazepine (CBZ-DH) in biological material using high-performance liquid chromatography (HPLC) was presented. The studies also involve isolation of studied compounds using solid phase extraction, SPE-Abselut NEXUS (Varian), establishment of calibration range and validation of analytical parameters. This was followed by a discussion of results obtained in routine diagnostic investigations in cases of intoxications, corroborating practical suitability of the designed technique.


The relation between Assessment for Learning and elementary students' cognitive and metacognitive strategy use.
Assessment for Learning (AfL) is believed to create a rich learning environment in which students develop their cognitive and metacognitive strategies. Monitoring student growth and providing scaffolds that shed light on the next step in the learning process are hypothesized to be essential elements of AfL that enhance cognitive and metacognitive strategies. However, empirical evidence for the relation between AfL and students' strategy use is scarce. This study investigates the relation between AfL and elementary school students' use of cognitive and metacognitive strategies. The sample comprised 528 grade four to six students (9- to 12-year-olds) from seven Dutch elementary schools. Students' perceptions of AfL and their cognitive and metacognitive strategy use were measured by means of questionnaires. Structural equation modelling was used to investigate the relations among the variables. The results reveal that monitoring activities that provide students an understanding of where they are in their learning process predict Students' task orientation and planning. Scaffolding activities that support students in taking the next step in their learning are positively related to the use of both surface and deep-level learning strategies and the extent to which they evaluate their learning process after performing tasks. The results underline the importance of assessment practices in ceding responsibility to students in taking control of their own learning.


Daclizumab induction, tacrolimus, mycophenolate mofetil and steroids as an immunosuppression regimen for primary kidney transplant recipients.
Recent reports have demonstrated the efficacy of interleukin-2-receptor blockers in lowering the incidence of early acute rejection in cyclosporine-treated kidney recipients when compared to patients not induced with an antibody product. The addition of daclizumab to a tacrolimus-mycophenolate mofetil-based immunosuppressive protocol was tested to evaluate whether there might be an additional reduction of the risk of rejection after renal transplantation. Since March 1998, we studied the effect of daclizumab in a nonrandomized, prospective study of 233 sequential recipients of first renal transplant. They were retrospective compared with a control group of 225 renal transplant recipients receiving a 10-day course of OKT3 induction, and tacrolimus, mycophenolate mofetil, and methylprednisolone maintenance. The study group received the same immunosuppressive regimen with the addition of daclizumab at 1 mg/kg for five doses over 10 weeks in the place of OKT3 therapy. There was at least 1HLA DR antigen compatibility match present between all donors and recipients. Patients were followed for 1 year after renal transplantation for the incidence of biopsy-proven acute rejection, patient and graft survival, and adverse events. At 12 months, patient and graft survival for the daclizumab was 98 and 96 vs. 96 and 94% for the OKT3 group, respectively, and were not statistically different. Acute rejection rates (<6 months) were lower in the daclizumab group as compared with the OKT3 group, i.e., 5 (2.1%) vs. 16 (7.1%) (P=0.011) respectively. The incidence of infection requiring hospitalization appeared to be lower with daclizumab (7.3 vs. 16%, P<0.0036) with a similar trend with cyclomegalovirus infection, i.e., 1.6 vs. 4%, respectively (P=0.14). The combination of daclizumab, tacrolimus, mycophenolate mofetil, and steroids is safe and effective for kidney transplant recipients in lowering the incidence of early acute rejection and without any increase in morbidity when compared to our previous protocol, which may have an eventual impact in long-term graft survival.


Female veterans seeking medical care at Veterans Affairs primary care clinics: psychiatric and medical illness burden and service use.
To examine rates of medical and psychiatric disorders among 187 female veterans recruited at four Veterans Affairs Medical Centers (VAMCs), the recognition of such disorders by VAMC care providers, and the use of relevant medical and mental health services by women both within and outside of the VA setting. We used a cross-sectional, epidemiological design incorporating self-report measures, structured interviews, and chart reviews to obtain relevant information for analyses. Forty-four percent (43.9%) of women met criteria for at least one psychiatric disorder; 34.0% of these women met criteria for two or more additional psychiatric diagnoses, and concordance rates between interview and chart diagnoses were low. Ninety-five percent (95.2%) of women had a medical condition noted in their charts; 86.6% had two or more additional medical conditions, and a significant number of women had both medical and psychiatric diagnoses. Forty-four percent (43.9%) of women with an identified mental health condition received specialized mental health care by the VA in the past year. Findings from this study suggest that female veterans treated in VAMCs had significant medical and psychiatric problems, and these women might not be getting their health care needs adequately met through the VA health care system. In light of our findings, we discuss relevant implications and future directions for research.


Involvement of the K+-Cl- co-transporter KCC2 in the sensitization to morphine-induced hyperlocomotion under chronic treatment with zolpidem in the mesolimbic system.
Benzodiazepines are commonly used as sedatives, sleeping aids, and anti-anxiety drugs. However, chronic treatment with benzodiazepines is known to induce dependence, which is considered related to neuroplastic changes in the mesolimbic system. This study investigated the involvement of K(+) -Cl(-) co-transporter 2 (KCC2) in the sensitization to morphine-induced hyperlocomotion after chronic treatment with zolpidem [a selective agonist of γ-aminobutyric acid A-type receptor (GABAA R) α1 subunit]. In this study, chronic treatment with zolpidem enhanced morphine-induced hyperlocomotion, which is accompanied by the up-regulation of KCC2 in the limbic forebrain. We also found that chronic treatment with zolpidem induced the down-regulation of protein phosphatase-1 (PP-1) as well as the up-regulation of phosphorylated protein kinase C γ (pPKCγ). Furthermore, PP-1 directly associated with KCC2 and pPKCγ, whereas pPKCγ did not associate with KCC2. On the other hand, pre-treatment with furosemide (a KCC2 inhibitor) suppressed the enhancing effects of zolpidem on morphine-induced hyperlocomotion. These results suggest that the mesolimbic dopaminergic system could be amenable to neuroplastic change through a pPKCγ-PP-1-KCC2 pathway by chronic treatment with zolpidem.


Automated structure prediction of trans-acyltransferase polyketide synthase products.
Bacterial trans-acyltransferase polyketide synthases (trans-AT PKSs) are among the most complex known enzymes from secondary metabolism and are responsible for the biosynthesis of highly diverse bioactive polyketides. However, most of these metabolites remain uncharacterized, since trans-AT PKSs frequently occur in poorly studied microbes and feature a remarkable array of non-canonical biosynthetic components with poorly understood functions. As a consequence, genome-guided natural product identification has been challenging. To enable de novo structural predictions for trans-AT PKS-derived polyketides, we developed the trans-AT PKS polyketide predictor (TransATor). TransATor is a versatile bio- and chemoinformatics web application that suggests informative chemical structures for even highly aberrant trans-AT PKS biosynthetic gene clusters, thus permitting hypothesis-based, targeted biotechnological discovery and biosynthetic studies. We demonstrate the applicative scope in several examples, including the characterization of new variants of bioactive natural products as well as structurally new polyketides from unusual bacterial sources.


Effect of limited trypsin digestion on the renal Na+-H+ exchanger and its regulation by cAMP-dependent protein kinase.
The Na+-H+ exchanger from solubilized rabbit renal brush border membranes is inhibited by cAMP-dependent protein kinase (PKA) mediated protein phosphorylation. To characterize this inhibitory response and its sensitivity to limited proteolysis, the activity of the transporter was assayed after reconstitution of the proteins into artificial lipid vesicles. Limited trypsin digestion increased the basal rate of proton gradient-stimulated, amiloride-inhibitable sodium uptake in reconstituted proteoliposomes and blocked the inhibitory response to PKA-mediated protein phosphorylation. To determine if the inhibitory response to PKA-mediated protein phosphorylation could be restored to the trypsin-treated solubilized proteins, nontrypsinized solubilized brush border membrane proteins were separated by column chromatography. The addition of small molecular weight polypeptides, fractionated on Superose-12 FPLC (Ve = 0.7), to trypsinized solubilized brush border membrane proteins restored the inhibitory response to PKA-mediated protein phosphorylation. Similarly, the addition of the 0.1 M NaCl fraction from an anion exchange column, Mono Q-FPLC, also restored the inhibitory response to PKA. Both protein fractions contained a common 42-43 kDa protein which was preferentially phosphorylated by PKA. These results indicate that limited trypsin digestion dissociates the activity of the renal Na+-H+ exchanger from its regulation by PKA. It is suggested that trypsin cleaves an inhibitory component of the transporter and that this component is the site of PKA-mediated regulation. Phosphoprotein analysis of fractions that restored PKA regulation raises the possibility that a polypeptide of 42-43 kDa is involved in the inhibition of the renal Na+-H+ exchanger by PKA-mediated protein phosphorylation.


Exclusion of T Cells From Pancreatic Carcinomas in Mice Is Regulated by Ly6C(low) F4/80(+) Extratumoral Macrophages.
Immunotherapies that induce T-cell responses have shown efficacy against some solid malignancies in patients and mice, but these have little effect on pancreatic ductal adenocarcinoma (PDAC). We investigated whether the ability of PDAC to evade T-cell responses induced by immunotherapies results from the low level of immunogenicity of tumor cells, the tumor's immunosuppressive mechanisms, or both. Kras(G12D/+);Trp53(R172H/+);Pdx-1-Cre (KPC) mice, which develop spontaneous PDAC, or their littermates (controls) were given subcutaneous injections of a syngeneic KPC-derived PDAC cell line. Mice were then given gemcitabine and an agonist of CD40 to induce tumor-specific immunity mediated by T cells. Some mice were also given clodronate-encapsulated liposomes to deplete macrophages. Tumor growth was monitored. Tumor and spleen tissues were collected and analyzed by histology, flow cytometry, and immunohistochemistry. Gemcitabine in combination with a CD40 agonist induced T-cell-dependent regression of subcutaneous PDAC in KPC and control mice. In KPC mice given gemcitabine and a CD40 agonist, CD4(+) and CD8(+) T cells infiltrated subcutaneous tumors, but only CD4(+) T cells infiltrated spontaneous pancreatic tumors (not CD8(+) T cells). In mice depleted of Ly6C(low) F4/80(+) extratumoral macrophages, the combination of gemcitabine and a CD40 agonist stimulated infiltration of spontaneous tumors by CD8(+) T cells and induced tumor regression, mediated by CD8(+) T cells. Ly6C(low) F4/80(+) macrophages that reside outside of the tumor microenvironment regulate infiltration of T cells into PDAC and establish a site of immune privilege. Strategies to reverse the immune privilege of PDAC, which is regulated by extratumoral macrophages, might increase the efficacy of T-cell immunotherapy for patients with PDAC.


Novelties in COPD prognosis: evolution of survival indexes.
Despite several techniques, such as non-invasive ventilation (NIV), have improved the outcome of the acute exacerbation, COPD remains affected by poor prognosis in the medium and long term. Moreover, the task of predicting prognosis remains a major challenge for respiratory physicians. In order to overcome this limitation, several indexes have been proposed to assess the COPD patient in his/her complexity. The rationale is that, by using numerical indexes physicians may improve their clinical judgment to tailor and share therapeutical choices, i.e. referring the patient for surgery or lung transplantation. On this ground, Almagro et al. recently proposed the CODEX index, as the latest evolution of the BODE through the BODEx (which takes into account exacerbations), by adding the evaluation of comorbidity to the severity of dyspnoea, airway obstruction and history of exacerbations. As afore mentioned, treatment of COPD with respiratory acidosis has been revolutionized by the use of NIV, by reducing the need for intubation and in-hospital mortality of patients with severe COPD exacerbations. Nowadays, new promising techniques, such as minimally invasive extracorporeal devices, may hasten the clearance of carbon dioxide and reduce the work of breathing and the need for ventilation of COPD patients. These techniques still lack of randomized controlled studies; however, the approach of extracorporeal CO2 removal has the potential to further improve the prognosis of severe exacerbation of COPD patients. In this paper we discuss the prognostic evaluation of patients affected by COPD through the evolution of dedicated indexes, which mirror the focus of current research on the disease.


Relationships Across Clinical Measures of Vocal Quality and Functioning and Their Relationship With Patient Perception.
Purpose The purpose of this study was to investigate the relationships among subjective auditory-perceptual ratings of vocal quality, objective acoustic and aerodynamic measures of vocal function, and patient-perceived severity of their vocal complaint. Method This study was a retrospective chart review of adult patients evaluated at a single outpatient center over a 1.5-year time period. Twenty-two clinical objective and subjective measures of voice were extracted from 676 charts (310 males, 366 females). To identify the underlying concepts addressed in an initial voice assessment, principal component analyses were conducted for males and females to account for sex differences. Linear regression models were conducted to examine the relationship between the principal components and patient perceived severity. Results Seven principal components were identified for both sexes and accounted for 75% and 71% of the variance in the clinical measures, respectively. Of these seven principal components, only two predicted male patient perceived severity, which accounted for 22% of the variance. In contrast, four principal components predicted female patient perceived severity of their voice disorder and accounted for 19% of the variance. Conclusions The results highlight the underlying aspects of vocal quality and functioning that are evaluated during an initial assessment. Male and female patients differ in which of these components may contribute self-perceived severity of a voice disorder. Identifying these underlying components may support clinical decision making when developing a clinical protocol and highlights the overlap between patient concerns and clinical measures. Supplemental Material https://doi.org/10.23641/asha.16879603.


Physical activity and screen time behaviour in metropolitan, regional and rural adolescents: a -sectional study of Australians aged 9-16 years.
While there is consistent evidence that rural adults in Australia are less active than their urban counterparts, studies relating geographical remoteness to activity patterns in Australian adolescents have yielded inconsistent results. The aim of this study was to describe objectively and subjectively measured patterns of physical activity and sedentary behaviours across remoteness categories in a representative sample of 9-16 year old Australians. Cross-sectional observational study. 2071 Australian adolescents provided self-report use of time data on four days and wore a pedometer for at least 6 days within the 2007 Australian National Children's Nutrition and Physical Activity Survey. Comparisons of activity patterns were made across four objectively-determined remoteness categories (Major City, Inner Regional, Outer Regional and Remote), adjusting for household income, parental education and age. Adolescents living in major cities self-reported 11-29 min less moderate to vigorous physical activity each day than their counterparts living in geographically more remote areas, and took 150-850 fewer steps each day. While there were no differences in time spent in sport or active transport, differences in free play participation were significant. Males in major cities also reported higher levels of screen time. Differences were somewhat more marked among males than among females. Activity levels among Australian adolescents show contrasting patterns of geographical differences to those found in Australian adults. Higher levels of free play among rural Australian adolescents may be due to more available space and less fear of traffic and stranger risks.


Meeting the social and behavioral health needs of students: rethinking the relationship between teachers and school social workers.
While school-based mental health professionals obviously must provide mental health services to students directly, the literature is increasingly identifying an empowerment role for these professionals, whereby they support teachers as primary service providers. The purpose of this study was to identify subtypes of school social workers within the context of collaborative practice, and to identify individual and contextual factors associated with these classifications as well as overall levels of collaboration. Latent class analysis, conducted using data collected as part of the National School Social Work Survey 2008 (N = 1639), was employed to examine underlying subtypes of school social work practitioners in relation to collaborative practices and to examine predictors of collaborative practice. Four broad categories of school social workers were identified, including (1) noncollaborators, (2) system-level specialists, (3) consultants, and (4) well-balanced collaborators. These classes were associated with the number of schools served, grade level, education, and clinical licensure status; level of administrative responsibility was not associated with class membership. While school social workers varied in collaborative practices, opportunities exist to enhance their role in educating and supporting teachers to serve as primary providers to students with social, mental health, and behavioral needs. The implications for school-based mental health providers, teachers, administrators, policymakers, and researchers are discussed.


DNA methylation of the fragile X locus in somatic and germ cells during fetal development: relevance to the fragile X syndrome and X inactivation.
To obtain insights into mechanisms responsible for methylation of CpG islands on the inactive X chromosome of normal females, we examined methylation of the fragile X (FraX) locus in a variety of tissues from normal fetuses and adults, and from males with the FraX syndrome. We identified 20 CCGG sites (MspI-HpaII sites M1-M20) within a 12-kb BglII fragment that includes the CpG island. Sites M3-M18, within the 1.2-kb CpG island are unmethylated on the active X in normal males and females at all ages and in all tissues studied. In contrast, these sites are at least partially methylated on the inactive X chromosome in a variety of tissues from normal females by six weeks from conception. The exceptional tissues are chorionic villi and gonads, which are significantly undermethylated. In addition, fetal germ cells are unmethylated at site M3, which is methylated on the inactive X in other tissues; thus, the methylation imprint of the inactive X has been erased. Methylation of the locus on the fragile X chromosome is similar to that of the normal inactive X but is more extensive and less heterogeneous. This suggests that the expansion of the island and the greater number of CpGs that result from amplification of the CGG repeat enhance the methylatibility of the island. Additional studies show that the chromatin of the CpG island is nuclease hypersensitive on the active X but insensitive on both inactive and FraX.


Association Analysis of Candidate Gene Polymorphisms and Audiometric Measures of Noise-Induced Hearing Loss in Young Musicians.
This study aimed to investigate the association between candidate genetic variants and audiometric measures of noise-induced hearing loss (NIHL) in young musicians. The study analyzed a database by Phillips et al. (Feasibility of a bilateral 4000-6000 Hz notch as a phenotype for genetic association analysis. Int J Audiol 2015;54:645-52.) which included behavioral hearing thresholds, distortion-product otoacoustic emissions (DPOAE), tympanometric, and genetic data of 166 participants meeting the inclusion criteria. Nineteen single nucleotide polymorphisms (SNPs) in 13 cochlear genes previously associated with NIHL in factory workers were included in the present investigation. The average hearing threshold at 3000 and 4000 Hz (AHT) and average DPOAE signal to noise ratio (DPOAE SNR) in both ears were calculated. The regression analyses showed that two SNPs- one in KCNE1 (rs2070358) and the other in CAT (rs12273124) revealed a statistically significant relationship with DPOAE SNR in both ears. Two SNPs in MYH14 and one in GJB4 revealed a significant association with DPOAE SNR in the left ear. Two SNPs in HSP70, one in CDH23 and one in KCNJ10 showed significant association with DPOAE SNR in the right ear. None of the included SNPs showed association with AHT in both ears. A genetic variant in KCNE1 was associated with the strength of the cochlear amplifier as assessed by DPOAE SNR. Musicians carrying causal genetic variants to NIHL might exhibit changes in their auditory functions early in the lifespan even when most subjects had their hearing thresholds within normal limits. These participants are likely to show the clinical manifestation of NIHL in the future if no preventive measures are applied.


High Stability of Methanol to Aromatic Conversion over Bimetallic Ca,Ga-Modified ZSM-5.
The production of valuable aromatics and the rapid catalyst deactivation due to coking are intimately related in the zeolite-catalyzed aromatization reactions. Here, we demonstrate that these two processes can be decoupled by promoting the Ga/HZSM-5 aromatization catalyst with Ca. The resulting bimetallic catalysts combine high selectivity to light aromatics with extended catalyst lifetime in the methanol-to-aromatics process. Evaluation of the catalytic performance combined with detailed catalyst characterization suggests that the added Ca interacts with the Ga-LAS, with a strong effect on the aromatization processes. A genetic algorithm approach complemented by ab initio thermodynamic analysis is used to elucidate the possible structures of bimetallic extraframework species formed under reaction conditions. The promotion effect of minute amounts of Ca is attributed to the stabilization of the intra-zeolite extraframework gallium oxide clusters with moderated dehydrogenation activity.


Prediction of nitrogen excretion in feces and urine of beef cattle offered diets containing grass silage.
Data from 286 beef cattle, obtained in total diet digestibility assessments, were used to examine effects of dietary and animal factors on N excretion in feces and urine and to develop prediction equations for N excretion in beef cattle. The animals used were mainly from beef breeds, at various ages (from growth to finishing) and live BW (153 to 580 kg), and offered diets containing grass silage at production feeding levels. Dietary forage proportion ranged from 199 to 1,000 g/kg of DM and dietary CP concentration from 108 to 217 g/kg of DM. Linear and multiple regression techniques were used to examine relationships between the efficiency of N utilization and dietary and animal variables with the experimental effects removed. The statistical analysis indicated that N excretion was related positively (P < 0.001) to live BW and intakes of DM, N, and ME, and negatively (P < 0.001) to dietary forage proportion. The prediction equation for N excretion, developed using N intake alone, produced a large r2 (0.898) and a small SE (12.3). Addition of live BW and forage proportion as supporting predictors to this relationship only marginally increased R2 to 0.915 and reduced SE to 11.2. Nitrogen excretion was less well related to live BW (r2 = 0.771, SE = 18.5) than to N intake. Addition of N intake as a proportion of DMI or ME intake to the relationship between live BW and N excretion increased R2 to 0.824 and reduced SE to 16.2. The internal validation of these equations revealed that using N intake as the primary predictor produced a very accurate prediction of N excretion. In situations where data on N intake are not available, prediction equations based on live BW and dietary N concentration together can produce a relatively accurate assessment of N excretion. A number of mitigation strategies to reduce N excretion in feces and urine in beef cattle are discussed, including manipulation of dietary N concentration, diet quality, and level of feeding. The prediction equations and mitigation strategies developed in the current study provide an approach for beef producers to quantify N excretion against production and to develop their own mitigation strategies to reduce N excretion.


Cost-effectiveness analysis and innovation.
While cost-effectiveness (CE) analysis has provided a guide to allocating often scarce resources spent on medical technologies, less emphasis has been placed on the effect of such criteria on the behavior of innovators who make health care technologies available in the first place. A better understanding of the link between innovation and cost-effectiveness analysis is particularly important given the large role of technological change in the growth in health care spending and the growing interest of explicit use of CE thresholds in leading technology adoption in several Westernized countries. We analyze CE analysis in a standard market context, and stress that a technology's cost-effectiveness is closely related to the consumer surplus it generates. Improved CE therefore often clashes with interventions to stimulate producer surplus, such as patents. We derive the inconsistency between technology adoption based on CE analysis and economic efficiency. Indeed, static efficiency, dynamic efficiency, and improved patient health may all be induced by the cost-effectiveness of the technology being at its worst level. As producer appropriation of the social surplus of an innovation is central to the dynamic efficiency that should guide CE adoption criteria, we exemplify how appropriation can be inferred from existing CE estimates. For an illustrative sample of technologies considered, we find that the median technology has an appropriation of about 15%. To the extent that such incentives are deemed either too low or too high compared to dynamically efficient levels, CE thresholds may be appropriately raised or lowered to improve dynamic efficiency.


[The architectonics of microbe ecology in the purulent surgery department of municipal clinical hospital].
S. aureus, S. pyogenes, P. aerugenosa, E. coli, P mirabilis, A. baumannii, S. epidermidis, K. pneumoniae, E. faecalis, E. cloacae are the priority pathogens of various forms of pyoinflammatory diseases. They form the architectonics of microbe ecology of the purulent surgery department of multi-type hospital of regional level with S.aureus subsp.aureus playing dominating role. In case of unchanged specter of priority pathogens of pyoinflammatory and pyoseptic diseases the number of gram-positive coccuses decreases at the expense of decrease of number of streptococcuses and staphylococcuses. At the same time, the number of enterobacteria and gram-negative non-fermentative bacteria increases. The resistance ofgram-positive coccuses increases regarding erythromycin, clyndamicin and cyprofloxacin. The resistance of gram-negative bacilli increases regarding ciprofloxacin, cephalosporins of III-IV generations, amikacin. The resistance is the highest among clinical isolates MRSA, K. pneumoniae, A. baumannii. The vancomycin is active regarding all gram-positive pathogens. The carbapenems are active regarding all enterobacteriae. The carbapenems, cefoperazone/tazobactam, cefepime are most active regarding non-fermentative glucose oxidizing bacteria. The netimicin is active regarding A.baumannii. The polymyxine is active regarding P. aerugenosa. The circulation of S. aureus hospital strain of particular genotype is established confirming the propagation of epidemic S. aureus strains in Moscow multi-type medical institutions. The strains are genetically affined to epidemic strains in European and other countries according the international data base (http://SpaServer.ridom.de). The genetic typing of S. aureus ssp. aureus out-hospital hemocultures detected their considerable genetic variety. The epidemic relationship between isolates from different patients is not established. The algorithms of rationale antibacterial chemotherapy of pyoinflammatory and pyoseptic diseases are developed to be implemented in the purulent surgery department of municipal clinical hospital of Moscow.


Tetracycline-regulated cardiac gene expression in vivo.
Tight regulation of foreign genes expressed in vivo would facilitate studies of many biologic processes and would be useful for gene transfer-based therapies. To test the ability of a tetracycline-regulated gene expression system to function in vivo, we directly injected chimeric tet repressor-VP16 transactivator expression plasmids and luciferase target genes into the hearts of adult rats. Cardiac luciferase activity increased over two orders of magnitude in response to small changes in input tetracycline-controlled transactivator DNA. Transactivation was repressed to background levels by subtherapeutic concentrations of tetracycline in a dose-dependent manner. Target gene expression could be rapidly and reversibly controlled by manipulating antibiotic administration. This system may be particularly useful for in vivo studies of gene function or gene therapies where the timing or extent of expression are critical variables.


A Cooperative Downloading Method for VANET Using Distributed Fountain Code.
Cooperative downloading is one of the effective methods to improve the amount of downloaded data in vehicular ad hoc networking (VANET). However, the poor channel quality and short encounter time bring about a high packet loss rate, which decreases transmission efficiency and fails to satisfy the requirement of high quality of service (QoS) for some applications. Digital fountain code (DFC) can be utilized in the field of wireless communication to increase transmission efficiency. For cooperative forwarding, however, processing delay from frequent coding and decoding as well as single feedback mechanism using DFC cannot adapt to the environment of VANET. In this paper, a cooperative downloading method for VANET using concatenated DFC is proposed to solve the problems above. The source vehicle and cooperative vehicles encodes the raw data using hierarchical fountain code before they send to the client directly or indirectly. Although some packets may be lost, the client can recover the raw data, so long as it receives enough encoded packets. The method avoids data retransmission due to packet loss. Furthermore, the concatenated feedback mechanism in the method reduces the transmission delay effectively. Simulation results indicate the benefits of the proposed scheme in terms of increasing amount of downloaded data and data receiving rate.


Effectiveness of interventions aimed at reducing screen time in children: a systematic review and meta-analysis of randomized controlled trials.
To evaluate the impact of interventions focused on reducing screen time. Medline, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, ERIC, and CINAHL through April 21, 2011. Included studies were randomized controlled trials of children aged 18 years or younger with interventions that focused on reducing screen time. Efforts to reduce screen time. The primary outcome was body mass index (BMI); the secondary outcome was screen time (hours per week). A total of 1120 citations were screened, and 13 studies were included in the systematic review. Study samples ranged in age (3.9-11.7 years) and size (21-1295 participants). Interventions ranged in length (1-24 months) and recruitment location (5 in schools, 2 in medical clinics, 1 in a community center, and 5 from the community). For the primary outcome, the meta-analysis included 6 studies, and the difference in mean change in BMI in the intervention group compared with the control group was -0.10 (95% confidence interval [CI], -0.28 to 0.09) (P = .32). The secondary outcome included 9 studies, and the difference in mean change from baseline in the intervention group compared with the control group was -0.90 h/wk (95% CI, -3.47 to 1.66 h/wk) (P = .49). A subgroup analysis of preschool children showed a difference in mean change in screen time of -3.72 h/wk (95% CI, -7.23 to -0.20 h/wk) (P = .04). Our systematic review and meta-analysis did not demonstrate evidence of effectiveness of interventions aimed at reducing screen time in children for reducing BMI and screen time. However, interventions in the preschool age group hold promise.


Intramedullary fixation of tibial shaft fractures using an expandable nail: early results of 54 acute tibial shaft fractures.
To evaluate and present our experience using the expandable nail system for the treatment of acute tibial shaft fractures. Retrospective study. Two level-1 trauma centers-University teaching hospitals. Fifty-four consecutive patients were treated by this nail system for acute tibial shaft fracture. Two nail diameters were used, 8.5 mm and 10 mm. Operation, hospitalization and healing times, reaming versus nonreaming, isolated versus multiple injuries, and reoperations were recorded and analyzed statistically. Follow-up was obtained either until fracture healing or for a minimum of 1 year with an average of 14 months (12 to 24). All fractures healed in an average time of 72 days (21 to 204). The average healing times for patients treated with 8.5-mm and 10-mm nails were 77.2 days (27 to 204) and 63.4 days (21 to 121), respectively. Average operative time was 103 minutes (40 to 185) if reamed and 56 minutes (30 to 80) if unreamed. Average healing times were 65.4 days (21 to 190) if reamed and 79.5 days (42 to 204) if unreamed. There were 11 complications (20.4%) related to the nailing: 3 deep infections, 2 superficial infections, 2 bone shortenings of 1 cm secondary to nail protrusion in the knee, 1 compartment syndrome, 1 fracture propagation, 1 distal malalignment, and 1 delayed union. Hardware was removed in 6 patients (3 infections, 2 patients' request and 1 protrusion into the knee), and 1 additional patient underwent exchange nailing due to a delayed union. The expandable nail offers the theoretical advantages of improved load sharing and rotational control without the need for interlocking screws. This study demonstrates satisfactory healing and alignment for the treatment of tibial shaft fractures using this device. However, caution must be exercised when using this nail in cases of significant comminution and in cases where the fracture pattern involves the more proximal or distal aspect of the tibial shaft.


An international study of the exposure of children to traffic.
To examine the extent of international differences in children's exposure to traffic as pedestrians or bicyclists. Children's travel patterns were surveyed using a parent-child administered questionnaire. Children were sampled via primary schools, using a probability cluster sampling design. Six cities in five countries: Melbourne and Perth (Australia), Montreal (Canada), Auckland (New Zealand), Umeå (Sweden), and Baltimore (USA). Children aged 6 and 9 years. Modes of travel on the school-home journey, total daily time spent walking, and the average daily number of roads crossed. Responses were obtained from the parents of 13423 children. There are distinct patterns of children's travel in the six cities studied. Children's travel in the three Australasian cities, Melbourne, Perth and Auckland, is characterised by high car use, low levels of bicycling, and a steep decline in walking with increasing car ownership. In these cities, over a third of the children sampled spent less than five minutes walking per day. In Montreal, walking and public transport were the most common modes of travel. In Umeå, walking and bicycling predominated, with very low use of motorised transport. In comparison with children in the Australasian and North American cities, children in Umeå spend more time walking, with 87% of children walking for more than five minutes per day. There are large international differences in the extent to which children walk and cycle. These findings would suggest that differences in 'exposure to risk' may be an important contributor to international differences in pedestrian injury rates. There are also substantial differences in pedestrian exposure to risk by levels of car ownership-differences that may explain socioeconomic differentials in pedestrian injury rates.


Characterization of the estrogen receptor and its dynamics in MCF-7 human breast cancer cells using a covalently attaching antiestrogen.
We have used a covalently attaching antiestrogen, tamoxifen aziridine [TA; (Z)-(1-[4-(2-[N-aziridinyl] ethoxy)phenyl])1,2-diphenyl-1-butene], to analyze the structure and dynamics of the estrogen receptor in MCF-7 human breast cancer cells. The labeling of receptor with [3H]TA is specific, being blocked only by estrogens and antiestrogens, and the labeling is very efficient in that TA labels covalently the same number of receptors that are labeled reversibly by estradiol. In cells exposed to [3H]TA for 1 h, most of the covalently associated radioactivity is found in the 0.6 M KCl extract of the nuclear fraction; this receptor has an apparent mol wt of 63,000 +/- 2000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and a pI of 5.7 by gel isoelectric focusing in the presence of 8 M urea. The mol wt and pI of cytosol receptor labeled with [3H] TA are identical. In cells labeled with [3H]TA (20 nM) for 1 h and then exposed to a chase of 10(-6) M estradiol, [3H]TA-labeled nuclear receptor disappears with a half-life of 4 h. Analysis of nuclear receptor by sodium dodecyl sulfate-gels during the chase period reveals that this loss reflects a decrease in the 63,000 mol wt species; no significant quantities of lower mol wt TA-labeled fragments are observed in the nuclear, cytosol, or membrane fractions. Affinity labeled receptor interacts with several monoclonal antibodies to MCF-7 estrogen receptor, and it can be purified extensively by immunoadsorbent chromatography. TA has a low affinity (8% that of tamoxifen) for microsomal antiestrogen-binding sites that are distinct from the estrogen receptor, but TA reacts reversibly, rather than covalently, with these sites. The findings of similar mol wt and isoelectric points for soluble cytosol and nuclear extracted receptors under strongly denaturing and disaggregating conditions reveal that nuclear localization of receptor after ligand binding is not associated with major structural alterations in the receptor component labeled by TA. In addition, the receptor, even when occupied by a covalently attached ligand, is rapidly turned over in these cells.


A controlled comparison of relaxation and diazepam in panic disorder.
Subjects with panic disorder (N = 23) were randomized into a crossover design involving diazepam, placebo, relaxation therapy, or control. Anxiety was measured by a 3-day hourly diary, psychological tests, and assessment of heart rate and skin conductance level during baseline, stress test, and interview. The greatest and only significant physiologic changes occurred with diazepam. The largest pre/posttreatment changes on the psychological tests and self-reported anxiety and depression occurred with relaxation, although the differences were not statistically significant. Relaxation therapy may be useful for treating the general anxiety associated with panic disorder.


Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016.
To generate estimates of the global prevalence and incidence of urogenital infection with chlamydia, gonorrhoea, trichomoniasis and syphilis in women and men, aged 15-49 years, in 2016. For chlamydia, gonorrhoea and trichomoniasis, we systematically searched for studies conducted between 2009 and 2016 reporting prevalence. We also consulted regional experts. To generate estimates, we used Bayesian meta-analysis. For syphilis, we aggregated the national estimates generated by using Spectrum-STI. For chlamydia, gonorrhoea and/or trichomoniasis, 130 studies were eligible. For syphilis, the Spectrum-STI database contained 978 data points for the same period. The 2016 global prevalence estimates in women were: chlamydia 3.8% (95% uncertainty interval, UI: 3.3-4.5); gonorrhoea 0.9% (95% UI: 0.7-1.1); trichomoniasis 5.3% (95% UI:4.0-7.2); and syphilis 0.5% (95% UI: 0.4-0.6). In men prevalence estimates were: chlamydia 2.7% (95% UI: 1.9-3.7); gonorrhoea 0.7% (95% UI: 0.5-1.1); trichomoniasis 0.6% (95% UI: 0.4-0.9); and syphilis 0.5% (95% UI: 0.4-0.6). Total estimated incident cases were 376.4 million: 127.2 million (95% UI: 95.1-165.9 million) chlamydia cases; 86.9 million (95% UI: 58.6-123.4 million) gonorrhoea cases; 156.0 million (95% UI: 103.4-231.2 million) trichomoniasis cases; and 6.3 million (95% UI: 5.5-7.1 million) syphilis cases. Global estimates of prevalence and incidence of these four curable sexually transmitted infections remain high. The study highlights the need to expand data collection efforts at country level and provides an initial baseline for monitoring progress of the World Health Organization global health sector strategy on sexually transmitted infections 2016-2021.


Hypercoagulable states and stroke: a selective review.
Blood disorders have been implicated in approximately 5% to 10% of ischemic stroke, with an increased frequency in younger patients. Most disorders are associated with an increased thrombotic tendency and, therefore, an increased risk of ischemic stroke. Less commonly, a bleeding diathesis may predispose a patient to intracranial hemorrhage. While many conditions predisposing to thrombosis have been associated with stroke, there are relatively few prospective, epidemiological studies addressing hypercoagulable states and arterial stroke compared with the number of studies on the genetic thrombophilias, which are predominantly associated with venous thrombosis. When ordering tests of coagulation in stroke patients, one should keep in mind whether the results will influence therapy and/or patient outcome. It is generally not advocated to screen all stroke patients for a "hypercoagulable workup". Typically, patients to be screened for coagulation defects will have a prior history of one or more unexplained thromboembolic events. The yield for diagnosing a hypercoagulable state is typically greatest for young stroke patients or those with a family history of thrombosis and who have no other explanations for their stroke (cryptogenic stroke). The yield in typically low in unselected ischemic stroke patients and older patients. Treatment of a first stroke with a documented hypercoagulable state is typically long-term or indefinite duration warfarin, although there is a paucity of clinical trial data supporting this clinical approach.


Advertising and the dental profession. Retrospective and prospective.
"Advertising" has become a very controversial topic, not just among dentists, but among all professionals. That controversy focuses on three questions. First, what are the legal issues surrounding dental advertising and how are these issues being resolved? Second, what are the attitudes toward advertising among practicing dentists and how are these attitudes changing? Finally, how many dentists advertise and what are those advertising dentists actually doing? The purpose of this paper is to neither praise nor excoriate advertising, but to refer to the law and to published research in order to provide dental practitioners with a broader understanding of this topic.


Effects of food supplements on periodontal status and local and systemic inflammation after nonoperative periodontal treatment.
The present study aimed to assess the effects of a multimicronutrient food supplement on periodontal clinical parameters and systemic/local inflammatory markers. Thirty patients with severe chronic periodontitis who adhered to the Mediterranean diet (MD) underwent non-surgical therapy and daily took either the micronutrient complex (group-A) or olive oil (group-B) from baseline (T0) to 3 months (T2). Supragingival debridement was performed at T0. One month later (T1), one-stage-full-mouth disinfection was performed. Periodontal clinical parameters were monitored and correlated with serum C-reactive protein (CRP) and salivary matrix metalloproteinase-8/9 (MMPs-8/9) quantified at each time point. Longitudinal analysis revealed that in group-A, the MMP-8/-9 levels were decreased at T2 compared with at T0 (P = 0.013 and P = 0.004, respectively) and that the MMP-9 levels were decreased at T1 (P = 0.004). These reductions were not significant in group-B. The CRP levels in both groups did not change over time. No between-group differences were noted for any parameter. The correlation between the full-mouth bleeding score and the MMP-8 level in both groups was significant (P < 0.001). The investigated local and systemic inflammatory parameters were not affected by the tested multimicronutrient supplement in patients who adhered to MD. In conclusion, MMP-8 is useful for assessing the reduction in periodontal inflammation.


Protein-polymer hybrid nanoparticles for drug delivery.
Amphiphilic bovine serum albumin-poly(methyl methacrylate) conjugate forms nanoparticles with the uniform size of ~100 nm by self-assembling. Loaded with the hydrophobic anti-tumor drug camptothecin, the nanoparticle efficiently delivers drugs into cancer cells, and thus inhibits ~79% of tumor growth in animals compared with free drug.


Persistent Acute Kidney Injury is Associated with Poor Outcomes and Increased Hospital Cost in Vascular Surgery.
Postoperative acute kidney injury (AKI) is common after major surgery and is associated with increased morbidity, mortality, and cost. Additionally, there are recent studies demonstrating that time to renal recovery may have a substantial impact on clinical outcomes. We hypothesized that patients with delayed renal recovery after major vascular surgery will have increased complications, mortality, and hospital cost. A single-center retrospective cohort of patients undergoing nonemergent major vascular surgery between 6/1/2014 and 10/1/2020 was analyzed. Development of postoperative AKI (defined using Kidney Disease Improving Global Outcomes (KDIGO) criteria: >50% or > 0.3 mg/dl absolute increase in serum creatinine relative to reference after surgery and before discharge) was evaluated. Patients were divided into 3 groups: no AKI, rapidly reversed AKI (<48 hours), and persistent AKI (≥48 hours). Multivariable generalized linear models were used to evaluate the association between AKI groups and postoperative complications, 90-day mortality, and hospital cost. A total of 1,881 patients undergoing 1,980 vascular procedures were included. Thirty five percent of patients developed postoperative AKI. Patients with persistent AKI had longer intensive care unit and hospital stays, as well as more mechanical ventilation days. In multivariable logistic regression analysis, persistent AKI was a major predictor of 90-day mortality (odds ratio 4.1, 95% confidence interval 2.4-7.1). Adjusted average cost was higher for patients with any type of AKI. The incremental cost of having any AKI ranged from $3,700 to $9,100, even after adjustment for comorbidities and other postoperative complications. The adjusted average cost for patients stratified by type of AKI was higher among patients with persistent AKI compared to those with no or rapidly reversed AKI. Persistent AKI after vascular surgery is associated with increased complications, mortality, and cost. Strategies to prevent and aggressively treat AKI, specifically persistent AKI, in the perioperative setting are imperative to optimize care for this population.


Costs and benefits of jasmonic acid induced responses in soybean.
In response to herbivory, plants have evolved defense strategies to reduce herbivore preference and performance. A strategy whereby defenses are induced only upon herbivory can mitigate costs of defense when herbivores are scarce. Although costs and benefits of induced responses are generally assumed, empirical evidence for many species is lacking. Soybean (Glycine max L. Merr.) has emerged as a model species with which to address questions about induced responses. To our knowledge, this is the first study to examine the fitness costs and benefits of jasmonic acid-induced responses by soybean in the absence and presence of soybean loopers (Chrysodeix includens Walker) (Lepidoptera: Noctuidae). In a greenhouse experiment we demonstrated that soybean induction was costly. Induced plants produced 10.1% fewer seeds that were 9.0% lighter, and had 19.2% lower germination rates than noninduced plants. However, induction provided only modest benefits to soybeans. In a choice experiment, soybean loopers significantly preferred leaves from noninduced plants, consuming 62% more tissue than from induced plants. Soybean loopers that fed on plants that were previously subjected to treatment with jasmonic acid matured at the same rate and to the same size as those that fed on control plants. However, at high conspecific density, soybean looper survivorship was reduced by 44% on previously induced relative to control plants. Reduced soybean looper preference and survivorship did not translate into fitness benefits for soybeans. Our findings support theoretical predictions of costly induced defenses and highlight the importance of considering the environmental context in studies of plant defense.


Unaltered Liver Regeneration in Post-Cholestatic Rats Treated with the FXR Agonist Obeticholic Acid.
: In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X-receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post-cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non-cholestatic livers in PHx-subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal Fgf15 mRNA expression but did not enhance post-PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post-cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.


Geographic variation in reproductive assurance of Clarkia pulchella.
Climate can affect plant populations through direct effects on physiology and fitness, and through indirect effects on their relationships with pollinating mutualists. We therefore expect that geographic variation in climate might lead to variation in plant mating systems. Biogeographic processes, such as range expansion, can also contribute to geographic patterns in mating system traits. We manipulated pollinator access to plants in eight sites spanning the geographic range of Clarkia pulchella to investigate geographic and climatic drivers of fruit production and seed set in the absence of pollinators (reproductive assurance). We examined how reproductive assurance and fruit production varied with the position of sites within the range of the species and with temperature and precipitation. We found that reproductive assurance in C. pulchella was greatest in populations in the northern part of the species' range and was not well explained by any of the climate variables that we considered. In the absence of pollinators, some populations of C. pulchella have the capacity to increase fruit production, perhaps through resource reallocation, but this response is climate dependent. Pollinators are important for reproduction in this species, and recruitment is sensitive to seed input. The degree of autonomous self-pollination that is possible in populations of this mixed-mating species may be shaped by historic biogeographic processes or variation in plant and pollinator community composition rather than variation in climate.


General practitioner training in paediatrics in the Trent region.
A total of 259 postal questionnaires were sent to all final year vocational trainees and new principals in general practice in the Trent region to find out how much training in paediatrics they had had. Questionnaires were returned by 105 trainees and 139 principals (244; 94%). Overall 72% (175) had taken up a hospital post in paediatrics during training, but among the 138 doctors who were on or had completed a three year vocational training scheme the proportion was slightly higher (82%; 115) (p = 0.01). Among the 175 who had had a post in paediatrics 108 (62%) had been given teaching sessions every week, and for half of these doctors the sessions lasted over one hour a week. Seventy five (54%) of the 139 principals reported that in their training in a general practice they had received no teaching about child health and a fifth said that they had not attended a clinic for children; 47 (34%) had received no training on procedures for dealing with cases of child abuse. The doctors who had held posts as senior house officers in paediatrics were more likely to report that they had adequate skills in paediatrics than those who had not, but overall only 62 (44%) reported that they could run a preschool child health surveillance programme. Extra paediatric posts in hospital are needed, but in the mean time improvements can be made to the teaching content in hospital and in the general practice attachment and postgraduate training in paediatrics provided for all general practitioners.


Metabolic Profiling Analysis of Liver in Landes Geese During the Formation of Fatty Liver via GC-TOF/MS.
Fatty liver production results from the process of overfeeding geese, inducing a dramatic increase in de novo liver lipogenesis. To investigate the alteration of liver metabolites by overfeeding, especially lipid metabolites, and the potential pathways causing these changes, 60 Landes geese at 65 days old were raised in three groups with 20 geese per group, namely, the D0 group (free from gavage), D7 group (overfeeding for 7 days), and D25 group (overfeeding for 25 days). At 90 days old, segments of liver tissue were collected from 10 geese of each group for gas chromatography time-of-flight/mass spectrometry (GC-TOF/MS) analysis. A large number of endogenous molecules in the livers of geese were altered dramatically by overfeeding. In the livers of overfed geese, the level of oleic acid was observed to continuously increase, while the levels of phenylalanine, methyl phosphate, sulfuric acid, and 3-hydroxybenzaldehyde were decreased. The most significantly different metabolites were enriched in amino acid, lipid, and nucleotide metabolism pathways. The present study further supports the idea that Landes geese efficiently produce fatty liver, and potential biomarkers and disturbed metabolic pathways during the process of forming fatty liver were identified. In conclusion, this study might provide some insights into the underlying mechanisms of fatty liver formation.


Novel paralogy relations among human chromosomes support a link between the phylogeny of doublesex-related genes and the evolution of sex determination.
Recent advances in the evolutionary genetics of sex determination indicate that DMRT1 may be a vertebrate equivalent of the Drosophila melanogaster master sex regulator gene, doublesex. The role of DMRT1 seems to be confined to some aspects of male sex differentiation, whereas in Drosophila, doublesex has wider developmental effects in both sexes. This suggests other homologs of doublesex may exist in the vertebrate genome and encode sex-specific functions not displayed by DMRT1. We identified and characterized five novel human DM genes, distinct from previously described family members. Human DM genes map to three well-defined regions of chromosomes 1, 9, and 19 (one gene on chromosome 19 having an additional homolog on chromosome X). We collated data indicating these chromosomal regions harbor multiple syntenic genes sharing highly specific paralogy relations, suggesting that they arose early during vertebrate evolution. The 9p21-p24.3 bands represent the ancestral copy and harbor closely linked DM genes that may reflect the overall diversity of the fruit fly DM gene family. The human genome contains a small number of potential doublesex homologs that may be involved in human sexual development. Identifying highly conserved chromosomal regions, such as distal 9p, is an important tool to trace complex ancient evolutionary processes inaccessible by other approaches.


Expression and activity of the calcitonin receptor family in a sample of primary human high-grade gliomas.
Glioblastoma (GBM) is the most common and aggressive type of primary brain cancer. With median survival of less than 15 months, identification and validation of new GBM therapeutic targets is of critical importance. In this study we tested expression and performed pharmacological characterization of the calcitonin receptor (CTR) as well as other members of the calcitonin family of receptors in high-grade glioma (HGG) cell lines derived from individual patient tumours, cultured in defined conditions. Previous immunohistochemical data demonstrated CTR expression in GBM biopsies and we were able to confirm CALCR (gene encoding CTR) expression. However, as assessed by cAMP accumulation assay, only one of the studied cell lines expressed functional CTR, while the other cell lines have functional CGRP (CLR/RAMP1) receptors. The only CTR-expressing cell line (SB2b) showed modest coupling to the cAMP pathway and no activation of other known CTR signaling pathways, including ERK1/2 and p38 MAP kinases, and Ca2+ mobilization, supportive of low cell surface receptor expression. Exome sequencing data failed to account for the discrepancy between functional data and expression on the cell lines that do not respond to calcitonin(s) with no deleterious non-synonymous polymorphisms detected, suggesting that other factors may be at play, such as alternative splicing or rapid constitutive receptor internalisation. This study shows that GPCR signaling can display significant variation depending on cellular system used, and effects seen in model recombinant cell lines or tumour cell lines are not always reproduced in a more physiologically relevant system and vice versa.


Suppression of the homeobox gene HDTF1 enhances resistance to Verticillium dahliae and Botrytis cinerea in cotton.
Development of pathogen-resistant crops, such as fungus-resistant cotton, has significantly reduced chemical application and improved crop yield and quality. However, the mechanism of resistance to cotton pathogens such as Verticillium dahliae is still poorly understood. In this study, we characterized a cotton gene (HDTF1) that was isolated following transcriptome profiling during the resistance response of cotton to V. dahliae. HDTF1 putatively encodes a homeodomain transcription factor, and its expression was found to be down-regulated in cotton upon inoculation with V. dahliae and Botrytis cinerea. To characterise the involvement of HDTF1 in the response to these pathogens, we used virus-induced gene silencing (VIGS) to generate HDTF1-silenced cotton. VIGS reduction in HDTF1 expression significantly enhanced cotton plant resistance to both pathogens. HDTF1 silencing resulted in activation of jasmonic acid (JA)-mediated signaling and JA accumulation. However, the silenced plants were not altered in the accumulation of salicylic acid (SA) or the expression of marker genes associated with SA signaling. These results suggest that HDTF1 is a negative regulator of the JA pathway, and resistance to V. dahliae and B. cinerea can be engineered by activation of JA signaling.


Development of a risk stratification scoring system for deep vein thrombosis upon psychiatric admission.
Psychiatric patients have increased risk of deep vein thrombosis (DVT). However, there is no systematic data on risk assessment of DVT among psychiatric inpatients. The aim of this study was to develop a risk stratification scoring system for DVT among psychiatic patients on admission. A systematic review of psychiatric patient's charts, who were admitted to the Tokyo Metropolitan Matsuzawa Hospital from June 2012 to February 2016 and underwent screening for DVT, was conducted. Patients were randomly divided into development (n = 2634) and validation (n = 2634) groups. Estimated risk values in the multiple logistic regression model for the development sample were rounded to the nearest integer, and used as points of associated factors in the risk stratification scoring system; the total scores were tested in the validation sample. The score's discriminatory ability was assessed with the area under the receiver operating characteristic curve (AUC). Among the 5268 patients, 258 (4.9%) had DVT. Advancing age, female sex, active cancer, previous venous thromboembolism, transfer from a general hospital, catatonia, and major depressive episode were all significantly associated with the presence of DVT in the development sample. The total score showed good discriminatory ability in the validation sample (AUC: 0.816, 95% confidence interval: 0.781-0.851); scores of 0-1, 2-3, 4-5, and ≥ 6 were associated with very low risk (0.7%), low risk (4.6%), moderate risk (14.9%), and high risk (35%) for DVT, respectively. Our risk stratification scoring system showed good performance for detection of DVT among psychiatric patients on admission.


Survey of talon cusps in the permanent dentition of a Turkish population.
Talon cusp is the name given to the accessory tubercles located on the lingual faces of anterior teeth. The occurrence of talon cusps has been reported among Europeans and Asians. However, there are few reports of this anomaly in Caucasians as well as a paucity of literature on its characteristics. Today there are seven million Turkish citizens of Caucasian origin that have settled in the Marmara, Central-Anatolia, East-Anatolia, and Black Sea regions of Turkey. The aim of this study is to present 27 Caucasian cases with 33 taloned teeth. This study is the first that was undertaken to investigate the characteristics of talon cusps in a group of Turkish people. A survey of 27 patients examined in the Department of Oral Diagnosis and Radiology at Ondokuz Mayis University in Samsun, Turkey between January, 2003 and June, 2006 was conducted. Their ages ranged from seven to 33 years. A total of 33 talon cusps were diagnosed in the 27 patients. The patients' records and radiographs were evaluated and the following variables were studied: age, sex distribution, affected tooth, type of talon cusp, radiographic evidence of pulp extension, and associated dental anomalies and complications. There were 13 male and 14 female patients with a gender ratio of approximately 1:1. Ten of 33 talon cusps (30%) were seen in maxillary right central incisors while four cases (12%) were in maxillary left central incisors and nine cases (27%) were in maxillary right lateral incisors. Eight cases (24%) were seen in maxillary left lateral incisors, one case (3%) was in a mandibular right central incisor, and one case (3%) was in a mandibular left canine. Fifteen (15) of the 33 talon cusps were Type 1 talons (45%), while eight cases (24%) were Type 2 talons and ten cases (30%) were Type 3 talons. Twelve of the 33 talon cusps (36%) showed radiographic evidence of pulpal extension into the tubercule on periapical radiographs. One patient had gemination (3%) on the maxillary permanent incisors and two patients had mesiodens (6%) in the maxillary anterior region. The talon cusp remains as one of the more uncommon dental anomalies worldwide and in Turkey and presents with different clinical features. The talon cusp may be more likely to be associated with other odontogenic anomalies and some systemic conditions; early recognition of this anomaly is essential to provide proper treatment.


Structural and theoretical studies suggest domain movement produces an active conformation of thymidine phosphorylase.
Two new crystal forms of Escherichia coli thymidine phosphorylase (EC 220.127.116.11) have been found; a monoclinic form (space group P21) and an orthorhombic form (space group I222). These structures have been solved and compared to the previously determined tetragonal form (space group P43212). This comparison provides evidence of domain movement of the alpha (residues 1 to 65, 163 to 193) and alpha/beta (residues 80 to 154, 197 to 440) domains, which is thought to be critical for enzymatic activity by closing the active site cleft. Three hinge regions apparently allow the alpha and alpha/beta-domains to move relative to each other. The monoclinic model is the most open of the three models while the tetragonal model is the most closed. Phosphate binding induces formation of a hydrogen bond between His119 and Gly208, which helps to order the 115 to 120 loop that is disordered prior to phosphate binding. The formation of this hydrogen bond also appears to play a key role in the domain movement. The alpha-domain moves as a rigid body, while the alpha/beta-domain has some non-rigid body movement that is associated with the formation of the His119-Gly208 hydrogen bond. The 8 A distance between the two substrates reported for the tetragonal form indicates that it is probably not in an active conformation. However, the structural data for these two new crystal forms suggest that closing the interdomain cleft around the substrates may generate a functional active site. Molecular modeling and dynamics simulation techniques have been used to generate a hypothetical closed conformation of the enzyme. Analysis of this model suggests several residues of possible catalytic importance. The model explains observed kinetic results and satisfies requirements for efficient enzyme catalysis, most notably through the exclusion of water from the enzyme's active site.


Epidemiology, preventive services, and illnesses of international travelers.
Medical preparation of travelers to overseas locations is an important part of military medical care. We reviewed pre-travel records of patients attending the travel clinic at the National Naval Medical Center (NNMC) and used a post-travel questionnaire to determine the most frequent medical problems associated with international travel. Among 1,416 individuals who received pre-travel care at NNMC, there were 760 (54%) males and 656 (46%) females, the median patient age was 48 years, the most common reason for travel was pleasure, and the median duration of travel was 21 days. The most common destinations were Asia (27%), Africa (15%), Europe (13%), Central America/Caribbean (12%), and South America (11%). The median number of immunizations prescribed was three. Malaria chemoprophylaxis was prescribed to 45%. The average cost of vaccines and medications to medically prepare a traveler was $67. Among 271 (82%) who returned the post-travel questionnaire, the most common illnesses reported were diarrhea (23%) and upper respiratory infections (19%); medical treatment was sought by 9%. Properly informed, military physicians can provide a valuable service at a reasonable cost to reduce the risk of travel-acquired medical problems and illnesses.


Resident Selection in the Wake of United States Medical Licensing Examination Step 1 Transition to Pass/Fail Scoring.
The numeric score for the United States Medical Licensing Examination Step 1 is one of the only universal, objective, scaled criteria for comparing the many students who apply to orthopaedic surgery residency. However, on February 12, 2020, it was announced that Step 1 would be transitioning to pass/fail scoring. The purpose of this study was to (1) determine the most important factors used for interview and resident selection after this change and (2) to assess how these factors have changed compared with a previous report on resident selection. A survey was distributed to the program directors (PDs) of all 179 orthopaedic surgery programs accredited by the Accreditation Council for Graduate Medical Education. Questions focused on current resident selection practices and the impact of the Step 1 score transition on expected future practices. A total of 78 PDs (44%) responded to the survey. Over half of PDs (59%) responded that United States Medical Licensing Examination Step 2 clinical knowledge (CK) score is the factor that will increase most in importance after Step 1 transitions to pass/fail, and 90% will encourage applicants to include their Step 2 CK score on their applications. The factors rated most important in resident selection from zero to 10 were subinternship performance (9.05), various aspects of interview performance (7.49 to 9.01), rank in medical school (7.95), letters of recommendation (7.90), and Step 2 CK score (7.27). Compared with a 2002 report, performance on manual skills testing, subinternship performance, published research, letters of recommendations, and telephone call on applicants' behalf showed notable increases in importance. As Step 2 CK is expected to become more important in the residency application process, current applicant stress on Step 1 scores may simply move to Step 2 CK scores. Performance on subinternships will remain a critical aspect of residency application, as it was viewed as the most important resident selection factor and has grown in importance compared with a previous report.


Integrating Social-Contextual and Intrapersonal Mechanisms of "Maturing Out": Joint Influences of Familial-Role Transitions and Personality Maturation on Problem-Drinking Reductions.
"Maturing out" of problem drinking is associated with both role transitions (e.g., getting married) and personality development. However, little is known concerning how these 2 mechanisms jointly influence problem-drinking desistance. This study investigated whether salutary effects of role transitions and personality occur at different points in young-adult development and whether they mediate one another's effects. Participants were initially recruited as first-year undergraduates, with family history of alcoholism overrepresented by design (N = 489). Using 4 waves of data at roughly ages 21, 25, 29, and 34, cross-lagged panel models estimated prospective relations among familial-role transitions (marriage or parenthood), personality (disinhibition, conscientiousness, and neuroticism), and problem drinking. Mixed support was found for the prediction of roles being more strongly associated with earlier maturing out of problem drinking and personality being more strongly associated with later maturing out. Regarding mediation, no evidence was found for the expectation that role effects would be mediated by personality. However, results did support mediation of personality effects by role transitions. Specifically, lower disinhibition and higher conscientiousness in emerging adulthood predicted role adoption, which, in turn, predicted later problem-drinking reductions. Family history of alcoholism also distally influenced these mediation processes. The differential timing of role and personality effects is consistent with the notion of decreasing contextual influences and increasing intrapersonal influences across development. In light of role incompatibility theory, results suggest that, over the course of development, the association of familial roles with problem drinking may increasingly reflect problem-drinking effects on role entry (i.e., role selection) and decreasingly reflect role entry effects on problem drinking (i.e., role socialization). As emerging-adult disinhibition and conscientiousness were associated with an apparent developmental cascade of both direct and indirect effects, findings highlight their potential importance as etiologic mechanisms and intervention targets.


[The biological specimen bank: methodological and organizational problems].
Little experience is available to solve methodological and organizational problems when setting up a biological specimen bank as a support to prospective studies on chronic diseases. Sample aliquots preparation, processing procedures and storage system are discussed in the present paper. Problems related to the quality of biological material stored, as to the influence of the very low temperature freezing physico-chemical effects, are discussed also in the appendix.


Myoplasty--a surgical option for end-stage heart failure.
Congestive heart failure is a growing problem in the Western world, which modern therapeutic options are doing little to ameliorate. Dynamic cardiomyoplasty may be one option which has great potential. This article reviews the use of skeletal muscle for circulatory assist and suggests that, with further work, it should take a significant place in the treatment armamentarium.


Development of SARS-CoV-2 Nucleocapsid Specific Monoclonal Antibodies.
The global COVID-19 pandemic has caused massive disruptions in every society around the world. To help fight COVID-19, new molecular tools specifically targeting critical components of the causative agent of COVID-19, SARS-Coronavirus-2 (SARS-CoV-2), are desperately needed. The SARS-CoV-2 nucleocapsid protein is a major component of the viral replication processes, integral to viral particle assembly, and is a major diagnostic marker for infection and immune protection. Currently available antibody reagents targeting the nucleocapsid protein were primarily developed against the related SARS-CoV virus and are not specific to SARS-CoV-2 nucleocapsid protein. Therefore, in this work we developed and characterized a series of new mouse monoclonal antibodies against the SARS-CoV-2 nucleocapsid protein. The anti-nucleocapsid monoclonal antibodies were tested in ELISA, western blot, and immunofluorescence analyses. The variable regions from the heavy and light chains from five select clones were cloned and sequenced, and preliminary epitope mapping of the sequenced clones was performed. Overall, the new antibody reagents described here will be of significant value in the fight against COVID-19.


Sensorized toys for measuring manipulation capabilities of infants at home.
Preterm infants, i.e. babies born after a gestation period shorter than 37 weeks, spend less time exploring objects. The quantitative measurement of grasping actions and forces in infants can give insights on their typical or atypical motor development. The aim of this work was to test a new tool, a kit of sensorized toys, to longitudinally measure, monitor and promote preterm infants manipulation capabilities with a purposive training in an ecological environment. This study presents preliminary analysis of grasping activity. Three preterm infants performed 4 weeks of daily training at home. Sensorized toys with embedded pressure sensors were used as part of the training to allow quantitative analysis of grasping (pressure and acceleration applied to toys while playing). Each toy was placed on the midline, while the infant was in supine position. Preliminary data show differences in the grasping parameters in relation to infants age and the performed daily training. Ongoing clinical trial will allow a full validation of this new tool for promoting object exploration in preterm infants.


Examination of the polypeptides of hepatitis B surface antigen.
When the polypeptides of hepatitis B surface antigen were examined by SDS-polyacrylamide gel electrophoresis under a variety of conditions, anomalous results were found to be due to (i) variable and at times incomplete dissociation of polypeptides after boiling with 1% SDS and reducing agent, (ii) reaggregation of solubilized material under certain electrophoretic conditions and during laboratory manipulations, and (iii) the variable presence of additional components in hepatitis B surface antigen prepared from certain individual donors. When these factors were taken into account, two major components were consistently identified by discontinuous buffer polyacrylamide gel electrophoresis, of apparent mol. wt. 60000 to 70000 and 12000 to 14000. However, in view of the demonstrated limitations of this technique in examining HBsAg polypeptides, alternative methods are necessary to confirm the true mol. wt. of the unique virus-specified amino acid sequence present.


The LH surge and ovulation re-visited: a systematic review and meta-analysis and implications for true natural cycle frozen thawed embryo transfer.
Efficient and safe embryo vitrification techniques have contributed to a marked worldwide increase in the use of elective frozen embryo transfer (FET). Pinpointing the day of ovulation, more commonly by documentation of the LH surge and less commonly by ultrasonography, is crucial for timing of FET in a true natural cycle (t-NC) to maximize the reproductive outcome. The definition of the onset of the LH surge should be standardized in t-NC FET cycles; however, a clear definition is lacking in the available literature. The first search question concerns the definition of the onset of the LH surge in a natural cycle. The second search question relates to the duration between the onset of the LH surge and ovulation. We searched PubMed, Web of Science and Cochrane Library databases for two search questions from inception until 31 August 2021. 'Luteinizing hormone'[MeSH] OR 'LH' AND 'surge' terms were used to identify eligible articles to answer the first question, whereas 'Luteinizing hormone'[MeSH] OR 'LH' AND 'surge' OR 'rise' AND 'ovulation'[MeSH] OR 'follicular rupture' OR 'follicular collapse' were the terms used regarding the second question. The included publications were all written in the English language, conducted in women of reproductive age with regular ovulatory cycles and in whom serial serum or urine LH measurement was performed. For the quality and risk of bias assessment of the included studies, the Strengthening the Reporting of Observational Studies in Epidemiology and modified Newcastle Ottawa Scale were used. A total of 10 and 8 studies were included for search Questions 1 and 2, respectively. Over the years, through different studies and set-ups, testing in either serum or urine, different definitions for the onset of the LH surge have been developed without a consensus. An increase in LH level varying from 1.8- to 6-fold above the baseline LH level was used in seven studies and an increase of at least two or three standard deviations above the mean of the preceding LH measurements was used in two studies. An LH level exceeding the 30% of the amplitude (peak-baseline LH level) of the LH surge was defined as the onset day by one study. A marked inter-personal variation in the time interval between the onset of the LH surge and ovulation was seen, ranging from 22 to 56 h. When meta-analysis was performed, the mean duration in hours between the onset of the LH surge and ovulation was 33.91 (95% CI = 30.79-37.03: six studies, 187 cycles). The definition of the onset of the LH surge should be precisely defined in future well-designed studies employing state-of-art laboratory and ultrasonographic equipment. The window of implantation in a natural cycle is still a black box, and future research is warranted to delineate the optimal interval to time the embryo transfer in t-NC FET cycles. Randomized controlled trials employing different precise endocrine and/or ultrasonographic criteria for timing of FET in a t-NC are urgently required.


Adenoma-like adenocarcinoma: clinicopathologic characterization of a newly recognized subtype of colorectal carcinoma.
The 5th edition of the World Health Organization (WHO) Classification of Tumours (Digestive System) recognizes a new subtype of colorectal adenocarcinoma, called adenoma-like adenocarcinoma. In this study, we sought to determine its clinicopathologic associations and how it is comparable with adenocarcinoma, of no special type (NOS). We retrospectively reviewed all available archival slides of stage I-III colonic adenocarcinoma resection specimens at our institution from 2013 to 2016.Ninety-one cases were classified as adenoma-like adenocarcinoma, and 251 cases were classified as adenocarcinoma, NOS. Of the adenoma-like adenocarcinoma cases, a majority (65 cases, 71%) were composed exclusively of adenoma-like features, designated as pure adenoma-like adenocarcinoma, whereas in the rest, the component of adenoma-like morphology was more than 50% but less than 100%, designated as mixed adenoma-like adenocarcinoma. Compared with adenocarcinoma, NOS, adenoma-like adenocarcinoma cases were significantly associated with the absence of tumor budding (P < 0.001), the absence of an immature/myxoid desmoplastic reaction (P < 0.001), the presence of intraepithelial tumor-infiltrating lymphocytes (P = 0.006), involvement of fewer lymph nodes ( P < 0.001), fewer tumor deposits (P = 0.042), lower pT stage (P = 0.047), lower pN stage (P < 0.001), and consequently the pTNM prognostic group (P < 0.001), as well as better recurrence-free survival (RFS), as per univariate analysis than adenocarcinoma, NOS cases (P = 0.026) but not as per multivariate analysis. However, mixed adenoma-like adenocarcinoma had a worse RFS than pure adenoma-like adenocarcinoma (hazard ratio = 1.639, 95% confidence interval = 0.494-5.437). Our findings not only support the importance of distinguishing this new subtype of colorectal adenocarcinoma but also raise the question whether mixed adenoma-like adenocarcinoma cases should be included in this category, and if so, whether 50% is an appropriate cutoff, as currently defined by the WHO.