Dynamic Construction of Reduced Representations in the Brain for Perceptual Decision Behavior.
Over the past decade, extensive studies of the brain regions that support face, object, and scene recognition suggest that these regions have a hierarchically organized architecture that spans the occipital and temporal lobes [1-14], where visual categorizations unfold over the first 250 ms of processing [15-19]. This same architecture is flexibly involved in multiple tasks that require task-specific representations-e.g. categorizing the same object as "a car" or "a Porsche." While we partly understand where and when these categorizations happen in the occipito-ventral pathway, the next challenge is to unravel how these categorizations happen. That is, how does high-dimensional input collapse in the occipito-ventral pathway to become low dimensional representations that guide behavior? To address this, we investigated what information the brain processes in a visual perception task and visualized the dynamic representation of this information in brain activity. To do so, we developed stimulus information representation (SIR), an information theoretic framework, to tease apart stimulus information that supports behavior from that which does not. We then tracked the dynamic representations of both in magneto-encephalographic (MEG) activity. Using SIR, we demonstrate that a rapid (∼170 ms) reduction of behaviorally irrelevant information occurs in the occipital cortex and that representations of the information that supports distinct behaviors are constructed in the right fusiform gyrus (rFG). Our results thus highlight how SIR can be used to investigate the component processes of the brain by considering interactions between three variables (stimulus information, brain activity, behavior), rather than just two, as is the current norm.


Predictors of sustained ventricular arrhythmias in cardiac resynchronization therapy.
Patients undergoing cardiac resynchronization therapy (CRT) are at high risk for ventricular arrhythmias (VAs), and risk stratification in this population remains poor. This study followed 269 patients (left ventricular ejection fraction <35%; QRS >120 ms; New York Heart Association class III/IV) undergoing CRT with a defibrillator for 553±464 days after CRT with defibrillator implantation to assess for independent predictors of appropriate device therapy for VAs. Baseline medication use, medical comorbidities, and echocardiographic parameters were considered. The 4-year incidence of appropriate device therapy was 36%. A Cox proportional hazard model identified left ventricular end-systolic diameter >61 mm as an independent predictor in the entire population (hazard ratio [HR], 2.66; P=0.001). Those with left ventricular end-systolic diameter >61 mm had a 51% 3-year incidence of VA compared with a 26% incidence among those with a less dilated ventricle (P=0.001). Among patients with left ventricular end-systolic diameter ≤61 mm, multivariate predictors of appropriate therapy were absence of β-blocker therapy (HR, 6.34; P<0.001), left ventricular ejection fraction <20% (HR, 4.22; P<0.001), and history of sustained VA (HR, 2.97; P=0.013). Early (<180 days after implant) shock therapy was found to be a robust predictor of hospitalization for heart failure (HR, 3.41; P<0.004) and mortality (HR, 5.16; P<0.001.) Among patients with CRT and a defibrillator, left ventricular end-systolic diameter >61 mm is a powerful predictor of VAs, and further risk stratification of those with less dilated ventricles can be achieved based on assessment of ejection fraction, history of sustained VA, and absence of β-blocker therapy.


Charting the Chronology of Research on Added Sugars: A Scoping Review and Evidence Map.
The objective of this study was to conduct a scoping review and produce a publicly available database characterizing the design and reporting elements of the literature on dietary added sugars and select health outcomes. Relevant studies published from 1990 to 2021 were identified to create a database containing information on study and population characteristics, reported added sugars source and concentrations, dietary energy balance, total energy intake, and outcome measures related to body composition, obesity, cardiovascular disease, and diabetes mellitus. There were 245 publications identified, 22% of which describe interventions, and 78% describe observational studies. Publications pertaining to added sugars have risen dramatically since 2010, led by studies primarily assessing body composition (36%) or cardiovascular health (32%), including adults (65%), measuring liquid-only sources of added sugars (56%). Over 65% of studies reported total energy intake, 61% controlled for total energy intake in the design and analysis, and fewer than 5% of studies reported the energy balance of subjects. There has been a significant increase in research on added sugars since 2010, with substantial heterogeneity across all facets of methodology-study designs, exposures and outcomes of interest, terminology, and reporting of dietary intake data-thus limiting the ability to synthesize evidence in this scope of the literature. This evidence map highlights gaps and important areas for improvement to strengthen the state of research and better inform future policies and dietary recommendations on added sugars.


Subjective well-being, social buffering and hedonic editing in the quotidian.
A previous study on the relationship between subjective well-being (SWB) and hedonic editing-the process of mentally integrating or segregating different events during decision-making-showed that happy individuals preferred the social-buffering strategy more than less happy individuals. The present study examined the relationship between SWB, social-buffering and hedonic outcomes in daily life. In Study 1, we used web-based diaries to measure the frequency with which individuals utilised social and non-social buffers as well as daily levels of happiness. Consistent with the previous finding, happy individuals utilised social buffers more frequently than less happy individuals. Interestingly, the utilisation of social buffers had a positive effect on daily happiness among all participants, regardless of individuals' levels of SWB. In Study 2, we found that although the use of social buffers yielded similar effects across groups on online evaluations of events, happy individuals showed a positive bias in global evaluations of past events. This finding suggests that how one construes and remembers the outcomes of social buffering may shape the different hedonic editing preferences among happy and less happy individuals.


Pterygium excision and conjunctival autograft: A comparative study of techniques.
Use of conjunctival autograft following excision has reduced the recurrence rate of primary pterygium. This study compares the use of fibrin glue, autologous blood, and sutures in placing the conjunctival autograft in reference to surgical time taken, postoperative discomfort, and recurrence during follow-up. Sixty patients with primary pterygium were included in the study and divided into three groups. In Group I, autograft was attached in place with help of 10-0 polyamide monofilament suture; in Group II, with autologous blood; and in Group III, with fibrin glue. All three groups were compared in terms of surgical time, postoperative discomfort, and recurrence. The average surgical time taken was least with fibrin glue group (Group III), i.e., 36.2 min, followed by 44.8 min with autologous blood group (Group II) and maximum of 53.3 min with suture group (Group I). Postoperative discomfort was seen maximum in th suture group (Group I) and was minimal in the fibrin glue group (Group III). At the end of final follow-up at 6 months, one case of recurrence was seen in both Group I and Group II. No recurrence was seen in Group III. The study concluded that fibrin glue remains the most effective method for attaching conjunctival autograft in pterygium surgery with least surgical time and postoperative discomfort. Autologous blood is an effective alternative which is easily available, economical, vis a vis fibrin glue with less surgical time and postoperative discomfort. Use of sutures is an older technique with maximum surgical time and postoperative discomfort. Recurrence is least with fibrin glue.


Gut microbiota and immune mediation: a Mendelian randomization study on granulomatosis with polyangiitis.
The gut microbiota plays a pivotal role in influencing various health outcomes, including immune-mediated conditions. Granulomatosis with Polyangiitis (GPA) is one such condition, and its potential associations with gut microbiota remain underexplored. Using a two-sample Mendelian randomization approach, we investigated the causal links between gut microbiota and GPA. We sourced our data from multiple cohorts and consortiums, including the MiBioGen consortium. Our study design incorporated both direct associations and mediation effects of immune traits on the relationship between gut microbiota and GPA. Our analysis revealed significant associations between 1 phylum, 1 family 9 genus microbiota taxa and GPA. Furthermore, we identified several immune cell traits that mediated the effects of gut microbiota on GPA. For instance, the family Defluviitaleaceae and genus Defluviitaleaceae UCG011 influenced GPA through CD11c in granulocytes. The mediation effect proportions further elucidated the complex dynamics between gut microbiota exposures, immune markers, and their combined influence on GPA. Our findings underscore the intricate relationship between gut microbiota, immune markers, and GPA. The identified associations and mediation effects provide valuable insights into the potential therapeutic avenues targeting gut microbiota to manage GPA.


A simple effective method for generation of a permanent record of the Critical View of Safety during laparoscopic cholecystectomy by intraoperative "doublet" photography.
The Critical View of Safety (CVS) is an established method for identifying the cystic duct during laparoscopic cholecystectomy. Its goal is to prevent misidentification of the bile ducts and avoid biliary injury. However, a visual record of CVS is not usually made. Intraoperative photography has the potential to record CVS and increase the safety of laparoscopic cholecystectomy. The objective of this study was to develop a simple and effective technique for recording CVS during laparoscopic cholecystectomy. Techniques for photographing and rating photographs of CVS were developed. Surgeons were trained in methods of photographing both anterior and posterior views of CVS during laparoscopic cholecystectomy. Independent observers scored these views individually and together. The term doublet view was used when both anterior and posterior views of CVS were used for rating. Three criteria for CVS were used for scoring photographs. A total score of ≥ 5 of 6 points was considered satisfactory, and a total score <5 of 6 points was considered unsatisfactory. Photographs of 28 patients were obtained. Critical View of Safety photographs were satisfactory in either anterior or posterior single images in 43 of 56 (76.8%) instances, and doublet photographs were satisfactory in 27 of 28 (96.4%) instances (p = 0.02). Body mass index >40 predicted a higher likelihood of unsatisfactory individual CVS photos (p = 0.02); however, there was no correlation between patient or pathologic factors and the scores of doublet views. With training and adherence to straightforward photographic techniques, intraoperative doublet photography can record CVS accurately. This method is performed easily, and could be used for recording of CVS in the medical record.


An inhibitory role for polyamines in protein kinase C activation and insulin secretion in mouse pancreatic islets.
The occurrence and function of polyamines in protein kinase C activation and insulin secretion in mouse pancreatic islets were studied. Determination of polyamines in mouse islets revealed 0.9 +/- 0.3 (mean +/- S.E.M., n = 6) pmol of putrescine, 11.7 +/- 3.2 (8) pmol of spermidine and 3.7 +/- 0.6 (8) pmol of spermine per islet, corresponding to intracellular concentrations of 0.3-0.5 mM-putrescine, 3.9-5.9 mM-spermidine and 1.2-1.9 mM-spermine in mouse islets. Stimulation of insulin secretion by glucose, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) or the sulphonylurea glibenclamide did not affect these polyamine contents. In accordance with a role for protein kinase C in insulin secretion, TPA stimulated both protein kinase C activity and insulin secretion. Stimulation of insulin secretion by TPA was dependent on a non-stimulatory concentration of glucose and was further potentiated by stimulatory concentrations of glucose, glibenclamide or 3-isobutyl-1-methylxanthine, suggesting that protein kinase C activation, Ca2+ mobilization and cyclic AMP accumulation are all needed for full secretory response of mouse islets. Spermidine (5 mM) and spermine (1.5 mM) at concentrations found in islets inhibited protein kinase C stimulated by TPA + phosphatidylserine by 55% and 45% respectively. Putrescine (0.5 mM) was without effect, but inhibited the enzyme at higher concentrations (2-10 mM). Inhibition of protein kinase C by polyamines showed competition with Ca2+, and Ca2+ influx in response to glucose or glibenclamide prevented inhibition of insulin secretion by exogenous polyamines at concentrations where they did not affect glucose oxidation. It is suggested that inhibition of protein kinase C by polyamines may be of significance for regulation of insulin secretion in vivo and that Ca2+ influx may function by displacing inhibitory polyamines bound to phosphatidylserine in membranes.


Current technical approaches to brain energy metabolism.
Neuroscience is a technology-driven discipline and brain energy metabolism is no exception. Once satisfied with mapping metabolic pathways at organ level, we are now looking to learn what it is exactly that metabolic enzymes and transporters do and when, where do they reside, how are they regulated, and how do they relate to the specific functions of neurons, glial cells, and their subcellular domains and organelles, in different areas of the brain. Moreover, we aim to quantify the fluxes of metabolites within and between cells. Energy metabolism is not just a necessity for proper cell function and viability but plays specific roles in higher brain functions such as memory processing and behavior, whose mechanisms need to be understood at all hierarchical levels, from isolated proteins to whole subjects, in both health and disease. To this aim, the field takes advantage of diverse disciplines including anatomy, histology, physiology, biochemistry, bioenergetics, cellular biology, molecular biology, developmental biology, neurology, and mathematical modeling. This article presents a well-referenced synopsis of the technical side of brain energy metabolism research. Detail and jargon are avoided whenever possible and emphasis is given to comparative strengths, limitations, and weaknesses, information that is often not available in regular articles.


Sustainability of cognitive behavioural interventions for chronic back pain: A long-term follow-up.
There is a significant research gap with respect to the long-term sustainability of psychological treatment effects in chronic pain patients. This study aimed to investigate long-term treatment effects of two psychological treatments: cognitive behavioural therapy (CBT) as a broad-spectrum approach and exposure as a specific intervention for fear-avoidant pain patients. Patients with chronic low back pain were randomized to CBT or exposure in vivo. Long-term follow-up (LTFU) data were available for 64 patients up to 8 years after treatment, with a response rate of 73%. The primary outcomes were pain-related disability and pain intensity and secondary outcomes were emotional distress, psychological flexibility, catastrophizing and pain-related fear. The data analysis was performed with longitudinal multilevel modelling. Multilevel analyses showed improvements in all primary outcomes as well as all secondary outcomes from pre-treatment to LTFU for both treatments. The mean proportion of cases meeting reliable and clinical improved criteria in all primary outcome was 36% (range: 22%-46%) in the exposure group and 50% (range: 33%-60%) in the CBT group. Dropout analyses revealed significantly higher deterioration rates over time. Pre-treatment to LTFU effect sizes of the primary outcomes ranged from 0.54 to 1.59. Our results indicate that the effects of psychological treatments might be stable over several years. Treatment gains for exposure as a stand-alone treatment seem to be of shorter duration than a general CBT intervention. Thus, psychological treatments might offer a promising and sustainable long-term perspective for patients with chronic back pain. The long-term stability of treatment effects is a highly neglected issue despite its inherent importance in the context of chronic pain. This study is the first to investigate treatment effects of cognitive behavioural therapy and in vivo exposure in chronic back pain sufferers up to 8 years after treatment. The findings contribute to an understanding of the sustainability of psychological cognitive behavioural therapy-based intervention effects.


Hereditary deficiency of the fifth component of complement in man. II. Biological properties of C5-deficient human serum.
The first known human kindred with hereditary deficiency of the fifth component of complement (C5) was documented in the accompanying report. This study examines several biological properties of C5-deficient (C5D) human serum, particularly sera obtained from two C5D homozygotes. The proband, who has inactive systemic lupus erythematosus is completely lacking C5, while her healthy half-sister has 1-2% of normal levels. Both sera were severely impaired in their ability to generate chemotactic activity for normal human neutrophils upon incubation with aggregated human gamma-globulin or Escherichia coli endotoxin. This function was fully restored in the sibling's serum, and substantially improved in the proband's serum, by addition of highly purified human C5 to normal serum concentrations. Sera from eight family members who were apparently heterozygous for C5 deficiency gave normal chemotactic scores. The ability of C5D serum to opsonize Saccharomyces cerevisiae (baker's yeast) or Candida albicans for ingestion by normal neutrophils was completely normal. In addition, C5D serum was capable of promoting normal phagocytosis and intracellular killing of Staphylococcus aureus. The proband's serum was incapable of mediating lysis of erythrocytes from a patient with paroxysmal nocturnal hemoglobinuria in both the sucrose hemolysia and acid hemolysis tests, and also lacked bactericidal activity against sensitized or unsensitized Salmonella typhi. The sibling's serum, containing only 1-2% of normal C5, effectively lysed S. typhi, but only at eightfold lower serum dilutions as compared to normals. These findings underscore the critical role of C5 in the generation of chemotactic activity and in cytolytic reactions, as opposed to a nonobligatory or minimal role in opsonization, at least for the organisms under study.


Underrepresentation of African Americans in online cancer support groups.
The Internet is increasingly important for many cancer survivors because it provides access to the latest information on cancer treatments and also allows them to receive support by participating in online cancer support groups. Unfortunately, little is known about why African-American cancer survivors are underrepresented in online cancer support groups. This article reviews the relevant literature and discusses three possible explanations for why African Americans are underrepresented in online cancer support groups: the digital divide/digital inequality, preferences for face-to-face support or culture-specific online support, and trust concerns. We conclude that a health inequity exists with regard to the utilization of information that can be obtained from online cancer support groups. However, with regard to the potential benefits of the psychosocial and emotional support aspect of online cancer support groups, a health inequity may not exist, as African Americans have other preferred avenues for obtaining needed support, and there is no evidence that this is detrimental to their health.


Prognostic value of clinically important deterioration in COPD: IMPACT trial analysis.
Clinically important deterioration (CID) is a multicomponent measure for assessing disease worsening in chronic obstructive pulmonary disease (COPD). This analysis investigated the prognostic value of a CID event on future clinical outcomes and the effect of single-inhaler triple versus dual therapy on reducing CID risk in patients in the IMPACT trial. IMPACT was a phase III, double-blind, 52-week, multicentre trial. Patients with symptomatic COPD and at least one moderate/severe exacerbation in the prior year were randomised 2:2:1 to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg, FF/VI 100/25 µg or UMEC/VI 62.5/25 µg. CID at the time-point of interest was defined as a moderate/severe exacerbation, ≥100 mL decrease in trough forced expiratory volume in 1 s or deterioration in health status (increase of ≥4.0 units in St George's Respiratory Questionnaire total score or increase of ≥2.0 units in COPD Assessment Test score) from baseline. A treatment-independent post hoc prognostic analysis compared clinical outcomes up to week 52 in patients with/without a CID by week 28. A prospective analysis evaluated time to first CID with each treatment. Patients with a CID by week 28 had significantly increased exacerbation rates after week 28, smaller improvements in lung function and health status at week 52 (all p<0.001), and increased risk of all-cause mortality after week 28 versus patients who were CID-free. FF/UMEC/VI significantly reduced CID risk versus dual therapies (all p<0.001). Prevention of short-term disease worsening was associated with better long-term clinical outcomes. FF/UMEC/VI reduced CID risk versus dual therapies; this effect may improve long-term prognosis in this population.


Space/time quantitation of thallium-201 myocardial scintigraphy.
A comprehensive method is described for quantitation of the spatial distribution of TI-201 in the myocardium and its changes with time. The method, applied here to 51 patients, uses bilinear interpolative background subtraction to compensate for tissue crosstalk, and circumferential profiles to quantitate the relative radionuclide activity in the myocardium as an angular function with origin at the center of the left-ventricular cavity. In addition, washout circumferential profiles are calculated as percent washout from the stress circumferential profiles. Abnormal thallium distribution or washout is identified by automatic computer comparison of each patient's profiles with the corresponding limits of normal profiles, determined from the pooled profiles of 31 normal patients. In these 31, the computer output was normal in all cases. In 20 patients with angiographically documented coronary artery disease, 19 were determined to be abnormal by this method. This new computerized treatment provides accurate objective assessment of the presence of coronary artery disease.


Future directions in neuropathic pain therapy: closing the translational loop.
In the majority of patients, existing therapies for neuropathic pain are far from effective. Furthermore, all current treatments are symptomatic rather than disease-modifying or curative. A range of therapeutic modalities is emerging, targeting a variety of mechanisms, but choosing the best target and evaluating the resulting therapies against the many types of neuropathic pain disorders is not an easy task. In this article, we suggest a shift in emphasis of the drug discovery paradigm toward unbiased evaluation of the particular neurobiological mechanisms contributing to neuropathic pain in individual patients. Genomewide association studies and other discovery science approaches to identify significant novel targets should be given priority as should the development of increasingly sophisticated tools for measuring and categorizing neuropathic pain.


Construction of SnS2-SnO2 heterojunctions decorated on graphene nanosheets with enhanced visible-light photocatalytic performance.
Heterostructures formed by the growth of one kind of nanomaterial in/on another have attracted increasing attention due to their microstructural characteristics and potential applications. In this work, SnS2-SnO2 heterostructures were successfully prepared by a facile hydrothermal method. Due to the enhanced visible-light absorption and efficient separation of photo-generated holes and electrons, the SnS2-SnO2 heterostructures display excellent photocatalytic performance for the degradation of rhodamine (RhB) under visible-light irradiation. Additionally, it is found that the introduction of graphene into the heterostructures further improved photocatalytic activity and stability. In particular, the optimized SnS2-SnO2/graphene photocatalyst can degrade 97.1% of RhB within 60 min, which is about 1.38 times greater than that of SnS2-SnO2 heterostructures. This enhanced photocatalytic activity could be attributed to the high surface area and the excellent electron accepting and transporting properties of graphene, which served as an acceptor of the generated electrons to suppress charge recombination. These results provide a new insight for the design and development of hybrid photocatalysts.


Lactate activates ATP-sensitive potassium channels in guinea pig ventricular myocytes.
The functional significance of cardiac ATP-sensitive potassium channels remains controversial because of the discrepancy between the low levels of ATP at which activation of the channels occurs and the much higher levels of ATP maintained during myocardial ischemia. We studied the effects of (+)-lactate, which accumulates in large quantity as a result of increased glycolysis during ischemia, on ATP-sensitive potassium channels in adult guinea pig ventricular myocytes using the whole-cell patch-clamp technique. Lactate at 20-40 mM in the internal solution activated ATP-sensitive potassium channels and shortened action potential duration. Activation of the channels occurred even in the presence of 2-5 mM ATP in the internal solution and was dependent on intracellular free magnesium levels. Our results suggest that intracellular lactate may play a significant role in activating cardiac ATP-sensitive potassium channels and shortening action potential duration even at ATP levels similar to those resulting from moderate to severe myocardial ischemia.


Induction of cortical plasticity and improved motor performance following unilateral and bilateral transcranial direct current stimulation of the primary motor cortex.
Transcranial direct current stimulation (tDCS) is a non-invasive technique that modulates the excitability of neurons within the primary motor cortex (M1). Research shows that anodal-tDCS applied over the non-dominant M1 (i.e. unilateral stimulation) improves motor function of the non-dominant hand. Similarly, previous studies also show that applying cathodal tDCS over the dominant M1 improves motor function of the non-dominant hand, presumably by reducing interhemispheric inhibition. In the present study, one condition involved anodal-tDCS over the non-dominant M1 (unilateral stimulation) whilst a second condition involved applying cathodal-tDCS over the dominant M1 and anodal-tDCS over non-dominant M1 (bilateral stimulation) to determine if unilateral or bilateral stimulation differentially modulates motor function of the non-dominant hand. Using a randomized, cross-over design, 11 right-handed participants underwent three stimulation conditions: 1) unilateral stimulation, that involved anodal-tDCS applied over the non-dominant M1, 2) bilateral stimulation, whereby anodal-tDCS was applied over the non-dominant M1, and cathodal-tDCS over the dominant M1, and 3) sham stimulation. Transcranial magnetic stimulation (TMS) was performed before, immediately after, 30 and 60 minutes after stimulation to elucidate the neural mechanisms underlying any potential after-effects on motor performance. Motor function was evaluated by the Purdue pegboard test. There were significant improvements in motor function following unilateral and bilateral stimulation when compared to sham stimulation at all-time points (all P < 0.05); however there was no difference across time points between unilateral and bilateral stimulation. There was also a similar significant increase in corticomotor excitability with both unilateral and bilateral stimulation immediately post, 30 minutes and 60 minutes compared to sham stimulation (all P < 0.05). Unilateral and bilateral stimulation reduced short-interval intracortical inhibition (SICI) immediately post and at 30 minutes (all P < 0.05), but returned to baseline in both conditions at 60 minutes. There was no difference between unilateral and bilateral stimulation for SICI (P > 0.05). Furthermore, changes in corticomotor plasticity were not related to changes in motor performance. These results indicate that tDCS induced behavioural changes in the non-dominant hand as a consequence of mechanisms associated with use-dependant cortical plasticity that is independent of the electrode arrangement.


Health disparities in the forensic sexual assault examination related to skin color.
Little is known about the role of skin color in the forensic sexual assault examination. The purpose of this study was to determine whether anogenital injury prevalence and frequency vary by skin color in women after consensual sexual intercourse. The sample consisted of 120 healthy (63 Black, 57 White) women who underwent a forensic sexual assault examination following consensual sexual intercourse. Experienced sexual assault forensic examiners using visual inspection, colposcopy technique with digital imaging, and toluidine blue application documented the number, type, and location of anogenital injuries. Although 55% of the total sample was observed to have at least one anogenital injury of any type following consensual intercourse, the percentages significantly differed for White (68%) and Black (43%) participants (p= 0.02). When the presence of anogenital injury was analyzed by specific anatomical region, a significant difference between White and Black participants was only evident for the external genitalia (White = 56%, Black = 24%, p= .003), but not for the internal genitalia (White = 28%, Black = 19%, p= .20) or anus (White = 9%, Black = 10%, p= 0.99). A one standard deviation-unit increase in L* values (lightness) was related to a 150% to 250% increase in the odds of external genitalia injury prevalence (p < 0.001). While Black and White participants had a significantly different genital injury prevalence, dark skin color rather than race was a strong predictor for decreased injury prevalence. Sexual assault forensic examiners, therefore, may not be able to detect injury in women with dark skin as readily as women with light skin, leading to health disparities for women with dark skin.


Dimensional changes after immediate implant placement with or without simultaneous regenerative procedures: a systematic review and meta-analysis.
To analyse alveolar ridge volume changes after immediate implant placement, with or without a regenerative technique. Studies investigating the effect of immediate implant placement on ridge dimensional changes were identified through an electronic search conducted using MEDLINE (PubMed) and EMBASE. Weighted mean changes (WMC) between baseline and follow-up time were calculated and subgroup analysis was performed according to study design, evaluation method and regenerative strategies. After immediate implant placement alone WMC of RCTs showed a loss in width and height of 1.1 mm. After flapless immediate implant placement with immediate provisionalization and a graft WMC showed a loss in width and height of 1.02 mm and 0.79 mm, while after flapped immediate implant placement and a graft WMC showed a gain of 1.79 mm. After immediate implant placement plus a non-resorbable membrane WMC showed a loss in height of 0.07 mm. After immediate implant placement plus a resorbable membrane and a graft WMC showed a gain in height of 1.09 mm. Immediate implant placement does not seem to counteract alveolar ridge modelling after tooth extraction. Furthermore, the currently available evidence does not allow for any conclusive statements regarding the efficacy of a concomitant regenerative technique in preventing the amount of alveolar reduction.


Synchrotron-based micro-CT imaging of the human lung acinus.
Structural data about the human lung fine structure are mainly based on stereological methods applied to serial sections. As these methods utilize 2D images, which are often not contiguous, they suffer from inaccuracies which are overcome by analysis of 3D micro-CT images of the never-sectioned specimen. The purpose of our study was to generate a complete data set of the intact three-dimensional architecture of the human acinus using high-resolution synchrotron-based micro-CT (synMCT). A human lung was inflation-fixed by formaldehyde ventilation and then scanned in a 64-slice CT over its apex to base extent. Lung samples (8-mm diameter, 10-mm height, N = 12) were punched out, stained with osmium tetroxide, and scanned using synMCT at (4 μm)(3) voxel size. The lung functional unit (acinus, N = 8) was segmented from the 3D tomographic image using an automated tree-analysis software program. Morphometric data of the lung were analyzed by ANOVA. Intra-acinar airways branching occurred over 11 generations. The mean acinar volume was 131.3 ± 29.2 mm(3) (range, 92.5-171.3 mm(3)) and the mean acinar surface was calculated with 1012 ± 26 cm(2). The airway internal diameter (starting from the bronchiolus terminalis) decreases distally from 0.66 ± 0.04 mm to 0.34 ± 0.06 mm (P < 0.001) and remains constant after the seventh generation (P < 0.5). The length of each generation ranges between 0.52 and 0.93 mm and did not show significant differences between the second and eleventh generation. The branching angle between daughter branches varies between 113-degree and 134-degree without significant differences between the generations (P < 0.3). This study demonstrates the feasibility of quantitating the 3D structure of the human acinus at the spatial resolution readily achievable using synMCT.


Propolis suppresses CdCl₂-induced cytotoxicity of COS7 cells through the prevention of intracellular reactive oxygen species accumulation.
Propolis is a natural product made by honeybees and contains various compounds, including flavonoids, amino acids and fatty acids. These compounds are considered to have antiviral, antibacterial and antioxidative properties. On the other hand, cadmium (Cd), an industrial and environmental pollutant, preferentially accumulates in the kidney and induces kidney injury. We previously reported that exposure to CdCl₂ induced cell death though intracellular reactive oxygen species (ROS) generation in kidney tubule epithelial COS7 cells. Here, we investigated whether propolis extracts suppress CdCl₂-induced cytotoxicity. Predictably, pretreatment with propolis extracts significantly suppressed CdCl₂-induced cytotoxicity and intracellular ROS generation. Propolis extracts not only showed superoxide dismutase and antioxidative activities, but also increased the expression of heme oxygenase-1 (HO-1), an antioxidative enzyme. Moreover, we determined the involvement of hypoxia inducible factor-1α in propolis extract-derived HO-1 induction. We demonstrate for the first time the utility of propolis for Cd-related COS7 cytotoxicity, and these novel findings are considered to contribute to the control of ROS-derived disorders.


Regulation of pain sensitivity in experimental osteoarthritis by the endogenous peripheral opioid system.
OA is the most common joint disease, affecting 10-15% of people over 60 years of age. However, up to 40% of individuals with radiologic damage are asymptomatic. The purpose of this study was to assess the role of the endogenous opioid system in delaying the onset of pain in a murine model of osteoarthritis (OA). Osteoarthritis was induced by transection of the medial meniscotibial ligament. Pain was assessed by monitoring weight distribution and activity. At various times postsurgery, the opioid receptor antagonists naloxone or peripherally restricted naloxone methiodide were administered, and pain was assessed. Levels of the micro-opioid receptor were assessed in the nerves innervating the joint by real-time reverse transcription-polymerase chain reaction analysis. As in human disease, significant joint damage occurred in mice before the onset of pain. To assess whether delayed pain was partly the result of increased endogenous opioid function, naloxone or naloxone methiodide was administered. Both opioid receptor antagonists led to pain onset 4 weeks earlier than in vehicle-treated mice, indicating a role of the peripheral opioid system in masking OA pain. The expression of the micro-opioid receptor in the peripheral nerves supplying the joint was transiently increased in naloxone-responsive mice. These findings indicate that a temporal induction of micro-opioid receptors in the early stages of OA delays the onset of pain. This is of clinical relevance and may contribute to the assessment of patients presenting with pain late in the disease. Furthermore, it may point to a mechanism by which the body blocks pain perception in moderate states of tissue damage, allowing an increased chance of survival.


Primary epithelial splenic cyst with micro-rupture and raised carbohydrate antigen CA 19-9: a paradigm of management.
Epithelial splenic cysts are rare entities which surgeons may not have previously encountered. Their management is based on historical studies. A 21-year-old woman presented with a cyst of the spleen that produced a high serum concentration of carbohydrate antigen CA 19-9. A partial splenectomy with removal of the entire cyst and preservation of the splenic parenchyma by laparotomy was performed and the patient made an uneventful recovery. A microscopic rupture of the wall of the cyst and blood degradation products in the fluid of the cyst were confirmed. A functional splenic parenchyma was documented 18 months after surgery. There was no infection during follow-up. Partial surgical splenectomy with resection of the entire cyst prevents recurrence and preserves splenic function.


Learning Adaptive Discriminative Correlation Filters via Temporal Consistency Preserving Spatial Feature Selection for Robust Visual Object Tracking.
With efficient appearance learning models, discriminative correlation filter (DCF) has been proven to be very successful in recent video object tracking benchmarks and competitions. However, the existing DCF paradigm suffers from two major issues, i.e., spatial boundary effect and temporal filter degradation. To mitigate these challenges, we propose a new DCF-based tracking method. The key innovations of the proposed method include adaptive spatial feature selection and temporal consistent constraints, with which the new tracker enables joint spatial-temporal filter learning in a lower dimensional discriminative manifold. More specifically, we apply structured spatial sparsity constraints to multi-channel filters. Consequently, the process of learning spatial filters can be approximated by the lasso regularization. To encourage temporal consistency, the filter model is restricted to lie around its historical value and updated locally to preserve the global structure in the manifold. Last, a unified optimization framework is proposed to jointly select temporal consistency preserving spatial features and learn discriminative filters with the augmented Lagrangian method. Qualitative and quantitative evaluations have been conducted on a number of well-known benchmarking datasets such as OTB2013, OTB50, OTB100, Temple-Colour, UAV123, and VOT2018. The experimental results demonstrate the superiority of the proposed method over the state-of-the-art approaches.


Analysis of genetic diversity of rapeseed genetic resources in Japan and core collection construction.
Diversity analysis of rapeseed accessions preserved in the Japanese Genebank can provide valuable information for breeding programs. In this study, 582 accessions were genotyped with 30 SSR markers covering all 19 rapeseed chromosomes. These markers amplified 311 alleles (10.37 alleles per marker; range, 3-39). The genetic diversity of Japanese accessions was lower than that of overseas accessions. Analysis of molecular variance indicated significant genetic differentiation between Japanese and overseas accessions. Small but significant differences were found among geographical groups in Japan, and genetic differentiation tended to increase with geographical distance. STRUCTURE analysis indicated the presence of two main genetic clusters in the NARO rapeseed collection. With the membership probabilities threshold, 227 accessions mostly originating from overseas were assigned to one subgroup, and 276 accessions mostly originating from Japan were assigned to the other subgroup. The remaining 79 accessions are assigned to admixed group. The core collection constructed comprises 96 accessions of diverse origin. It represents the whole collection well and thus it may be useful for rapeseed genetic research and breeding programs. The core collection improves the efficiency of management, evaluation, and utilization of genetic resources.


Aromatic abietane diterpenoids: their biological activity and synthesis.
In this study, the biological properties of natural abietane-type diterpenoids with an aromatic C ring are reviewed. An overview of the synthetic studies of this group of abietanes, including dehydroabietic acid, callitrisic acid and ferruginol, is presented. The review contains about 160 references.


Design Requirements for Annulus Fibrosus Repair: Review of Forces, Displacements, and Material Properties of the Intervertebral Disk and a Summary of Candidate Hydrogels for Repair.
There is currently a lack of clinically available solutions to restore functionality to the intervertebral disk (IVD) following herniation injury to the annulus fibrosus (AF). Microdiscectomy is a commonly performed surgical procedure to alleviate pain caused by herniation; however, AF defects remain and can lead to accelerated degeneration and painful conditions. Currently available AF closure techniques do not restore mechanical functionality or promote tissue regeneration, and have risk of reherniation. This review determined quantitative design requirements for AF repair materials and summarized currently available hydrogels capable of meeting these design requirements by using a series of systematic PubMed database searches to yield 1500+ papers that were screened and analyzed for relevance to human lumbar in vivo measurements, motion segment behaviors, and tissue level properties. We propose a testing paradigm involving screening tests as well as more involved in situ and in vivo validation tests to efficiently identify promising biomaterials for AF repair. We suggest that successful materials must have high adhesion strength (∼0.2 MPa), match as many AF material properties as possible (e.g., approximately 1 MPa, 0. 3 MPa, and 30 MPa for compressive, shear, and tensile moduli, respectively), and have high tensile failure strain (∼65%) to advance to in situ and in vivo validation tests. While many biomaterials exist for AF repair, few undergo extensive mechanical characterization. A few hydrogels show promise for AF repair since they can match at least one material property of the AF while also adhering to AF tissue and are capable of easy implantation during surgical procedures to warrant additional optimization and validation.


ACG practice guidelines: esophageal reflux testing.
Investigations and technical advances have enhanced our understanding and management of gastroesophageal reflux disease. The recognition of the prevalence and importance of patients with endoscopy-negative reflux disease as well as those refractory to proton pump inhibitor therapy have led to an increasing need for objective tests of esophageal reflux. Guidelines for esophageal reflux testing are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the Board of Trustees. Issues regarding the utilization of conventional, catheter-based pH monitoring are discussed. Improvements in the interpretation of esophageal pH recordings through the use of symptom-reflux association analyses as well as limitations gleaned from recent studies are reviewed. The clinical utility of pH recordings in the proximal esophagus and stomach is examined. Newly introduced techniques of duodenogastroesophageal reflux, wireless pH capsule monitoring and esophageal impedance testing are assessed and put into the context of traditional methodology. Finally, recommendations on the clinical applications of esophageal reflux testing are presented.


Why sleep is important for health: a psychoneuroimmunology perspective.
Sleep has a critical role in promoting health. Research over the past decade has documented that sleep disturbance has a powerful influence on the risk of infectious disease, the occurrence and progression of several major medical illnesses including cardiovascular disease and cancer, and the incidence of depression. Increasingly, the field has focused on identifying the biological mechanisms underlying these effects. This review highlights the impact of sleep on adaptive and innate immunity, with consideration of the dynamics of sleep disturbance, sleep restriction, and insomnia on (a) antiviral immune responses with consequences for vaccine responses and infectious disease risk and (b) proinflammatory immune responses with implications for cardiovascular disease, cancer, and depression. This review also discusses the neuroendocrine and autonomic neural underpinnings linking sleep disturbance and immunity and the reciprocal links between sleep and inflammatory biology. Finally, interventions are discussed as effective strategies to improve sleep, and potential opportunities are identified to promote sleep health for therapeutic control of chronic infectious, inflammatory, and neuropsychiatric diseases.


Learning from the parallel pathways of Makers to broaden pathways to engineering.
Makers are a growing community of STEM-minded people who bridge technical and non-technical backgrounds to imagine, build and fabricate engineering systems. Some have engineering training, some do not. This paper presents a study to explore the educational pathways of adult Makers and how they intersect with engineering. This research is guided by the following research questions: (1) What can we learn about the educational pathways of adult Makers through the lens of constructivist grounded theory? and (2) How do the educational pathways of Makers intersect with engineering? This study relied on qualitative interviews, using artifact elicitation interviews and constructivist critical incident technique interviews, of 42 adult Makers. Through inductive analysis of a collection of interviews with Makers, a theme emerged where Makers from different educational backgrounds and with different careers (e.g., art, STEM, business) were making artifacts that had similar purposes. We present two cases of parallel pathways, (1) musical artifacts and (2) large-scale interactive artifacts, to demonstrate the multiple, parallel life pathways that Makers take to making their artifacts and the contextual events and activities that are critical to the direction of these pathways. The stories and life pathways of adult learners engaged in Making can offer valuable insight into how we might identify practices that promote the access and success of a larger and more diverse population of students for engineering. Makers are engaged in activities that embody the Engineer of 2020 (e.g., lifelong learning, creativity, and practical ingenuity). By studying Makers, we can consider the multiplicity of pathways into engineering majors and careers.


In Vitro and in Vivo Study of the Effect of Osteogenic Pulsed Electromagnetic Fields on Breast and Lung Cancer Cells.
Introduction: Although there have been significant advances in research and treatments over the past decades, cancer remains a leading cause of morbidity and mortality, mostly due to resistance to standard therapies. Pulsed electromagnetic field (PEMF), a newly emerged therapeutic strategy, has been highly regarded as less invasive and almost safe to patients, is now a clinically accepted form to treat diseases including cancer. Breast and lung cancer are the most prevalent forms of human cancers, yet reported investigations on exploring regimes including PEMF are limited. Methods: Intended to examine the anti-tumor effects of a clinically accepted osteogenic PEMF and the possibility of including PEMF in breast and lung cancer treatments, we studied the effects of 2 PEMF signals (PMF1 and PMF2) on breast and lung cancer cell growth and proliferation, as well as the possible underline mechanisms in vitro and in vivo. Results: We found that both signals caused modest but significant growth inhibition (∼5%) in MCF-7 and A549 cancer cells. Interestingly, mice xenograft tumors with A549 cells treated by PEMF were smaller in sizes than controls. However, for mice with MCF-7 tumor implants, treatment with PMF1 resulted in a slight increase (2.8%) in mean tumor size, while PMF2 treated tumors showed a 9% reduction in average size. Furthermore, PEMF increased caspase 3/7 expression levels and percentage of annexin stained cells, indicating the induction of apoptosis. It also increased G0 by 8.5%, caused changes in the expression of genes associated with cell growth suppression, DNA damage, cell cycle arrest, and apoptosis. When cancer cells or xenograft tumors treated with combined PEMF and chemotherapy drugs, PEMF showed growth inhibition effect independent of cisplatin in A549 cells, but with added effect by pemetrexed for the inhibition of MCF-7 growth. Conclusion: Together, our data suggested that clinically used osteogenic PEMF signals moderately suppressed cancer cell growth and proliferation both in vitro and in vivo.


Training and experience of nurses in responding to alcohol misuse in rural communities.
Alcohol misuse by farmers continues to challenge rural nurses. This article reports on the experiences of Australian nurses participating in the Alcohol Intervention Training Program (AITP). Qualitative interviews of 15 rural and remote nurses. Semi-structured phone interviews were utilized to assess the response to and implementation of the AITP-an intervention designed to build nurses' knowledge, confidence and skills when responding to alcohol misuse. It comprises practical and theoretical components and was designed for rural and remote settings where nurses encounter alcohol misuse. Nurses found the training provided new-or built on existing-knowledge of alcohol misuse and offered practical hands-on "real life" skills. A range of workplace and personal situations where the content of the training was now being utilized were identified, and future use anticipated. Barriers to using the new knowledge and skills included both rural and generic issues. Constructive feedback to increasingly target the training to rural settings was recommended. The AITP is an effective training program. It can be further tailored to meet common needs of rural and remote nurses working with farmers who misuse alcohol, while recognizing diversity in rural practice.


Is perfect good? A meta-analysis of perfectionism in the workplace.
Although the concept of perfectionism is familiar to most people, its relationships with organizationally relevant variables remain unclear because of the dispersed and multidisciplinary nature of extant research. The state of the literature is particularly concerning given the likely widespread influence perfectionism has on individuals' workplace attitudes and behaviors. Moreover, research in multiple disciplines of psychology has revealed the phenomenon of perfectionism to be multidimensional. In addition, the totality of effects surrounding perfectionism remains unclear as perfectionism carries both benefits as well as consequences for employees and organizations. To cogently synthesize and empirically disentangle the possible differential effects associated with perfectionism at work, the authors conducted a meta-analysis of perfectionism and work-related antecedents and outcomes. The resulting qualitative and quantitative review reveals perfectionism to have sizable and consistent relationships with several organizationally relevant factors but an equivocal overall relationship with job performance. The authors provide a theoretical and empirical overview of the state of the literature and suggest avenues for future research that may facilitate better integration of perfectionism into organizational research. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Salvage of distal tibia metaphyseal nonunions with the 90 degrees cannulated blade plate.
Nonunion of distal tibia metaphyseal fractures after trauma is a major problem. Treating these nonunions is made more challenging by the presence of symptomatic ipsilateral tibiotalar arthrosis. The current study examined the use of the 90 degrees cannulated blade plate as an alternative method of stable internal fixation for 13 distal tibia metaphyseal nonunions and simultaneous fusion of three arthritic tibiotalar joints in 13 patients (seven males and six females) with an average age of 42.4 years (range, 21-73 years). Each patient had an average of three prior procedures (range, 2-6). Patients were followed up for an average of 34.2 months (range, 24-55 months). All 13 patients achieved radiographic and clinical union an average of 15.6 weeks (range, 12-20 weeks) from the date of the definitive procedure. There were two broken screws, but no secondary procedures were required to obtain fusion. All patients were ambulatory without support at the last followup. The implant proved effective for stable internal fixation of distal tibia metaphyseal nonunions alone or with simultaneous fusion of the tibiotalar joint.


Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift.
This paper describes a new program SnpSift for filtering differential DNA sequence variants between two or more experimental genomes after genotoxic chemical exposure. Here, we illustrate how SnpSift can be used to identify candidate phenotype-relevant variants including single nucleotide polymorphisms, multiple nucleotide polymorphisms, insertions, and deletions (InDels) in mutant strains isolated from genome-wide chemical mutagenesis of Drosophila melanogaster. First, the genomes of two independently isolated mutant fly strains that are allelic for a novel recessive male-sterile locus generated by genotoxic chemical exposure were sequenced using the Illumina next-generation DNA sequencer to obtain 20- to 29-fold coverage of the euchromatic sequences. The sequencing reads were processed and variants were called using standard bioinformatic tools. Next, SnpEff was used to annotate all sequence variants and their potential mutational effects on associated genes. Then, SnpSift was used to filter and select differential variants that potentially disrupt a common gene in the two allelic mutant strains. The potential causative DNA lesions were partially validated by capillary sequencing of polymerase chain reaction-amplified DNA in the genetic interval as defined by meiotic mapping and deletions that remove defined regions of the chromosome. Of the five candidate genes located in the genetic interval, the Pka-like gene CG12069 was found to carry a separate pre-mature stop codon mutation in each of the two allelic mutants whereas the other four candidate genes within the interval have wild-type sequences. The Pka-like gene is therefore a strong candidate gene for the male-sterile locus. These results demonstrate that combining SnpEff and SnpSift can expedite the identification of candidate phenotype-causative mutations in chemically mutagenized Drosophila strains. This technique can also be used to characterize the variety of mutations generated by genotoxic chemicals.


Association between Body Mass Index and Gestational Weight Gain with Obstetric and Neonatal Complications in Pregnant Women with Gestational Diabetes.
Gestational diabetes is a condition that predisposes to complications during pregnancy and to the newborn. The aim of this study was to assess the association between body mass index and gestational weight gain and obstetric and neonatal complications in pregnant women with gestational diabetes. Retrospective cohort study involving 13 467 singleton pregnancies with gestational diabetes, diagnosed between 2014 and 2018, in Portugal. This sample was distributed according to the World Health Organization body mass index categories (underweight, normal, overweight, or obese) and according to the Institute of Medicine guidelines for gestational weight gain groups (adequate, insufficient, or excessive). Binomial and multinomial logistic regression models were applied to determine risk factors for complications in pregnant women with gestational diabetes. Data analysis was performed with SPSS version 25. Pregestational overweight and obesity were associated with an increased risk of maternal morbidity (aOR: 1.31; aOR: 2.42), gestational hypertension (aOR: 1.56; aOR: 2.79) and caesarean section (aOR: 1.22; aOR: 1.77) whilst reducing the risk for small for gestational age [aOR: 0.73; aOR: 0.64 (Fenton chart); aOR: 0.69; aOR: 0.66 (Portuguese chart)]. Obesity alone was associated with increased preeclampsia events (aOR: 3.05), respiratory distress syndrome (aOR: 1.69), admission to neonatal intensive care unit (aOR: 1.54), macrosomia (aOR: 2.18), and large for gestational age [aOR: 2.03 (Fenton); aOR: 1.87 (Portuguese)] and decreased risk of low birthweight newborns (aOR: 0.62). Insufficient gestational weight gain was associated with a decreased risk of gestational hypertension (aOR: 0.69), preeclampsia (aOR: 0.44), Caesarean section (aOR: 0.81) and large for gestational age [aOR: 0.74 (Portuguese)] and increased risk of low birthweight (aOR: 1.36) and small for gestational age [aOR: 1.40 (Fenton)]. Excessive gestational weight gain was associated with increased risk of gestational hypertension (aOR: 1.53), hydramnios (aOR: 2.05), macrosomia (aOR: 2.02), and large for gestational age [aOR: 1.94 (Fenton); aOR: 1.92 (Portuguese)]. Pregestational overweight and obesity, as well as excessive weight gain are associated with an increased risk of certain obstetric and neonatal complications. It is essential to have an appropriate pre- onceptional surveillance and a close follow-up during pregnancy in order to reduce the associated risks and the probable predisposition of these newborns to severe outcomes.


Heparin protects human endothelial cells infected by Rickettsia rickettsii.
Routine culture of endothelial cells currently includes the use of heparin, which significantly reduces cell doubling time and increases cell population size. Heparin protects cultured arterial endothelial cells from damage by toxic oxygen metabolites produced by the action of xanthine and xanthine oxidase. Because of our hypothesis implicating free radicals in cell injury caused by Rickettsia rickettsii, we have carried out a series of experiments to examine the effects of heparin on injury to endothelial cells infected by this microorganism. These studies showed that heparin does not inhibit replication of R. rickettsii in the cytoplasm of endothelial cells. Furthermore, heparin appears to exhibit a protective effect on the infected host cell as measured by (i) reduced plaque size, (ii) increased longevity of the cell monolayer, (iii) reduction in the amount of lactic dehydrogenase released from infected cells, and (iv) reduction in the levels of intracellular peroxides formed in infected cells. Electron microscopic studies also show a significant reduction in dilatation of the rough-surfaced endoplasmic reticulum of the infected cells in the presence of heparin. These observations appear to lend additional support to involvement of an oxidative mechanism in human endothelial cell injury caused by R. rickettsii.


Bombesin, vasopressin, and endothelin rapidly stimulate tyrosine phosphorylation in intact Swiss 3T3 cells.
The mitogenic neuropeptides bombesin and vasopressin markedly increased tyrosine and serine phosphorylation of multiple substrates in quiescent Swiss 3T3 fibroblasts, including two major bands of Mr 90,000 and 115,000. Tyrosine phosphorylation of these proteins was increased as judged by immunoprecipitation of 32Pi-labeled cells and immunoblotting of unlabeled cells with monoclonal antiphosphotyrosine antibodies, elution with phenyl phosphate, and phospho amino acid analysis. Phosphotyrosyl proteins generated by bombesin and vasopressin did not correspond either by apparent molecular weight or by immunological and biochemical criteria to several known tyrosine kinase substrates, including phospholipase C gamma, the microtubule-associated protein 2 kinase, GTPase-activating protein, or phosphatidylinositol kinase. The effect was rapid (within seconds), concentration dependent, and inhibited by specific receptor antagonists for both bombesin and vasopressin. The endothelin-related peptide, vasoactive intestinal contractor, also elicited a rapid and concentration-dependent tyrosine/serine phosphorylation of a similar set of substrates. These results demonstrate that neuropeptides, acting through receptors linked to GTP-binding proteins, stimulate tyrosine phosphorylation of a common set of substrates in quiescent Swiss 3T3 cells and suggest the existence of an additional signal transduction pathway in neuropeptide-induced mitogenesis.


Inhibitory effects of a luteinizing hormone-releasing hormone agonist on basal and epidermal growth factor-induced cell proliferation and metastasis-associated properties in human epidermoid carcinoma A431 cells.
The purpose of this study was to investigate the effects of a potent LHRH agonist, [D-Trp(6)]LHRH on the basal and EGF-induced cell proliferation and the metastasis-associated properties in A431 human epidermoid carcinoma. [D-Trp(6)]LHRH time-dependently inhibited the basal and EGF-stimulated growth of A431 cancer cells. It is assumed that phosphorylation/dephosphorylation of cellular proteins is highly related to cell growth. This study demonstrates that [D-Trp(6)]LHRH decreased the basal and EGF-induced total cellular kinase activity, particularly the tyrosine phosphorylation of several cellular proteins including the EGFR. In contrast, [D-Trp(6)]LHRH did not cause detectable changes in basal and EGF-stimulated serine/threonine phosphorylation of A431 cellular proteins. The inhibitory effect of [D-Trp(6)]LHRH on A431 cell proliferation was associated with apoptosis as evidenced by the cell morphology and DNA integrity (ladder pattern), the expression of interleukin 1beta-converting enzyme (ICE) and activation of caspase. Furthermore, EGF could rescue the remaining attached A431 cells following [D-Trp(6)]LHRH treatment for 48 hr, which suggests that limited exposure to [D-Trp(6)]LHRH did not channel all cells to irreversible apoptotic process. We also determined the effects of [D-Trp(6)]LHRH on metastasis-associated properties in A431 cells. [D-Trp(6)]LHRH reduced both basal and EGF-stimulated secretion of MMP-9 and MMP-2. In addition, [D-Trp(6)]LHRH suppressed the basal and EGF-induced invasive activity of A431 cells based on an in vitro invasion assay. In conclusion, this study indicates that [D-Trp(6)]LHRH may act partly through activating tyrosine phosphatase activity to inhibit cell proliferation and the metastasis-associated properties of A431 cancer cells. Our work suggests that [D-Trp(6)]LHRH may be therapeutically useful in limiting the tumor growth and metastasis of some neoplasms.


Preoperative multimodal prehabilitation before elective colorectal cancer surgery in patients with WHO performance status I or II: randomized clinical trial.
Multimodal prehabilitation is a promising adjunct to the current surgical treatment pathway for colorectal cancer patients to further improve postoperative outcomes, especially for high-risk patients with low functional capacity. The aim of the present study was to test the effect of prehabilitation on immediate postoperative recovery. The study was designed as a RCT with two arms (intervention and control). The intervention consisted of 4 weeks of multimodal prehabilitation, with supervised physical training, nutritional support and medical optimization. The control group received standard of care. A total of 40 patients with colorectal cancer (WHO performance status I or II) undergoing elective surgery with curative intent were included. The primary outcome was postoperative recovery within the first 3 postoperative days, measured by Quality of Recovery-15, a validated questionnaire with a scoring range between 0 and 150 and a minimal clinically relevant difference of 8. In total, 36 patients were analysed with 16 in the intervention group and 20 in the control group. The mean age of the included patients was 79 years. The overall treatment effect associated with the intervention was a 21.9 (95% c.i. 4.5-39.3) higher quality of recovery-15 score during the first 3 postoperative days compared to control, well above the minimal clinically relevant difference. Four weeks of multimodal prehabilitation prior to elective curative intended colorectal cancer surgery in patients with WHO performance status I or II was associated with a clinically relevant improvement in postoperative recovery.Registration number: NCT04167436 (http://www.clinicaltrials.gov).


Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential.
Glucagon-like peptide-1 (GLP-1) is an intestinally derived insulinotropic hormone currently under investigation for use as a novel therapeutic agent in the treatment of type 2 diabetes. One of several important effects of GLP-1 is on nutrient-induced pancreatic hormone release and is mediated by binding to a specific G-protein coupled receptor resulting in the activation of adenylate cyclase and an increase in cAMP generation. In the beta-cell, cAMP binds and modulates activities of both protein kinase A and cAMP-regulated guanine nucleotide exchange factor II, thereby enhancing glucose-dependent insulin secretion. The stimulatory action of GLP-1 on insulin secretion involves interaction with a plethora of signal transduction processes including ion channel activity, intracellular Ca(2+) handling and exocytosis of the insulin-containing granules. In this review we focus principally on recent advances in our understanding on the cellular mechanisms proposed to underlie GLP-1's insulinotropic effect and attempt to incorporate this knowledge into a working model for the control of insulin secretion. Lastly, this review discusses the applicability of GLP-1 as a therapeutic agent for the treatment of type 2 diabetes.


Thyroid papillary microcarcinoma: a descriptive and meta-analysis study.
The authors review anatomical, clinical characteristics and prevalence of thyroid microcarcinoma. Diagnostic procedures and risk factors of aggressiveness at diagnosis and during follow-up are also covered. The possible clinical, pathologic and therapeutic risk factors are analyzed by meta-analysis study. Treatment procedures by different authors and guidelines suggested by societies are reported.


Antagonistic effects of Plasmodium-helminth co-infections on malaria pathology in different population groups in Côte d'Ivoire.
Plasmodium spp. and helminths are co-endemic in many parts of the tropics; hence, co-infection is a common phenomenon. Interactions between Plasmodium and helminth infections may alter the host's immune response and susceptibility and thus impact on morbidity. There is little information on the direction and magnitude of such interactions and results are conflicting. This study aimed at shedding new light on the potential interactions of Plasmodium and helminth co-infections on anemia and splenomegaly in different population groups in Côte d'Ivoire. Parasitologic and clinical data were obtained from four cross-sectional community-based studies and a national school-based survey conducted between 2011 and 2013 in Côte d'Ivoire. Six scenarios of co-infection pairs defined as Plasmodium infection or high parasitemia, combined with one of three common helminth infections (i.e., Schistosoma mansoni, S. haematobium, and hookworm) served for analysis. Adjusted logistic regression models were built for each scenario and interaction measures on additive scale calculated according to Rothman et al., while an interaction term in the model served as multiplicative scale measure. All identified significant interactions were of antagonistic nature but varied in magnitude and species combination. In study participants aged 5-18 years from community-based studies, Plasmodium-hookworm co-infection showed an antagonistic interaction on additive scale on splenomegaly, while Plasmodium-Schistosoma co-infection scenarios showed protective effects on multiplicative scale for anemia and splenomegaly in participants aged 5-16 years from a school-based study. No exacerbation from co-infection with Plasmodium and helminths was observed, neither in participants aged 5-18 years nor in adults from the community-based studies. Future studies should unravel underlying mechanisms of the observed interactions, as this knowledge might help shaping control efforts against these diseases of poverty.


Complement-associated deposits in the human retina.
The purpose of this study was to investigate complement activation and associated inflammatory mechanisms in normal, aged human retina. Evidence of complement activation and associated mechanisms was assessed in normal human retina (n = 52) using a panel of antibodies directed against membrane attack complex (C5b-9), microglia (CD11b), amyloid precursor protein (APP), scavenger receptor (CD36), and a phytolectin (RCA-I). Fifty-two eyes, categorized into two age groups, were used. Nineteen "younger" eyes (<56 years) and 33 "older" eyes (>69 years) with no history of ocular disease were processed between 4 and 22 hours, with a median delay of 14 hours postmortem. Age-dependent expression was evident in C5b-9, APP, CD11b, and RCA-I, but not CD36, immunoreactivity. Immunoreactivity for C5b-9 was robust in Bruch membrane (BM) and the intercapillary pillars of Bruch. Immunoreactivity for APP was robust in the basal cytoplasm of the retinal pigment epithelium. Immunoreactivity for CD11b was robust on the surface of the retinal pigment epithelial cell, in the choriocapillaris, and in BM. Lectin binding of RCA-I was strong throughout the neuroretina. Robust immunostaining for APP in older donor eyes suggested that amyloid beta peptides may be one of the triggers of complement activation during the normal aging process. Microglial markers CD11b and RCA-I also increase with age, suggesting a concomitant inflammatory response to C5b-9 deposits in the retinal pigment epithelium, BM, and CC. Immunoreactivity for CD36 was strong in both age groups; the lack of age dependence in this candidate receptor for amyloid beta suggested that complement activation may arise from interactions of amyloid beta with other candidate receptors in normal human retina.


Sever's injury: treatment with insoles provides effective pain relief.
Sever's injury (apophysitis calcanei) is considered to be the dominant cause of heel pain among children between 8 and 15 years. The traditional advice is to reduce and modify the level of physical activity. Recommended treatment in general is the same as for adults with Achilles tendon pain. The purpose of the study was to find out if insoles, of two different types, were effective in relieving heel pain in a group of boys (n=38) attending a Sports Medicine Clinic for heel pain diagnosed as Sever's injury. The type of insole was randomized, and self-assessed pain during physical activity in the treatment phase with insoles was compared with pain in the corresponding pre- and post-treatment phases without insoles. There were no other treatments added and the recommendations were to stay on the same activity level. All patients maintained their high level of physical activity throughout the study period. Significant pain reduction during physical activity when using insoles was found. Application of two different types of insoles without any immobilization, other treatment, or modification of sport activities results in significant pain relief in boys with Sever's injury.


The difficult relationship between occlusal interferences and temporomandibular disorder - insights from animal and human experimental studies.
The aetiology of temporomandibular disorder (TMD) is multifactorial, and numerous studies have addressed that occlusion may be of great importance. However, whether occlusion plays a crucial role in the pathogenesis of TMD remains controversial. Study designs utilising animal models have been used to study the effects of artificial occlusal alterations. Experimental traumatic occlusion affects blood flow in the temporomandibular joint and results in changes in the condylar cartilage, and artificial occlusal interference induces masticatory muscle nociceptive responses that are associated with peripheral sensitisation and lead to central sensitisation, which maintains masticatory muscle hyperalgesia. The possibility that occlusal interference results in TMD has been investigated in humans using a double-blind randomised design. Subjects without a history of TMD show fairly good adaptation to interferences. In contrast, subjects with a history of TMD develop a significant increase in clinical signs and self-report stronger symptoms (occlusal discomfort and chewing difficulties) in response to interferences. Meanwhile, psychological factors appear meaningful for symptomatic responses to artificial interferences in subjects with a history of TMD. Thus, individual differences in vulnerability to occlusal interferences do exist. Although there are advantages and disadvantages to using human and animal occlusal interference models, these approaches are indispensable for discovering the role of occlusion in TMD pathogenesis.


[Population research on ischemic heart disease in middle-aged men in Tashkent].
Prophylactic examination of a random representative sample of the male population aged 40-59 in one of the administrative districts of Tashkent using unified diagnostic methods showed a high CHD prevalence. During examination of 2405 persons (80% of those invited) CHD was revealed in 10.8% of the cases, 9.5% of this rate in the indigenous population. The history of myocardial infarction (MI) was noted in 1.5% of the examined persons, angina of effort (without MI) in 4.4%, a painless form of CHD (based on ECD changes) in 4.9%. A 4.6-year follow-up revealed high mortality among CHD patients diagnosed according to epidemiological criteria, particularly with the history of MI. Mortality rates from MI among males aged 40-59 were 4 per 1000 of population annually. The study showed a necessity to improve methods of secondary prevention of CHD under out-patient conditions.


[Histiocytoid cardiomyopathy in an infant].
We present a description of a clinical observation of a histiocytoid cardiomyopathy in a female patient aged 4 months. This pathology is rare in pediatric cardiology. Its etiology is linked with mutation of the gene encoding mitochondrial cytochrome B (mitochondrial transport of electrons). This mutation leads to a specific morphological and functional abnormalities of cardiomyocytes. Purkinje cells and cells of conduction system at microscopy appear as histiocytolike foam cells cytoplasm of which contain large amount of lipids and glycogen. Girls prevail among those affected. The case reflects clinical picture characteristic for this nosology: malignant arrhythmia and cardiomegaly with fatal outcome.


Sendai virus M protein binds independently to either the F or the HN glycoprotein in vivo.
We have analyzed the mechanism by which M protein interacts with components of the viral envelope during Sendai virus assembly. Using recombinant vaccinia viruses to selectively express combinations of Sendai virus F, HN, and M proteins, we have successfully reconstituted M protein-glycoprotein interaction in vivo and determined the molecular interactions which are necessary and sufficient to promote M protein-membrane binding. Our results showed that M protein accumulates on cellular membranes via a direct interaction with both F and HN proteins. Specifically, our data demonstrated that a small fraction (8 to 16%) of M protein becomes membrane associated in the absence of Sendai virus glycoproteins, while > 75% becomes membrane bound in the presence of both F and HN proteins. Selective expression of M protein together with either F or HN protein showed that each viral glycoprotein is individually sufficient to promote efficient (56 to 73%) M protein-membrane binding. Finally, we observed that M protein associates with cellular membranes in a time-dependent manner, implying a need for either maturation or transport before binding to glycoproteins.


The prevalence of doping among Saudi athletes: Results from the National Anti-Doping Program.
The abuse of substances banned by anti-doping authorities is a significant problem in sports. Recently, several doping cases have been reported by the media. Additionally, a large number of athletes have been found guilty of using banned substances. Although athletes believe that doping is against the spirit of sports and are aware of its consequences, they continue to use these substances. The consumption of banned substances among Saudi athletes is rising. This study aimed to investigate the abuse of drugs among Saudi athletes. A systematic random sampling cross-sectional survey was administered to all 15-45-year-old Saudi male athletes who were registered with Saudi Sports Federations and the General Sports Authority. From 2009 to 2018, 388 doping control officers participated in the National Anti-Doping Program across 460 facilities. The study necessitated 171 city visits for data collection. A total of 6306 samples were tested during the study period. There were 6165 negative and 141 (2.24%) positive samples for doping. We report a doping prevalence of 2.24% among Saudi athletes. During the study period, Saudi athletes from all types of sports were tested positive for doping. The number of positive samples was significantly higher among competing athletes than non-competing athletes. Doping is a significant problem in KSA. For safe and fair play by all Saudi athletes, the National Anti-Doping Program should enhance the educational campaigns for all athletes in the country.


Would better adherence to guidelines improve childhood immunization rates?
To evaluate the contribution of three provider practices to underimmunization of children with financial coverage for vaccines. Retrospective cohort study of children in a large health maintenance organization, based on computerized databases and chart review. Large health maintenance organization in northern California. The population included 24,268 children who had at least one immunization recorded in the health plan tracking system and had continuous health plan membership between 15 and 24 months of age in 1992 through 1993. The study group (N = 4691) were those who had missed one or more of the immunizations due during their second year. Most (57%) of the underimmunized children had made at least one clinic visit between 15 and 24 months of age. Among those underimmunized children who made well care visits, 90% had been partially immunized at the visit but had not been simultaneously given all vaccines for which they were eligible. When a provider did not give all possible vaccines simultaneously, there was a 9% chance that the child would go on to miss the remaining immunization. Simultaneous administration alone would have achieved full second year coverage of 30% of the underimmunized children in this population. Most underimmunized children (53%), including 35% of those children who had not made any well care visits, had made urgent visits between 15 and 24 months of age. Chart review of randomly sampled patients showed no obstacle or contraindication to immunization at 79% of urgent visits and at 71% of well care visits at which vaccines were withheld. A policy to use weekday urgent visits to promote immunization could potentially reach 27% of the underimmunized children. Provider practices play an important role in underimmunization of children who have insurance coverage for vaccines. Of the three guidelines evaluated, simultaneous administration of all possible vaccines has the greatest potential effectiveness to improve coverage rates in this population. Other guidelines, such as immunizing at urgent visits, are potentially effective but their costs and logistics need further study.


Minimally invasive computer-navigated total hip arthroplasty, following the concept of femur first and combined anteversion: design of a blinded randomized controlled trial.
Impingement can be a serious complication after total hip arthroplasty (THA), and is one of the major causes of postoperative pain, dislocation, aseptic loosening, and implant breakage. Minimally invasive THA and computer-navigated surgery were introduced several years ago. We have developed a novel, computer-assisted operation method for THA following the concept of "femur first"/"combined anteversion", which incorporates various aspects of performing a functional optimization of the cup position, and comprehensively addresses range of motion (ROM) as well as cup containment and alignment parameters. Hence, the purpose of this study is to assess whether the artificial joint's ROM can be improved by this computer-assisted operation method. Second, the clinical and radiological outcome will be evaluated. A registered patient- and observer-blinded randomized controlled trial will be conducted. Patients between the ages of 50 and 75 admitted for primary unilateral THA will be included. Patients will be randomly allocated to either receive minimally invasive computer-navigated "femur first" THA or the conventional minimally invasive THA procedure. Self-reported functional status and health-related quality of life (questionnaires) will be assessed both preoperatively and postoperatively. Perioperative complications will be registered. Radiographic evaluation will take place up to 6 weeks postoperatively with a computed tomography (CT) scan. Component position will be evaluated by an independent external institute on a 3D reconstruction of the femur/pelvis using image-processing software. Postoperative ROM will be calculated by an algorithm which automatically determines bony and prosthetic impingements. In the past, computer navigation has improved the accuracy of component positioning. So far, there are only few objective data quantifying the risks and benefits of computer navigated THA. Therefore, this study has been designed to compare minimally invasive computer-navigated "femur first" THA with a conventional technique for minimally invasive THA. The results of this trial will be presented as soon as they become available. DRKS00000739.


Program priorities of crippled children's agencies: a survey.
State Crippled Children's (CC) programs are known for their diversity in organization and varying coverage of diagnostic categories. Relatively little information is available concerning the programmatic priorities of CC agencies. To identify the activities central to the mission of State CC agencies, a survey was undertaken. Results from the survey revealed considerable unanimity among CC directors in identifying activities deemed to be very important to their agencies' missions. However, CC program directors indicated that their agencies were unable to spend sufficient amounts of time working on many of these activities. With few exceptions, the same activities were accorded high priority regardless of the particular organizational type of CC program and regardless of the tenure of the director. Directors of CC programs were also consistent in identifying activities that were relatively less important to their agencies' missions, including activities related to community-based care. Together with improvements in the treatment of childhood chronic illness, changes in the availability and financing of specialty medical care have substantially altered the problems that now face State CC programs. Despite major differences across the State CC programs, survey results reflect a broad consensus among CC directors concerning the current role of their agencies in the care of children with special health needs. Such a consensus may be an important element in gaining the additional resources needed to address current problems and to ensure high quality of care for these children and their families.


Evaluation of Durability as a Function of Fabric Strength and Residual Bio-Efficacy for the Olyset Plus and Interceptor G2 LLINs after 3 Years of Field Use in Tanzania.
Long-lasting insecticidal nets (LLINs) are prone to reduction in insecticide content and physical strength due to repeated washes and usage. The significant loss to these features jeopardizes their protection against bites from malaria vectors. Insecticide washout is attributed to routine use, friction, and washing, while fabric damage is associated with routine use in households. To maintain coverage and cost-effectiveness, nets should maintain optimal bio-efficacy and physical strength for at least 3 years after distribution. In this study, the bio-efficacy and fabric strength of Olyset plus (OP) LLINs and Interceptor G2 (IG2), that were used for 3 years, were assessed in comparison to untreated and new unwashed counterparts. Both IG2 and OP LLINs (unused, laboratory-washed, and 36 months used) were able to induce significant mortality and blood feeding inhibition (BFI) to mosquitoes compared to the untreated nets. Significantly higher mortality was induced by unused IG2 LLIN and OP LLIN compared to their 36-month-old counterparts against both pyrethroid resistant and susceptible Anopheles gambiae sensu strito. The physical strength of the IG2 LLIN was higher than that of the Olyset Plus LLIN with a decreasing trend from unwashed, laboratory-washed to community usage (36 months old). Malaria control programs should consider bio-efficacy and physical integrity prior to an LLINs' procurement and replacement plan.


Synthetic, structural and biological studies of the ubiquitin system: synthesis and crystal structure of an analogue containing unnatural amino acids.
Ubiquitin is a 76-amino acid protein involved in the targeting for destruction of proteins in the cell. The protein can readily be synthesized chemically affording an extra dimension to studies of protein stability. Ubiquitin with various modifications to the hydrophobic core has been synthesized. In particular, two core amino acids have been replaced by aminobutyric acid (Val-26) and norvaline (for Ile-30) and the product crystallized. The refined crystal structure shows an overall contraction of the molecule and the side chain of Nva-30 rotates relative to Ile-30. However, the side chain rotation is not sufficient to compensate for the effect of the loss of the methyl group and hence a small cavity is introduced into the structure, which decreases the stability of the protein. The biological behaviour of the modified protein is unaltered. The observed changes in stability are of the magnitude expected for the removal of methyl groups from the hydrophobic core of a protein. Interestingly, the effect appears to be independent of the position of the removed methyl group. The intact structure, but not its stability, is important for recognition by the biological conjugating system.


Passive smoking as well as active smoking increases the risk of acute stroke.
To estimate the relative risk of stroke associated with exposure to environmental tobacco smoke (ETS, passive smoking) and to estimate the risk of stroke associated with current smoking (active smoking) using the traditional baseline group (never-smokers) and a baseline group that includes lifelong non-smokers and long-term (> 10 years) ex-smokers who have not been exposed to ETS. Population-based case-control study in residents of Auckland, New Zealand. Cases were obtained from the Auckland stroke study, a population-based register of acute stroke. Controls were obtained from a cross-sectional survery of major cardiovascular risk factors measured in the same population. A standard questionnaire was administered to patients and controls by trained nurse interviewers. Information was available for 521 patients with first-ever acute stroke and 1851 community controls aged 35-74 years. After adjusting for potential confounders (age, sex, history of hypertension, heart disease, and diabetes) using logistic regression, exposure to ETS among non-smokers and long-term ex-smokers was associated with a significantly increased risk of stroke (odds ratio (OR) = 1.82; 95% confidence interval (95% CI) = 1.34 to 2.49). The risk was significant in men (OR = 2.10; 95% CI = 1.33 to 3.32) and women (OR = 1.66; 95% CI = 1.07 to 2.57). Active smokers had a fourfold risk of stroke compared with people who reported they had never smoked cigarettes (OR = 4.14; 95% CI = 3.04 to 5.63); the risk increased when active smokers were compared with people who had never smoked or had quit smoking more than 10 years earlier and who were not exposed to ETS (OR = 6.33; 95% CI = 4.50 to 8.91). This study is one of the few to investigate the association between passive smoking and the risk of acute stroke. We found a significantly increased risk of stroke in men and in women. This study also confirms the higher risk of stroke in men and women who smoke cigarettes compared with non-smokers. The stroke risk increases further when those who have been exposed to ETS are excluded from the non-smoking reference group. These findings also suggest that studies investigating the adverse effects of smoking will underestimate the risk if exposure to ETS is not taken into account.


Psychometric Validation of the Athens Insomnia Scale Among Nurses: A Robust Approach Using Both Classical Theory and Rating Scale Model Parameters.
Few studies have investigated the validity of the Athens insomnia scale (AIS) using a robust approach of both classical theory and the rating scale model. Therefore, in this study, we investigated psychometric validation of the AIS using both of these approaches in nurses. Nurses (n= 563, age= 33.2±7.1 years) working in health facilities in Saudi Arabia participated in a cross-sectional study. Participants completed the AIS, socio-demographics tool, and sleep health-related questions. Confirmatory factor analysis (CFA) favored a 2-factor structure with both comparative fit index (CFI), and incremental fit index (IFI) having values above 0.95. The 2-factor model had the lowest values of Akaike information criterion (AIC), root mean square error of approximation (RMSEA), χ 2, and χ 2/df. This 2-factor structure showed configural invariance (CFI more than 0.95, RMSEA less than 0.08, and Χ2/df less than 3), and metric, scalar, and strict invariance (based on Δ CFI ≤-0.01, and Δ RMSEA ≥ 0.015 criteria). No ceiling/floor effects were seen for the AIS total scores. Infit and outfit mean square values for all the items were within the acceptable range (<1.4, >0.6). The threshold estimates for each item were ordered as expected. Cronbach's α for the AIS tool, factor-1 score, factor-2 score was 0.86, 0.82, and 0.72, respectively. AIS factor scores-1/2 were significantly associated with a habitual feeling of tiredness after usual night sleep (p<0.001), Impairment of daytime socio-occupational functioning (p<0.05), and with a feeling of daytime fatigue, irritability, and restlessness (p<0.05). The findings favor the validity of a 2-factor structure of the AIS with adequate item properties, convergent validity, and reliability in nurses.


Novel health systems service design checklist to improve healthcare access for marginalised, underserved communities in Europe.
Marginalised communities such as homeless people, people who use drugs (PWUD), lesbian, gay, bisexual, transgender and intersex people (LGBTI), prisoners, sex workers and undocumented migrants are at high risk of poor health and yet face substantial barriers in accessing health and support services. The Nobody Left Outside (NLO) Service Design Checklist aims to promote a collaborative, evidence-based approach to service design and monitoring based on equity, non-discrimination and community engagement. The Checklist was a collaborative project involving nine community advocacy organisations, with a focus on homeless people, PWUD, LGBTI people, prisoners, sex workers, and undocumented migrants. The Checklist was devised via a literature review; two NLO platform meetings; a multistakeholder policy workshop and an associated published concept paper; two conference presentations; and stakeholder consultation via a European Commission-led Thematic Network (including webinar). The NLO Checklist has six sections in line with the WHO Health Systems Framework. These are: (1) service delivery, comprising design stage (6 items), services provided (2 items), accessibility and adaptation (16 items), peer support (2 items); (2) health workforce (12 items); (3) health information systems (7 items); (4) medical products and technologies (1 item); (5) financing (3 items); and (6) leadership and governance (7 items). It promotes the implementation of integrated (colocated or linked) healthcare services that are community based and people centred. These should provide a continuum of needs-based health promotion, disease prevention, diagnosis, treatment and management, together with housing, legal and social support services, in alignment with the goals of universal health coverage and the WHO frameworks on integrated, people-centred healthcare. The Checklist is offered as a practical tool to help overcome inequalities in access to health and support services. Policymakers, public health bodies, healthcare authorities, practitioner bodies, peer support workers and non-governmental organisations can use it when developing, updating or monitoring services for target groups. It may also assist civil society in wider advocacy efforts to improve access for underserved communities.


Second-line treatment trends and long-term outcomes of 392 children with chronic immune thrombocytopenic purpura: the French experience over the past 25 years.
Childhood chronic immune thrombocytopenic purpura (cITP) is a rare disease. In severe cases, there is no evidence for the optimal therapeutic strategy. Our aim was to describe the real-life management of non-selected children with cITP at diagnosis. Since 2004, patients less than 18 years old with cITP have been enrolled in the national prospective cohort, OBS'CEREVANCE. From 1990 to 2014, in 29 centres, 392 children were diagnosed with cITP. With a median follow-up of six years (2·0-25), 45% did not need second-line therapy, and 55% (n = 217) received one or more second lines, mainly splenectomy (n = 108), hydroxychloroquine (n = 61), rituximab (n = 61) or azathioprine (n = 40). The overall five-year further second-line treatment-free survival was 56% [95% CI 49·5-64.1]. The use of splenectomy significantly decreased over time. Hydroxychloroquine was administered to children with positive antinuclear antibodies, more frequently older and girls, and reached 55% efficacy. None of the patients died. Ten years after the initial diagnosis, 55% of the 56 followed children had achieved complete remission. Children with cITP do not need second-line treatments in 45% of cases. Basing the treatment decision on the pathophysiological pathways is challenging, as illustrated by ITP patients with positive antinuclear antibodies treated with hydroxychloroquine.


Using registry data to suggest which birth defects may be more susceptible to artifactual clusters and trends.
Some birth defects appear to be more susceptible than others to artifactual prevalence variability over time or geographically. This article uses an empirical approach to try to identify them. Assumption: Variation in clinical practice and other artifactual sources of variability impact observed variation in prevalence of mild cases more than severe cases for a given birth defect. Data were examined from Texas Birth Defects Registry deliveries from 1999-2003. For each of 312 delivery hospitals, birth prevalence for mild cases was calculated for birth defect X. The 5(th) percentile was subtracted from the 95(th) percentile to measure spread in the frequency distribution of all hospitals. That was repeated for severe cases. The ratio of the mild:severe spread was calculated for 49 defects, and the defects ranked into quintiles. That was repeated using birth prevalence based on county, and using isolated cases. The percentages of severe cases were calculated and also ranked into quintiles. A sensitivity analysis and simulation were conducted. Forty-nine birth defects were ranked from those least susceptible to differences in mild:severe prevalence variability (e.g., anencephaly, hypoplastic left heart syndrome) to most susceptible (e.g., atrial septal defect, fetal alcohol syndrome). Resulting quintile ranks based on the three measures were highly correlated, whether based on all cases or isolated cases. This empirical approach may be helpful for a number of public health applications. Birth defects and other health outcomes more susceptible to prevalence variability may be more likely to exhibit artifactual trends or clusters.