Isolation and characterization of biologically active and inactive cholecystokinin-octapeptides from human brain.
Cholecystokinin-like immunoreactivity (CCK-LI) in 0.9 kg human brain was extracted by 2% trifluoroacetic acid at 4 degrees C. Sephadex G50 gel filtration of crude extract revealed one main molecular form of CCK, detected by a carboxy-terminal antibody (5135), that eluted in the position of CCK8. When the CCK-LI in the extract was purified by affinity chromatography using another carboxyl-terminal CCK antibody followed by several steps of reverse phase high pressure liquid chromatography (HPLC), a component was isolated that was found by sequence analysis to be identical to the carboxyl-terminal CCK-octapeptide of porcine CCK33, isolated from intestinal mucosa, and to CCK-octapeptide, isolated from sheep brain. This component possessed comparable biological potencies to synthetic sulfated CCK8 in eliciting amylase release and in competitively displacing radioiodinated CCK33 from isolated mouse pancreatic acini. Furthermore, it exhibited a similar binding characteristic to CCK8 in binding to specific receptors on mouse brain cortical particulate preparations. On high pressure liquid chromatography another minor, earlier eluting immunoreactive peak was observed, which had the same amino acid composition and sequence as CCK8. These findings suggested that this material was oxidized CCK8. This earlier eluting component, exhibiting CCK8-like immunoreactivity, did not induce amylase release from acini and had no or minimal effect in inhibiting tracer CCK33 binding to receptors on isolated acini or on mouse brain cortical particulate preparations at the concentrations tested.


Congenital pseudarthrosis of the forearm.
Early treatment of congenital pseudarthrosis of the forearm is necessary to prevent permanent angulation and shortening of the forearm with resulting loss of function. Total replacement of defective bone and complete excision of the destructive, abnormal fibrous tissue seem to be essential if an effective treatment is to be accomplished.


Subtle and underrecognized side effects of neuroleptic treatment in children with Tourette's disorder.
A variety of side effects developed in children treated with neuroleptics for Tourette's disorder. Of 208 children, 34 manifested dose-related symptoms of dysphoria, nine experienced a worsening of symptoms of Tourette's disorder that was attributed to akathisia, five became hostile and aggressive, three developed "fog states" that disappeared with discontinuation of neuroleptics or treatment with primidone, and three experienced symptoms of tardive dyskinesia that resolved with time. This data base of neuroleptic-treated children with Tourette's disorder demonstrates a variety of subtle and underrecognized side effects that may not be as readily discernible in children receiving neuroleptics for a primary psychiatric disorder.


Perception of Shame in Otolaryngology-Head and Neck Surgery Training.
This survey was developed to assess the prevalence and effects of the perception of shame in otolaryngology-head and neck surgery residency training in the United States. Survey. US otolaryngology training programs. Faculty and trainees in US otolaryngology training programs. A 14-item survey to assess the prevalence of the experience of shame and the attitudes toward use of shame in otolaryngology residency training was sent to all otolaryngology-head and neck surgery program directors for distribution among their respective faculty and resident cohorts. A total of 267 responses were received (women, 24.7%; men, 75.3%): 42.7% of respondents were trainees; 7.0% of trainees thought that shame was a necessary/effective tool, compared with 11.4% of faculty; 50% of respondents felt that they had been personally shamed during residency; and 69.9% of respondents had witnessed another trainee being shamed during residency training. Trainees were most commonly shamed in the operating room (78.4%). Otolaryngology faculty members did the shaming 95.1% of the time. Although shaming prompted internal reflection/self-improvement in 57.4% of trainees, it also caused loss of self-confidence in 52.5%. Trainees who had been shamed were more likely to view shame as an appropriate educational tool (P < .05). Half of respondents have felt shamed during their residency training, and a majority has witnessed a colleague being shamed. Understanding the negative impact that shaming behaviors have on the learning environment and on the performance of the individual within it is an important first step in creating an environment maximally conducive to learning, professional development, and patient safety.


Endosulfan use and the risk of thyroid cancer: an ecological study.
Endosulfan, an organochlorine pesticide, has been understudied in the literature on thyroid cancer. The aim of this ecological study was to assess the correlation between endosulfan exposure and thyroid cancer incidence rates (IRs) in the United States (US). Age-adjusted thyroid cancer IRs per 100,000 people per state for the years 1999 to 2019 were obtained from the Center for Disease Control and Prevention (CDC). To assess the state-level use of endosulfan, data were obtained from the US Geological Survey (USGS). Endosulfan usage estimates (kilograms/acres cropland; quintiles) and thyroid cancer IRs were mapped together. The correlation between age-adjusted thyroid cancer IRs and statewide endosulfan use was calculated using the Spearman correlation. Overall endosulfan usage in the US trended downwards between 1992 and 2007 (T = -0.77; P < 0.001), while thyroid cancer IR trended upwards between 1999 and 2019 (T = 0.69; P < 0.001). There was a statistically significant correlation between 1992 endosulfan use and 2012 (r = 0.32; P = 0.03) and 2014 (r = 0.32; P = 0.03) thyroid cancer IRs. Although restrictions on endosulfan use seem effective, the potential impact of endosulfan exposure remains due to the persistent, semi-volatile, bioaccumulative, and biomagnifying properties of endosulfan metabolites in particular, indicating the need for future thyroid research of highly exposed populations.


Highly Anisotropic Even-Denominator Fractional Quantum Hall State in an Orbitally Coupled Half-Filled Landau Level.
The even-denominator fractional quantum Hall states (FQHSs) in half-filled Landau levels are generally believed to host non-Abelian quasiparticles and be of potential use in topological quantum computing. Of particular interest is the competition and interplay between the even-denominator FQHSs and other ground states, such as anisotropic phases and composite fermion Fermi seas. Here, we report the observation of an even-denominator fractional quantum Hall state with highly anisotropic in-plane transport coefficients at Landau level filling factor ν=3/2. We observe this state in an ultra-high-quality GaAs two-dimensional hole system when a large in-plane magnetic field is applied. By increasing the in-plane field, we observe a sharp transition from an isotropic composite fermion Fermi sea to an anisotropic even-denominator FQHS. Our data and calculations suggest that a unique feature of two-dimensional holes, namely the coupling between heavy-hole and light-hole states, combines different orbital components in the wave function of one Landau level, and leads to the emergence of a highly anisotropic even-denominator fractional quantum Hall state. Our results demonstrate that the GaAs two-dimensional hole system is a unique platform for the exploration of exotic, many-body ground states.


Legal, ethical and professional aspects of duty of care for nurses.
Duty of care is a fundamental aspect of nursing, and many nurses consider this to be an important part of their professional duties as a nurse. However, the legal underpinnings of duty of care are often overlooked, and, as such, nurses may be unsure about when to act if they encounter emergency situations or serious incidents, especially when they are off duty. This article examines the legal, ethical and professional aspects of duty of care, what these mean for nurses in practice, and how duty of care is intrinsically linked with standards of care and negligence.


Structure and Mutations of SARS-CoV-2 Spike Protein: A Focused Overview.
The spike protein (S-protein) of SARS-CoV-2, the protein that enables the virus to infect human cells, is the basis for many vaccines and a hotspot of concerning virus evolution. Here, we discuss the outstanding progress in structural characterization of the S-protein and how these structures facilitate analysis of virus function and evolution. We emphasize the differences in reported structures and that analysis of structure-function relationships is sensitive to the structure used. We show that the average residue solvent exposure in nearly complete structures is a good descriptor of open vs closed conformation states. Because of structural heterogeneity of functionally important surface-exposed residues, we recommend using averages of a group of high-quality protein structures rather than a single structure before reaching conclusions on specific structure-function relationships. To illustrate these points, we analyze some significant chemical tendencies of prominent S-protein mutations in the context of the available structures. In the discussion of new variants, we emphasize the selectivity of binding to ACE2 vs prominent antibodies rather than simply the antibody escape or ACE2 affinity separately. We note that larger chemical changes, in particular increased electrostatic charge or side-chain volume of exposed surface residues, are recurring in mutations of concern, plausibly related to adaptation to the negative surface potential of human ACE2. We also find indications that the fixated mutations of the S-protein in the main variants are less destabilizing than would be expected on average, possibly pointing toward a selection pressure on the S-protein. The richness of available structures for all of these situations provides an enormously valuable basis for future research into these structure-function relationships.


Pre-clinical medical students' perceptions of their patient safety skills in a simulated emergency department.
Patient safety has emerged as an important topic for inclusion in medical curricula. However, there is limited literature describing how medical students are taught, learn and self-assess patient safety skills. The present study aimed to seek pre-clinical medical students' perceptions of (i) their individual performance at a range of safety skills; and (ii) how they define patient safety in a simulated ED. Data were collected in the form of questionnaire responses at the end of the Bond University Simulated ED activity in October 2014. The simulated ED is a session for pre-clinical medical students prior to their clinical rotations, aimed at preparing them for the clinical environment. Likert scale and short answer responses were used to describe students' perceptions of their safety skills and to identify themes related to patient safety. Seventy-eight out of 92 students completed the questionnaires (85% response rate). The majority of students thought their patients were safe from adverse events during their shift. However, students' perception of patient safety was wide-ranging and demonstrated a number of misconceptions. The most frequent strategies employed by students to ensure patient safety were asking for help from nursing staff or senior doctors, ensuring good communication with the patient and checking allergies before administering medication. Students had a favourable opinion of their own safety skills. However, answers to free text question revealed misconceptions about the nature of patient safety despite significant teaching on this topic.


Isolation of entomopathogenic fungi from soils and Ixodes scapularis (Acari: Ixodidae) ticks: prevalence and methods.
Entomopathogenic fungi are commonly found in forested soils that provide tick habitat, and many species are pathogenic to Ixodes scapularis Say, the blacklegged tick. As a first step to developing effective biocontrol strategies, the objective of this study was to determine the best methods to isolate entomopathogenic fungal species from field-collected samples of soils and ticks from an Eastern deciduous forest where I. scapularis is common. Several methods were assessed: (1) soils, leaf litter, and ticks were plated on two types of media; (2) soils were assayed for entomopathogenic fungi using the Galleria bait method; (3) DNA from internal transcribed spacer (ITS) regions of the nuclear ribosomal repeat was extracted from pure cultures obtained from soils, Galleria, and ticks and was amplified and sequenced; and (4) DNA was extracted directly from ticks, amplified, and sequenced. We conclude that (1) ticks encounter potentially entomopathogenic fungi more often in soil than in leaf litter, (2) many species of potentially entomopathogenic fungi found in the soil can readily be cultured, (3) the Galleria bait method is a sufficiently efficient method for isolation of these fungi from soils, and (4) although DNA extraction from ticks was not possible in this study because of small sample size, DNA extraction from fungi isolated from soils and from ticks was successful and provided clean sequences in 100 and 73% of samples, respectively. A combination of the above methods is clearly necessary for optimal characterization of entomopathogenic fungi associated with ticks in the environment.


Effect of new persistent opioid use on physiologic and psychologic outcomes following bariatric surgery.
New persistent opioid use following surgery is a common iatrogenic complication, developing in roughly 6% of patients after elective surgery. Despite increased awareness of misuse and associated morbidity, opioids remain the cornerstone of pain management in bariatric surgery. The potential impact of new persistent opioid use on long-term postoperative outcomes is unknown. We sought to determine the relationship between new persistent opioid use and 1-year postoperative outcomes for patients undergoing bariatric surgery. Using data from the MBSC registry, we identified patients undergoing primary bariatric surgery between 2006 and 2016. Using previously validated patient-reported survey methodology, we evaluated patient opioid use preoperatively and at 1 year following surgery. New persistent use was defined as a previously opioid-naïve patient who self-reported opioid use 1 year after surgery. We used multivariable logistic regression models to evaluate the association between new persistent opioid use, risk-adjusted weight loss, and psychologic outcomes (psychological wellbeing, body image, and depression). 27,799 patients underwent primary bariatric surgery between 2006 and 2016. Among opioid-naïve patients, the rate of new persistent opioid use was 6.3%. At 1-year after surgery, patients with new persistent opioid user lost significantly less excess body weight compared to those without new persistent use (57.6% vs. 60.3%; p < 0.0001). Patients with new persistent opioid use had significantly worse psychological wellbeing (35.0 vs. 33.1; p < 0.0001), body image (19.9 vs. 18.0; p < 0.0001), and depression scores (2.4 vs. 5.0; p < 0.0001). New persistent opioid users also reported less overall satisfaction with their bariatric surgery (75.1% vs. 85.7%; p < 0.0001). New persistent opioid use is common following bariatric surgery and associated with significantly worse physiologic and psychologic outcomes. More effective screening and postoperative surveillance tools are needed to identify these patients, who likely require more aggressive counseling and treatment to maximize the benefits of bariatric surgery.


How Did Distribution Patterns of Particulate Matter Air Pollution (PM2.5 and PM10) Change in China during the COVID-19 Outbreak: A Spatiotemporal Investigation at Chinese City-Level.
Due to the suspension of traffic mobility and industrial activities during the COVID-19, particulate matter (PM) pollution has decreased in China. However, rarely have research studies discussed the spatiotemporal pattern of this change and related influencing factors at city-scale across the nation. In this research, the clustering patterns of the decline rates of PM2.5 and PM10 during the period from 20 January to 8 April in 2020, compared with the same period of 2019, were investigated using spatial autocorrelation analysis. Four meteorological factors and two socioeconomic factors, i.e., the decline of intra-city mobility intensity (dIMI) representing the effect of traffic mobility and the decline rates of the secondary industrial output values (drSIOV), were adopted in the regression analysis. Then, multi-scale geographically weighted regression (MGWR), a model allowing the particular processing scale for each independent variable, was applied for investigating the relationship between PM pollution reductions and influencing factors. For comparison, ordinary least square (OLS) regression and the classic geographically weighted regression (GWR) were also performed. The research found that there were 16% and 20% reduction of PM2.5 and PM10 concentration across China and significant PM pollution mitigation in central, east, and south regions of China. As for the regression analysis results, MGWR outperformed the other two models, with R2 of 0.711 and 0.732 for PM2.5 and PM10, respectively. The results of MGWR revealed that the two socioeconomic factors had more significant impacts than meteorological factors. It showed that the reduction of traffic mobility caused more relative declines of PM2.5 in east China (e.g., cities in Jiangsu), while it caused more relative declines of PM10 in central China (e.g., cities in Henan). The reduction of industrial operation had a strong relationship with the PM10 drop in northeast China. The results are crucial for understanding how the decline pattern of PM pollution varied spatially during the COVID-19 outbreak, and it also provides a good reference for air pollution control in the future.


Bioavailability and diurnal variation in absorption of sustained release theophylline in asthmatic children.
The absolute oral bioavailability of a sustained release theophylline tablet (Nuelin-SR250), given 12 hourly was determined in 14 asthmatic children aged 5 to 13 years. In 4 of the patients, mean bioavailability of the fourth dose was 38.9 +/- 8.4% and that of the sixth dose was 67.9 +/- 25.9% (p less than 0.05) in the other ten patients. This suggests steady-state had not been achieved after four doses. In the initial study with 9 patients, a significant diurnal variation in predose plasma theophylline concentrations was observed, as the mean morning predose concentrations were 2.9 fold greater than the mean evening predose concentrations (p less than 0.005). Dual peak plasma concentrations occurred in 5 out of the 9 patients. The mechanism of this diurnal variation was investigated in a further 5 asthmatic children (10.8 years +/- 1.6). Morning and night steady-state plasma theophylline concentrations during a continuous intravenous infusion of aminophylline were not different (14.9 +/- 5.3 mg/l vs. 15.6 +/- 5.9 mg/l), demonstrating that there was no diurnal variation in the plasma clearance of theophylline. The diurnal variation in predose concentrations with Neulin-SR250 was confirmed with the morning concentrations again being 2.6 fold greater than those in the evening. However, bioavailability was not significantly different for day (09.00-21.00) and night (21.00-09.00) dosing intervals after doses 6 and 7 respectively of Nuelin-SR250. The plasma concentration versus time profiles suggested that the diurnal variation in predose concentrations was due to slower absorption of the evening dose.


Short-term Effects of Ambient Air Pollution on Emergency Department Visits for Asthma: An Assessment of Effect Modification by Prior Allergic Disease History.
The goal of this study was to investigate the short-term effect of ambient air pollution on emergency department (ED) visits in Seoul for asthma according to patients' prior history of allergic diseases. Data on ED visits from 2005 to 2009 were obtained from the Health Insurance Review and Assessment Service. To evaluate the risk of ED visits for asthma related to ambient air pollutants (carbon monoxide [CO], nitrogen dioxide [NO2], ozone [O3], sulfur dioxide [SO2], and particulate matter with an aerodynamic diameter <10 μm [PM10]), a generalized additive model with a Poisson distribution was used; a single-lag model and a cumulative-effect model (average concentration over the previous 1-7 days) were also explored. The percent increase and 95% confidence interval (CI) were calculated for each interquartile range (IQR) increment in the concentration of each air pollutant. Subgroup analyses were done by age, gender, the presence of allergic disease, and season. A total of 33 751 asthma attack cases were observed during the study period. The strongest association was a 9.6% increase (95% CI, 6.9% to 12.3%) in the risk of ED visits for asthma per IQR increase in O3 concentration. IQR changes in NO2 and PM10 concentrations were also significantly associated with ED visits in the cumulative lag 7 model. Among patients with a prior history of allergic rhinitis or atopic dermatitis, the risk of ED visits for asthma per IQR increase in PM10 concentration was higher (3.9%; 95% CI, 1.2% to 6.7%) than in patients with no such history. Ambient air pollutants were positively associated with ED visits for asthma, especially among subjects with a prior history of allergic rhinitis or atopic dermatitis.


Blood use for transvenous lead extractions at a high-volume center.
Transvenous lead extractions (TLEs) have increased in number due to an increased prevalence of cardiac implantable devices. Bleeding complications associated with TLEs can be catastrophic, and many institutions order blood components to be available in the procedure room. There are few studies supporting or refuting this practice. We evaluated transfusion rates for TLEs at a single, high-volume center to assess the need for having blood in the procedure room. Patients undergoing TLEs from April 2010 to February 2019 were identified from our institutional database. The percentage of patients transfused intraoperatively, the number of units transfused, and the reasons for transfusion were determined from the database and by manual chart review. A total of 473 patients underwent a TLE during this time frame. Of these, only 17 patients (3.6%) received a red blood cell (RBC) transfusion. Ten of the 17 patients received RBCs secondary to preoperative anemia. Of the remaining seven patients, only four patients received more than 2 RBC units, and only one received more than 10 RBC units. No patient received more than 2 RBC units or any plasma or platelets in the past 4 years. Due to improvements in procedural techniques, advent of accessible remote blood allocation systems, and changes in transfusion practice (e.g., electronic crossmatch), routinely having blood components in the procedure room for every TLE may be an outdated practice for high-volume centers.


Ultrasound-guided optical coherence tomography needle probe for the assessment of breast cancer tumor margins.
The purpose of this study was to evaluate a new imaging technique for the assessment of breast cancer tumor margins. The technique entails deployment of a high-resolution optical imaging needle under ultrasound guidance. Assessment was performed on fresh ex vivo tissue samples. Use of the ultrasound-guided optical needle probe allowed in situ assessment of fresh tissue margins. The imaging findings corresponded to the histologic findings.


A Longitudinal 1H NMR-Based Metabolic Profile Analysis of Urine from Hospitalized Premature Newborns Receiving Enteral and Parenteral Nutrition.
Preterm newborns are extremely vulnerable to morbidities, complications, and death. Preterm birth is a global public health problem due to its socioeconomic burden. Nurturing preterm newborns is a critical medical issue because they have limited nutrient stores and it is difficult to establish enteral feeding, which leads to inadequate growth frequently associated with poor neurodevelopmental outcomes. Parenteral nutrition (PN) provides nutrients to preterm newborns, but its biochemical effects are not completely known. To study the effect of PN treatment on preterm newborns, an untargeted metabolomic 1H nuclear magnetic resonance (NMR) assay was performed on 107 urine samples from 34 hospitalized patients. Multivariate data (Principal Component Analysis, PCA, Orthogonal partial least squares discriminant analysis OPLS-DA, parallel factor analysis PARAFAC-2) and univariate analyses were used to identify the association of specific spectral data with different nutritional types (NTs) and gestational ages. Our results revealed changes in the metabolic profile related to the NT, with the tricarboxylic acid cycle and galactose metabolic pathways being the most impacted pathways. Low citrate and succinate levels, despite higher glucose relative urinary concentrations, seem to constitute the metabolic profile found in the studied critically ill preterm newborns who received PN, indicating an energetic dysfunction that must be taken into account for better nutritional management.


Nolz1 is induced by retinoid signals and controls motoneuron subtype identity through distinct repressor activities.
The acquisition and maintenance of final neuronal identity depends in part upon the implementation of fate-specification programs in postmitotic neurons; however, the mechanisms involved remain unclear. In the developing spinal cord, retinoic acid (RA) signaling pathways specify the columnar and divisional identities of postmitotic motoneurons (MNs). Here we show that RA signals induce expression of the NET transcriptional regulator Nolz1 in differentiated chick MNs, where it regulates the progressive specification of prospective Lim3-negative motor columns. Nolz1 controls the initial formation of forelimb and thoracic Lim3-negative motor columns by downregulating Lim3 expression and maintaining the expression of key homeodomain proteins necessary for MN identity and survival. At forelimb levels, Nolz1 specifies lateral motor column (LMC) identity by inducing the expression of the postmitotic LMC determinant Hoxc6, and implements the partial specification of lateral LMC identity through Lim1 induction. The specificity of Nolz1 function depends upon distinct repressor activities that require, in part, the modulatory activity of Grg5, an atypical member of the Gro-TLE family of co-repressors. Thus, RA signals regulate diverse events in MN subtype specification by inducing the expression of a key transcriptional regulator that controls multiple developmental pathways via functionally distinct repressor complexes.


Rating Hospital Performance in China: Review of Publicly Available Measures and Development of a Ranking System.
In China, significant emphasis and investment in health care reform since 2009 has brought with it increasing scrutiny of its public hospitals. Calls for greater accountability in the quality of hospital care have led to increasing attention toward performance measurement and the development of hospital ratings. Despite such interest, there has yet to be a comprehensive analysis of what performance information is publicly available to understand the performance of hospitals in China. This study aims to review the publicly available performance information about hospitals in China to assess options for ranking hospital performance. A review was undertaken to identify performance measures based on publicly available data. Following several rounds of expert consultation regarding the utility of these measures, we clustered the available options into three key areas: research and development, academic reputation, and quality and safety. Following the identification and clustering of the available performance measures, we set out to translate these into a practical performance ranking system to assess variation in hospital performance. A new hospital ranking system termed the China Hospital Development Index (CHDI) is thus presented. Furthermore, we used CHDI for ranking well-known tertiary hospitals in China. Despite notable limitations, our assessment of available measures and the development of a new ranking system break new ground in understanding hospital performance in China. In doing so, CHDI has the potential to contribute to wider discussions and debates about assessing hospital performance across global health care systems.


The role of CX3CL1 in fetal-maternal interaction during human gestation.
Embryo implantation and subsequent placentation require a fine balanced fetal-maternal cross-talk of hormones, cytokines and chemokines. Amongst the group of chemokines, CX3CL1 (also known as fractalkine) has recently attracted attention in the field of reproductive research. It exists both as membrane-bound and soluble isoforms. On the basis of current experimental evidence, fractalkine is suggested to regulate adhesion and migration processes in fetal-maternal interaction at different stages of human pregnancy. Expressed by uterine glandular epithelial cells, predominantly during the mid-secretory phase of the menstrual cycle, fractalkine appears to prime the blastocyst for forthcoming implantation. After implantation, fractalkine is suggested to regulate invasion of extravillous trophoblasts by altering their expression profile of adhesion molecules. With onset of perfusion of the intervillous space at the end of first trimester, fractalkine present at the apical microvillous plasma membrane of the syncytiotrophoblast may mediate close interaction of placental villi with circulating maternal blood cells.


Reversible and Versatile On-Tether Modification of Chiral-Center-Induced Helical Peptides.
Modification of the cross-linker of constrained peptides has recently received considerable attention. Here, we present a versatile approach to modifing the cross-linking tether of chiral-center-induced helical (CIH) peptides via the S-alkylation reaction. The alkylation process displayed high conversion efficiency, selectivity, and substrate tolerance. Notably, although on-tether S-alkylation could lead to a pair of peptide epimers, the major alkylated product retained the helical structure of its helical precursor peptide. This S-alkylation was readily reversible under reductive conditions, which provides a simple method for traceless modification. In addition to expanding the chemical space of CIH peptides, this strategy is the first on-tether modification platform with known retention of the peptides' original helicity.


Prognostic Factors for Distant Metastasis in Patients with Locoregional Recurrence after Mastectomy.
The purpose of this study was to identify patients with high risk of distant metastasis (DM) after salvage treatment for postmastectomy locoregional recurrence (LRR). We retrospectively reviewed 142 patients who received salvage radiotherapy with or without wide excision for isolated LRR after mastectomy between January 1999 and December 2012. Distant metastasis-free survival (DMFS) was estimated from the date of diagnosis of isolated LRR to the date of DM or last follow-up using the Kaplan-Meier method, and Cox regression analysis was performed to identify prognostic factors for DM. The median follow-up period was 54 months. The major failure pattern was DM (56%) and the 5-year DMFS was 43%. In multivariate analysis, initial N (iN) stage, recurrent N (rN) stage, and hormone receptor (HR) status were significant prognostic factors for DM (5-year DMFS: iN0 vs. iN1-3, 73% vs. 25%, p<0.001; rN0 vs. rN1-3, 61% vs. 29%, p<0.001; HR+ vs. HR-, 49% vs. 21%, p<0.001). Patients with lymph node involvement and/or HR- specimens seem to experience more DM than patients with chest wall-only recurrence and HR+ specimens. Further studies are needed to investigate the role of chemotherapy in these patients.


Injection-site Reactions to Sustained-release Meloxicam in Sprague-Dawley Rats.
An extended-release formulation of the NSAID meloxicam (MSR) is used to provide 72 h of continuous analgesia in many species, including rodents. Although standard formulations of meloxicam are frequently used in rats with no observable injection-site reactions, the potential adverse effects from MSR have not been characterized sufficiently nor has a prospective study of these effects been performed in rats. To address this deficiency, we evaluated injection-site reactions after a single subcutaneous administration of MSR (n = 16) or sterile saline (SC, n = 6) in the flank of age- and sex-matched Sprague-Dawley rats. Mass and erythema scores were measured daily for 2 wk, and injection sites were collected for histopathology after euthanasia. Rats were randomly selected for euthanasia at 7 d (n = 12) or 14 d (n = 10) after injection to capture the subacute and chronic phases of mass and erythematic lesion formation. No rats in the SC group developed lesions, whereas all 16 MSR-treated rats developed masses. The median time to first mass in the MSR treatment group was 3 d (95% CI, 2-3 d), and nearly 8 d for erythema (95% CI, 6.7-9.1 d). The trajectory of mass lesion severity showed rapid progression from score 1 at onset (day 2 or 3) to score 2 for almost all animals by day 5 or 6. Histopathology was characterized by localized inflammation with central necrosis and peripheral fibrosis, with some sections showing developing draining tracts. Given the high prevalence and severity of localized skin reactions, MSR analgesia should be considered carefully for Sprague-Dawley rats.


Detection of Velogenic Avian Paramyxoviruses in Rock Doves in New York City, New York.
Avian paramyxovirus 1 (APMV-1), also known as Newcastle disease virus (NDV), causes severe and economically important disease in poultry around the globe. Although a limited amount of APMV-1 strains in urban areas have been characterized, the role of the urban wild bird population as an APMV-1 reservoir is unclear. Because urban birds may have an important role for long-term circulation of the virus, fecal and swab samples were collected by community scientists from wild birds in New York City (NYC), New York, United States. These samples were screened for APMV-1 and genotypically characterized by sequencing of the complete genome. A total of 885 samples were collected from NYC parks and from a local wildlife rehabilitation clinic from October 2020 through June 2021, and 255 samples obtained from 197 birds have been processed to date. Eight birds (4.1%) screened positive for the APMV-1 nucleoprotein gene by conventional reverse transcription PCR (RT-PCR), and two live viruses were isolated via egg culture. A multibasic F protein cleavage sequence, 112R R K K R F117, an indicator of highly pathogenic velogenic APMV-1 strains, was present in the two samples fully sequenced by next generation sequencing. Phylogenetic analysis of the F gene coding sequence classified both isolates into genotype VI, a diverse and predominant genotype responsible for APMV-1 outbreaks in pigeon and dove species worldwide. IMPORTANCE Here we describe the first large-scale effort to screen for APMV-1 in New York City's wild bird population as part of the New York City Virus Hunters program, a community science initiative. We characterized two isolates of APMV-1, with phylogenetic analyses suggesting diversity in established and circulating strains of pigeon paramyxoviruses. Our isolates are also domestic reference strains for future APMV-1 vaccine developments. Future surveillance in this region may contribute to our understanding of APMV-1's evolution and genetic diversity, as well as inform poultry husbandry and vaccination practices in New York State.


Surface relaxations, current enhancements, and absolute distances in high resolution scanning tunneling microscopy.
We have performed the most realistic simulation to date of the operation of a scanning tunneling microscope. Probe-sample distances from beyond tunneling to actual surface contact are covered. We simultaneously calculate forces, atomic displacements, and tunneling currents, allowing quantitative comparison with experimental values. A distance regime below which the probe becomes unstable is identified. It is shown that the real distance differs substantially from previous estimates because of large atomic displacements on the surface and at the probe tip.


Preparation and characterization of soluble dietary fiber from tiger nut residues, showing enhanced antioxidant activity and metal-ion-binding properties.
To improve the utilization of soluble dietary fiber (SDF) from tiger nut residues, the response surface methodology was used to optimize the conditions of superfine grinding to produce SDF with antioxidant and metal-ion-binding properties. The yield was increased (30.56%) and the average particle diameter of SDF was decreased (D50: 32.80 μm) under the optimal conditions (a proportion of grinding medium of 100%, a feeding mass of 0.90 kg, a grinding time of 20 min, and a moisture content of 8.00%). In addition, superfine grinding substantially modified the surface morphology and increased the SDF content and the proportion of monosaccharides by decreasing the molecular weight. Moreover, superfine grinding remarkably enhanced the in vitro antioxidant activities (ABTS+, DPPḤ, and ·OH) of the SDF, which also exhibited favorable metal-ion-binding properties (Ca2+, Zn2+, and Co2+). These results suggest that superfine grinding can be used as a technique to modify dietary fiber to manufacture functional SDF.


Restriction fragment length polymorphism analysis of Cryptococcus neoformans isolates from environmental (pigeon excreta) and clinical sources in New York City.
Restriction fragment length polymorphism analysis of environmental (pigeon excreta) and clinical Cryptococcus neoformans var. neoformans isolates in a limited geographic area distinguished 6 strains among 8 environmental isolates and 12 strains among 17 clinical isolates. Clusters of patients with three strains types accounted for 47% of clinical isolates. Despite this diversity, two strains were shared by environmental and clinical isolates.


Dolichyl monophosphate and its sugar derivatives in plants.
A glucose acceptor was isolated from soya beans by extraction with chloroform/methanol (2:1, v/v), followed by DEAE-cellulose column chromatography of the extract. This acceptor could not be distinguished from liver dolichyl monophosphate by t.l.c. It could replace dolichyl monophosphate as a mannose acceptor with a liver enzyme and its glucosylated derivative could replace dolichyl monophosphate glucose as a glucose donor in the same system. These results, together with those already reported [Pont Lezica, Brett, Romero Martinez & Dankert (1975) Biochem, Biophys. Res. Commun. 66, 980-987], indicate that the acceptor from soya bean is a dolichyl monophosphate. Gel filtration of its glucosylated derivative on Sephadex G-75 in the presence of sodium deoxycholate indicated that the acceptor contained 17 or 18 isoprene units. An enzyme preparation from pea seedlings was shown to use endogenous acceptors to form lipid phosphate sugars containing mannose and N-acetylglucosamine from GDP-mannose and UDP-N-acetylglucosamine. Chromatographic and degradative techniques indicated that the compounds formed were lipid monophosphate mannose, lipid pyrophosphate N-acetylglucosamine, lipid pyrophosphate chitobiose and a series of lipid pyrophosphate oligosaccharides containing both mannose and N-acetylglucosamine. None of these compounds was degraded by catalytic hydrogenation, and so the lipid moiety in each case was probably an alpha-saturated polyprenol. The endogenous acceptors for mannose and N-acetylglucosamine in peas may therefore be dolichyl monophosphate, as has been found in mammalian systems.


New trends in psychosomatic research.
Advances in physiological psychology and neuroendocrinology, together with epidemiological studies, have added new dimensions to psychosomatic research. Psychological influences still are accepted as exacerbators or trigger mechanisms, if less often as causes. Theories of psychosomatics which connected specific personality profiles with specific psychosomatic illnesses have lost favor, and multifactorial explanations, which include heredity, environment, social class, life stress, endocrines, brain areas, neurohormones, and immunological mechanisms, are new areas of research. Research methods have become more sophisticated scientifically, particularly in the selection and size of samples tested, and the variety of situations investigated. Psychological reactions to illness in general, terminal disease, and death, and psychological experiences of pain, in addition to variable effects of psychotherapeutic methods and psychotherapists' personality, are identifiable but unquantified influences which seem acceptable as contributors to, if not causes of, psychophysiological disorders.


Polymer inclusion membrane to access Zn speciation: Comparison with root uptake.
Metal speciation studies can be performed with a new technique based on a functionalized membrane. The estimation of not only the total amount of metal, but also the metal available to living organisms is very important. In this context, we have investigated the use of a polymer inclusion membrane (PIM) in a new tool for the determination of free metal ion concentration. In order to check the usefulness of PIM devices in metal speciation studies and metal availability to potato plants (Solanum tuberosum), Zn has been chosen as a case study. The PIM designed for Zn transport uses polyvinyl chloride (PVC) as polymer and di-(2-ethylhexyl) phosphoric acid (D2EHPA) as carrier, with 0.01M nitric acid in the receiving solution. The stability of the PIM has been demonstrated and good linearity of PIM-device fluxes (JPIM) with free metal concentration was observed for total metal concentrations ranging from 3μM up to 70μM. The presence of different ligands, such as ethylenediaminetetraacetic acid (EDTA), humic acid (HA) and citrate, greatly influences the measured JPIM because the formation of metal complexes in the donor phase decreases the free Zn concentration in the sample. Good correlation has been found when comparing PIM fluxes and metal accumulation in potato plants roots in the presence of EDTA. But, the root uptake did not change when adding citrate and HA to the hydroponic medium, so the uptake does not always follows the Free Ion Activity Model (FIAM). These ligands might induce physiological changes in the roots and enhance metal uptake.


Optimal single-pulse excitation of rotational impulsive molecular phase modulation.
The full transient macroscopic linear optical susceptibility tensor induced in a transiently aligned molecular gas by a single, linearly polarized intense alignment pulse is studied. We determine the optimal properties of the pulse that forms the rotational wave packet. Significantly, we demonstrate that the optimal pulse for phase modulation differs from the optimal alignment pulse. Finally, we show that the limited information about rotational wave packets obtained by measuring the linear optical susceptibility can be augmented by also measuring the time-varying nonlinear optical susceptibilities.


Fetal fluid responses to long-term 5 M NaCl infusion: where does all the salt go?
The fetus must obtain Na and Cl ions in order to grow. However, the regulation of electrolyte acquisition by the fetus is not well understood. To explore fetal electrolyte balance, we intravenously infused 5 M NaCl at a rate equal to 80% of the total fetal body Na+ and Cl- content per day (240 mM/day) for 3 days into late-gestation fetal sheep. We hypothesized that the increase in fetal osmolality resulting from the infusion would cause a transplacental water movement into the fetal compartment, leading to hydrops fetalis and/or polyhydramnios. The fetal-to-maternal osmotic gradient was initially -2.8 +/- 0.9 (SE) mosmol/kgH2O and rose by 4.8 +/- 1.8 mosmol/kgH2O during the infusion. Fetal plasma [Na+] and [Cl-] increased (3.0 +/- 0.4 and 5.5 +/- 0.5 meq/l, respectively), but the normal maternal-to-fetal transplacental concentration gradients for these ions were not reversed. Most of the infused Na+ (92 +/- 14%) and Cl- (82 +/- 12%) was excreted by the fetus in large volumes of hypotonic urine. Amniotic fluid osmolality and [Na+] were unchanged, but amniotic [Cl-] increased 5.7 +/- 2.4 meq/l. The amniotic plus allantoic fluid volume, as estimated by ultrasonography, was increased (43.5 +/- 14.5%) at day 2 and returned to control by day 3 of infusion. There was no fetal edema during the study or at autopsy. In light of these results, we propose a novel and somewhat complex mechanism for transplacental fluid and electrolyte movement in which placental capillary permeability increases along the length of the capillary.(ABSTRACT TRUNCATED AT 250 WORDS)


Precision Profiling of the Cardiovascular Post-Translationally Modified Proteome: Where There Is a Will, There Is a Way.
There is an exponential increase in biological complexity as initial gene transcripts are spliced, translated into amino acid sequence, and post-translationally modified. Each protein can exist as multiple chemical or sequence-specific proteoforms, and each has the potential to be a critical mediator of a physiological or pathophysiological signaling cascade. Here, we provide an overview of how different proteoforms come about in biological systems and how they are most commonly measured using mass spectrometry-based proteomics and bioinformatics. Our goal is to present this information at a level accessible to every scientist interested in mass spectrometry and its application to proteome profiling. We will specifically discuss recent data linking various protein post-translational modifications to cardiovascular disease and conclude with a discussion for enablement and democratization of proteomics across the cardiovascular and scientific community. The aim is to inform and inspire the readership to explore a larger breadth of proteoform, particularity post-translational modifications, related to their particular areas of expertise in cardiovascular physiology.


Engineered modular microphysiological models of the human airway clearance phenomena.
Mucociliary clearance is a crucial mechanism that supports the elimination of inhaled particles, bacteria, pollution, and hazardous agents from the human airways, and it also limits the diffusion of aerosolized drugs into the airway epithelium. In spite of its relevance, few in vitro models sufficiently address the cumulative effect of the steric and interactive barrier function of mucus on the one hand, and the dynamic mucus transport imposed by ciliary mucus propulsion on the other hand. Here, ad hoc mucus models of physiological and pathological mucus are combined with magnetic artificial cilia to model mucociliary transport in both physiological and pathological states. The modular concept adopted in this study enables the development of mucociliary clearance models with high versatility since these can be easily modified to reproduce phenomena characteristic of healthy and diseased human airways while allowing to determine the effect of each parameter and/or structure separately on the overall mucociliary transport. These modular airway models can be available off-the-shelf because they are exclusively made of readily available materials, thus ensuring reproducibility across different laboratories.


Predicting stuttering onset by the age of 3 years: a prospective, community cohort study.
Our goals were to document (1) the onset of stuttering and (2) whether specific child, family, or environmental factors predict stuttering onset in children aged up to 3 years. Participants included a community-ascertained cohort of 1619 2-year-old Australian children recruited at 8 months of age to study the longitudinal development of early language. The main outcome measure was parental telephone report of stuttering onset, verified by face-to-face expert diagnosis. Preonset continuous measures of the child's temperament (approach/withdrawal) and language development were available. Information on a range of predictor measures hypothesized to be associated with stuttering onset was obtained (maternal mental health and education levels, gender, premature birth status, birth weight, birth order, twinning, socioeconomic status, family history of stuttering). By 3 years of age, the cumulative incidence of stuttering onset was 8.5%. Onset often occurred suddenly over 1 to 3 days (49.6%) and involved the use of word combinations (97.1%). Children who stuttered were not more shy or withdrawn. Male gender, twin birth status, higher vocabulary scores at 2 years of age, and high maternal education were associated with stuttering onset. The multivariable model, however, had low predictive strength; just 3.7% of the total variation in stuttering onset was accounted for. The cumulative incidence of stuttering onset was much higher than reported previously. The hypothesized risk factors for stuttering onset together explained little of the variation in stuttering onset up to 3 years of age. Early onset was not associated with language delay, social and environmental factors, or preonset shyness/withdrawal. Health professionals can reassure parents that onset is not unusual up to 3 years of age and seems to be associated with rapid growth in language development.


Monopolar high-frequency language mapping: can it help in the surgical management of gliomas? A comparative clinical study.
OBJECT Intraoperative language mapping is traditionally performed with low-frequency bipolar stimulation (LFBS). High-frequency train-of-five stimulation delivered by a monopolar probe (HFMS) is an alternative technique for motor mapping, with a lower reported seizure incidence. The application of HFMS in language mapping is still limited. Authors of this study assessed the efficacy and safety of HFMS for language mapping during awake surgery, exploring its clinical impact compared with that of LFBS. METHODS Fifty-nine patients underwent awake surgery with neuropsychological testing, and LFBS and HFMS were compared. Frequency, type, and site of evoked interference were recorded. Language was scored preoperatively and 1 week and 3 months after surgery. Extent of resection was calculated as well. RESULTS High-frequency monopolar stimulation induced a language disturbance when the repetition rate was set at 3 Hz. Interference with counting (p = 0.17) and naming (p = 0.228) did not vary between HFMS and LFBS. These results held true when preoperative tumor volume, lesion site, histology, and recurrent surgery were considered. Intraoperative responses (1603) in all patients were compared. The error rate for both modalities differed from baseline values (p < 0.001) but not with one another (p = 0.06). Low-frequency bipolar stimulation sensitivity (0.458) and precision (0.665) were slightly higher than the HFMS counterparts (0.367 and 0.582, respectively). The error rate across the 3 types of language errors (articulatory, anomia, paraphasia) did not differ between the 2 stimulation methods (p = 0.279). CONCLUSIONS With proper setting adjustments, HFMS is a safe and effective technique for language mapping.


Increased susceptibility of a triclabendazole (TCBZ)-resistant isolate of Fasciola hepatica to TCBZ following co-incubation in vitro with the P-glycoprotein inhibitor, R(+)-verapamil.
A study was carried out to investigate whether the action of triclabendazole sulphoxide (TCBZ.SO) against the liver fluke, Fasciola hepatica is altered by inhibition of P-glycoprotein (Pgp)-linked drug efflux pumps. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible fluke isolates were used for this in vitro study and the Pgp inhibitor selected was R(+)-verapamil [R(+)-VPL]. For experiments with the Oberon isolate, flukes were incubated for 24 h with either R(+)-VPL (1×10-4 m) on its own, TCBZ.SO (15 μg mL-1) alone, a combination of R(+)-VPL (1×10-4 m) plus TCBZ.SO (15 μg mL-1), TCBZ.SO (50 μg mL-1) on its own, or a combination of TCBZ.SO (50 μg mL-1) plus R(+)-VPL (1×10-4 m). They were also incubated in TCBZ.SO (50 μg mL-1) alone or in combination with R(+)-VPL (1×10-4 m) until they became inactive; and in TCBZ.SO (50 μg mL-1) alone for a time to match that of the combination inactivity time. Flukes from the Cullompton isolate were treated with either TCBZ.SO (50 μg mL-1) alone or in combination with R(+)-VPL (1×10-4 m) until they became inactive, or with TCBZ.SO (50 μg mL-1) alone time-matched to the combination inactivity time. Morphological changes resulting from drug treatment and following Pgp inhibition were assessed by means of scanning electron microscopy. Incubation in R(+)-VPL alone had a minimal effect on either isolate. TCBZ.SO treatment had a relatively greater impact on the TCBZ-susceptible Cullompton isolate. When R(+)-VPL was combined with TCBZ.SO in the incubation medium, however, the surface disruption to both isolates was more severe than that seen after TCBZ.SO treatment alone; also, the time taken to reach inactivity was shorter. More significantly, though, the potentiation of drug activity was greater in the Oberon isolate; also, it was more distinct at the higher concentration of TCBZ.SO. So, the Oberon isolate appears to be particularly sensitive to efflux pump inhibition. The results of this study suggest that enhanced drug efflux in the Oberon isolate may be involved in the mechanism of resistance to TCBZ.


[Geriatric aspects for the management of diabetes mellitus (Update 2023)].
There is a high prevalence of diabetes mellitus in the elderly population of industrial countries. The present article provides recommendations for the screening, prevention and treatment of elderly diabetic patients according to current scientific evidence.


Transcutaneous tibial nerve stimulation: 2 years follow-up outcomes in the management of anticholinergic refractory overactive bladder.
To evaluate long-term use, efficacy and tolerability of transcutaneous tibial nerve stimulation (TTNS) in the treatment of refractory overactive bladder (OAB). We performed a prospective observational study and included all patients treated in a single center for OAB persisting after first-line anticholinergic treatment, with ≥ 24 months follow-up. The protocol consisted of daily stimulation at home. The primary outcome was treatment persistence. Amelioration was defined as an improvement in urinary symptom profile (USP) score. We assessed 84 consecutive patients. After a mean follow-up of 39.3 months and a mean treatment use of 8.3 months, almost two-thirds of patients (71.8%) had discontinued TTNS. Treatment continuation was > 12 months for 28 patients (33.3%) and > 18 months for 16 patients (19%). TTNS was successful following 3 months of treatment in 60 (71%) patients. Mean USP score stayed significantly lower than baseline until 12 months of treatment, but was not significant anymore after 18 months. Discontinuation therapy reasons were a lack of sufficient symptom relief for 59 (70%) patients, compliance difficulty for 5 (6%) patients and becoming asymptomatic for 6 (8%) patients. No serious adverse events occurred. The present study confirms the utility of TTNS as a treatment option for patients with resistant OAB. In the long-term use, few patients continued with therapy, mostly because of a decreased effectiveness with time.


Protective effects of the synthetic cannabinoids CP55,940 and JWH-015 on rat brain mitochondria upon paraquat exposure.
The effects of cannabinoids in mitochondria after acute oxidative stress insult are not fully established. We investigated the ability of CP55,940 and JWH-015 to scavenge reactive oxygen species and their effect on mitochondria permeability transition (MPT) in either a mitochondria-free superoxide anion generation system, intact rat brain mitochondria or in sub-mitochondrial particles (SMP) treated with paraquat (PQ). Oxygen consumption, mitochondrial membrane potential (Deltapsi(m)) and MPT were determined as parameters of mitochondrial function. It is found that both cannabinoids effectively attenuate mitochondrial damage against PQ-induced oxidative stress by scavenging anion superoxide radical (O(2)(*-)) and hydrogen peroxide (H(2)O(2)), maintaining Deltapsi(m) and by avoiding Ca(2+)-induced mitochondrial swelling. Understanding the mechanistic action of cannabinoids on mitochondria might provide new insights into more effective therapeutic approaches for oxidative stress related disorders.


Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy.
To investigate the prevalence, metabolic features and risk factors of a particular pattern of fat redistribution (FR), characterized by a progressive enlargement of breast and abdominal girth associated with a wasting of the lower limbs, observed in HIV-infected women treated with combined antiretroviral (ARV) therapy. Cross-sectional study. Outpatients attending the Institute of Infectious Diseases, University of Milan, Milan, Italy. HIV-infected women treated with two or more ARV drugs, observed between December 1997 and February 1998. FR was confirmed by means of a physical examination and dual-energy X-ray absorptiometry (DEXA). The metabolic and endocrinological measurements in patients with FR were compared with those in FR-free women. FR was observed in 32 out of 306 women (10.5%). DEXA revealed more trunk fat (P < 0.01) and less leg fat (P < 0.001) in the patients with FR than in the matched controls. There were no significant differences in laboratory test results between the two groups. All of the FR patients were taking lamivudine-containing regimens; 20 of them were also taking a protease inhibitor (PI). The association of FR with lamivudine-including regimens was statistically significant (P = 0.017). Among the patients taking lamivudine, the risk associated with treatments including PI was 1.8 (95% CI 0.8-3.8, P = 0.12). A total duration of ARV therapy of more than 1000 days was associated with a greater risk of developing FR (OR 10.8; 95% CI 1.4-80.5; P = 0.0207). Stepwise logistic regression analyses indicated that prolonged ARV therapy and a viral load of more than 10000 copies per ml at the beginning of the last ARV regimen were the only variables that significantly and independently correlated with the risk of FR. The observed body modifications are caused by a redistribution of body fat without fat loss that is apparently not associated with hyperlipidemia, altered glucose metabolism or other endocrinological disorders. The development of FR in patients receiving only reverse transcriptase (RT) inhibitors suggests the presence of a PI-independent mechanism that deserves further investigation.


anti-tumor effect of AlkB homolog 3 knockdown in hormone- independent prostate cancer cells.
Castrate resistant prostate cancer (CRPC) is a disease that is resistant to both hormone therapy and chemotherapy. At present, no curative therapy for CRPC has been established. Therefore, it is necessary to determine a novel molecular target for the development of therapeutic agents. We previously reported that AlkB homolog 3 (ALKBH3) is highly expressed in prostate cancer but not in benign prostatic hyperplasia or in normal prostate epithelium and that the expression levels of ALKBH3 protein are significantly correlated with the hormone-independent state of prostate cancer. Moreover, ALKBH3 regulates the invasion of prostate cancer cells via the regulation of matrix metalloproteinase 9. Here, we show that ALKBH3 gene silencing markedly induces apoptosis in hormone-independent prostate cancer cell line DU145 but not in the normal prostate epithelial cell line PNT2. Moreover, the in vivo tumorigenicity of DU145 cells was significantly inhibited by the administration of ALKBH3 siRNA. Furthermore, the anchorage-independent growth of DU145 cells was inhibited by ALKBH3 knockdown and promoted by ALKBH3 overexpression, significantly. ALKBH3 shRNA-expressing prostate cancer cells formed significantly smaller tumors than those of control shRNA transfectants in an in vivo xenograft model. These findings suggest that ALKBH3 is a promising target molecule for the development of CRPC therapeutic agents.


An overview of the O-ring implant overdenture attachment: clinical reports.
The O-ring is used to increase retention of implant complete and partial overdenture prostheses. They possess a number of advantages, including ease of use and maintenance, low cost, and possible elimination of a superstructure bar. O-rings wear over time, gradually lose retention, and must be replaced periodically. It is essential that O-ring abutments be parallel to each other. Two cases are presented showing the use of O-rings with a complete mandibular implant overdenture and a maxillary removable partial denture.


Addiction research centres and the nurturing of creativity: the Centre for Addictions Research of British Columbia, Canada.
The Centre for Addictions Research of British Columbia (CARBC) was established as a multi-campus and multi-disciplinary research centre administered by the University of Victoria (UVic) in late 2003. Its core funding is provided from interest payments on an endowment of CAD 10.55 million dollars. It is supported by a commitment to seven faculty appointments in various departments at UVic. The Centre has two offices, an administration and research office in Victoria and a knowledge exchange unit in Vancouver. The two offices are collaborating on the implementation of CARBC's first 5-year plan which seeks to build capacity in British Columbia for integrated multi-disciplinary research and knowledge exchange in the areas substance use, addictions and harm reduction. Present challenges include losses to the endowment caused by the 2008/2009 economic crisis and difficulties negotiating faculty positions with the university administration. Despite these hurdles, to date each year has seen increased capacity for the Centre in terms of affiliated scientists, funding and staffing as well as output in terms of published reports, electronic resources and impacts on policy and practice. Areas of special research interest include: drug testing in the work-place, epidemiological monitoring, substance use and injury, pricing and taxation policies, privatization of liquor monopolies, polysubstance use, health determinants of indigenous peoples, street-involved youth and other vulnerable populations at risk of substance use problems. Further information about the Centre and its activities can be found on http://www.carbc.ca.


Characterisation of the frequent exacerbator phenotype in COPD patients in a large UK primary care population.
The 'frequent exacerbator' is recognised as an important phenotype in COPD. Current understanding about this phenotype comes from prospective longitudinal clinical trials in secondary/tertiary care with little information reported in primary care populations. To characterize the frequent-exacerbator phenotype and identify associated risk factors in a large UK primary care COPD population. Using a large database of primary care patients from 80 UK general practices, patients were categorised using GOLD 2014 criteria into high and low risk groups based on exacerbation history. A multivariate logistic regression model was used to investigate covariates associated with the frequent-exacerbator phenotype and risk of experiencing a severe exacerbation (leading to hospitalisation). Of the total study population (n = 9219), 2612 (28%) fulfilled the criteria for high risk frequent-exacerbators. Independent risk factors (adjusted odds ratio [95% CI]) for ≥2 exacerbations were: most severely impaired modified Medical Research Council (mMRC) dyspnoea score (mMRC grade 4: 4.37 [2.64-7.23]), lower FEV1 percent predicted (FEV1 <30%: 2.42 [1.61-3.65]), co-morbid cardiovascular disease (1.42 [1.19-1.68]), depression (1.56 [1.22-1.99]) or osteoporosis (1.54 [1.19-2.01]), and female gender (1.20 [1.01-1.43]). Older patients (≥75 years), those with most severe lung impairment (FEV1 <30%), those with highest mMRC score and those with co-morbid osteoporosis were identified as most at risk of experiencing exacerbations requiring hospitalisation. Although COPD exacerbations occur across all grades of disease severity, female patients with high dyspnoea scores, more severely impaired lung function and co-morbidities are at greatest risk. Elderly patients, with severely impaired lung function, high mMRC scores and osteoporosis are associated with experience of severe exacerbations requiring hospitalisation.


The Relation between the Radial Collapse and the Number of Metaphyseal Screws for Distal Radius Fractures.
The purpose of this study is the evaluation of radial collapse, based on the number of screws used in the metaphyseal region and by distal dorsal distance (DDD) and lunate facet distance (LFD) measurement. Between 2015 and 2019, 60 patients who were being treated with volar locking plates due to isolated distal radius fracture were evaluated. Control radiographs were taken on the first day and at 3rd-, 6th- and 12th-month follow-ups. Distal dorsal cortex distance and lunate facet distance were measured in the lateral radiographs. The number of screws used in the metaphyseal region was also evaluated. According to the number of screws, the amount of collapse was analysed based on both the LFD and the DDD. The mean age of patients was 43.5±12.7 years. Thirty-three of the patients included in the study were male and 27 were female, and the minimum follow-up period was one year. According to the mean number of screws, groups were defined as up to 6 screws or 7 screws and above. There was a statistically significant difference between the groups in terms of DDD collapse at the 6th-month and 12th-month follow-ups (p<0.005). It was observed that the radial collapse and decrease in DDD and LFD were lower in plates with seven screws and above. Decreases in either DDD or LFD, or radial collapse were observed less in patients who had seven or more metaphyseal screws inserted. These findings might be useful for surgeons treating distal radius fractures to reduce radial collapse.


Appropriate glove use in the prevention of cross-infection.
This article aims to promote evidence-based practice in glove use and infection control. Evidence indicates that improvements in infection control practice can reduce the incidence of healthcare-associated infection and exposure to communicable disease among healthcare workers. The correct use of gloves is vital in the healthcare environment. Gloves should be worn for invasive procedures, any contact with sterile sites, non-intact skin, mucous membranes and exposure to blood, body fluids and sharp or contaminated instruments. They should be worn only once, for one aspect of care and one patient, disposed of as clinical waste, and the hands decontaminated after removal.


Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study.
A collection of 1,108 case-parent trios ascertained through an isolated, nonsyndromic cleft lip with or without cleft palate (CL/P) was used to replicate the findings from a genome-wide association study (GWAS) conducted by Beaty et al. (Nat Genet 42:525-529, 2010), where four different genes/regions were identified as influencing risk to CL/P. Tagging SNPs for 33 different genes were genotyped (1,269 SNPs). All four of the genes originally identified as showing genome-wide significance (IRF6, ABCA4 and MAF, plus the 8q24 region) were confirmed in this independent sample of trios (who were primarily of European and Southeast Asian ancestry). In addition, eight genes classified as 'second tier' hits in the original study (PAX7, THADA, COL8A1/FILIP1L, DCAF4L2, GADD45G, NTN1, RBFOX3 and FOXE1) showed evidence of linkage and association in this replication sample. Meta-analysis between the original GWAS trios and these replication trios showed PAX7, COL8A1/FILIP1L and NTN1 achieved genome-wide significance. Tests for gene-environment interaction between these 33 genes and maternal smoking found evidence for interaction with two additional genes: GRID2 and ELAVL2 among European mothers (who had a higher rate of smoking than Asian mothers). Formal tests for gene-gene interaction (epistasis) failed to show evidence of statistical interaction in any simple fashion. This study confirms that many different genes influence risk to CL/P.


Regulation of miR-61 and col-19 via TGF-β and Notch signalling in Caenorhabditis elegans against Klebsiella aerogenes infection.
Klebsiella aerogenes, previously known as Enterobacter aerogenes, is a gram-negative bacterium typically present in the gastrointestinal tract. While numerous studies reported the pathogenicity and drug resistance of this bacterium there remains a lack of comprehensive research on K. aerogenes induced alterations in the host cellular mechanisms. In this study, we identify a previously uncharacterized C. elegans miR-61 that defines an evolutionarily conserved miRNA important for development and innate immunity regulation through Notch and TGF-β signaling pathway. We employed C. elegans wild-type (N2) as well as mutant strains, such as TGF-β (sma-6) and notch-signaling pathway mutants (adm-4 and mir-61). Our results have demonstrated that the K. aerogenes infected mutants exhibited significantly reduced survival rate, reduced pharyngeal pumping, altered swimming and chemotactic behavior. Moreover, K. aerogenes affects the healthspan by increasing ROS level in the mutants. The gene expression analysis revealed that K. aerogenes upregulated egl-30, tph-1 and sod-1 in adm-4, mir-61 mutants not in sma-6. The in-silico analysis indicated an interaction between mir-61 and col-19, which was confirmed by the upregulation of miR-61 expression and the downregulation of col-19 in sma-6, adm-4, and wild-type strains. These findings suggest that C. elegans activates mir-61 and col-19 regulation through the Notch and TGF-β signaling pathway against K. aerogenes infection.


Double-Locking Mechanism of Self-Compatibility in Arabidopsis thaliana: The Synergistic Effect of Transcriptional Depression and Disruption of Coding Region in the Male Specificity Gene.
Self-compatibility in Arabidopsis thaliana represents the relatively recent disruption of ancestral obligate cross pollination, recognized as one of the prevalent evolutionary pathways in flowering plants, as noted by Darwin. Our previous study found that inversion of the male specificity gene (SP11/SCR) disrupted self-incompatibility, which was restored by overexpressing the SCR with the reversed inversion. However, SCR in A. thaliana has other mutations aside from the pivotal inversion, in both promoter and coding regions, with probable effects on transcriptional regulation. To examine the functional consequences of these mutations, we conducted reciprocal introductions of native promoters and downstream sequences from orthologous loci of self-compatible A. thaliana and self-incompatible A. halleri. Use of this inter-species pair enabled us to expand the scope of the analysis to transcriptional regulation and deletion in the intron, in addition to inversion in the native genomic background. Initial analysis revealed that A. thaliana has a significantly lower basal expression level of SCR transcripts in the critical reproductive stage compared to that of A. halleri, suggesting that the promoter was attenuated in inducing transcription in A. thaliana. However, in reciprocal transgenic experiments, this A. thaliana promoter was able to restore partial function if coupled with the functional A. halleri coding sequence, despite extensive alterations due to the self-compatible mode of reproduction in A. thaliana. This represents a synergistic effect of the promoter and the inversion resulting in fixation of self-compatibility, primarily enforced by disruption of SCR. Our findings elucidate the functional and evolutionary context of the historical transition in A. thaliana thus contributing to the understanding of the molecular events leading to development of self-compatibility.


Learning of monochromatic stimuli in Apis cerana and Apis mellifera by means of PER conditioning.
Honey bees are globally distributed and have received increased attention due to their high economic and ecological value for pollination, their exceptional eusocial lifestyle and complex behavioral repertoire. Interestingly, most research on learning and memory in honey bees has been performed in the Western honey bee, Apis mellifera L., and other honey bee species were largely neglected. In the current study, we thus compared visual learning performance of A. mellifera and the Eastern honey bee, A. cerana Fabr., using the proboscis extension response (PER) paradigm. Workers of A. mellifera and A. cerana were differentially conditioned to two monochromatic light stimuli, with peak maxima at 435 and 528 nm. Both honey bee species were able to form an association between the color stimulus and a sugar reward and significantly distinguished between the two color stimuli in a differential discrimination test. However, besides similar performance levels during visual learning, A. cerana showed a reduced mid-term memory (tested after 2 h) compared to A. mellifera. Finally, performance of the visual PER conditioning in our study reached similar levels as found in olfactory PER conditioning, and we thus recommend the visual PER conditioning approach in addition to olfactory conditioning as a useful tool for studying species-specific learning and memory capabilities in honey bees under controlled laboratory conditions.


Detection of DNA sequence polymorphisms among wheat varieties.
A DNA marker detection strategy that allows the rapid, efficient resolution of high levels of polymorphism among closely related lines of common wheat (Triticum aestivum) has been developed to circumvent the apparent lack of restriction fragment length polymorphism in many important self-pollinated crop species. The technique of randomly amplified polymorphic DNA (RAPD) was combined with a denaturing gradient gel electrophoresis system (DGGE) to explore DNA sequence polymorphisms among different genotypes of wheat. Of the 65 primer combinations used for the polymerase chain reaction (PCR) amplifications, over 38% of them produced readily detectable and reproducible DNA polymorphisms between a spring wheat line, SO852, and a winter wheat variety, 'Clark'. A high level of polymorphism was observed among a number of commercial varieties and breeding lines of wheat. This procedure was also used to detect polymorphisms in a recombinant inbred population to test the feasibility of its application in genome mapping. This DNA polymorphism detection system provides an opportunity for pedigree analysis and fingerprinting of developed wheat lines as well as construction of a high density genetic map of wheat. Without the need for (32)P and sophisticated DNA extraction procedures, this approach should make it feasible to utilize marker-based selection in a plant breeding program.


[Destabilization of the DNA Duplex of Actively Replicating Promoters of T7-Like Bacteriophages].
The relation between the processes of replication and transcription has been actively studied over several decades, but detailed mechanisms for their interaction have not been established reliably. Among the initiating transcription promoters of bacteria and bacteriophages, there are both promoters having an additional function of the secondary origin of replication (OR) and promoters not participating in this process. In this paper, we describe the stability of DNA by Stress-Induced Duplex Destabilization (SIDD) profiles for a complete set of promoters and the primary OR of the bacteriophage T7 genome. It has been shown that, among the native T7 promoters, only those that have an additional function of secondary OR are characterized by high destabilization. These include the phiOL and phiOR promoters adjoining the 5' and 3' terminal repeats of bacteriophage T7, and of six other T7 group phages. In each case, these two promoters are located in the regions of DNA with high destabilization of the duplex. Additionally, the genomes of seven representatives of the T7 group without annotated phiOL and phiOR have been considered. For three of them, high peaks of SIDD profiles have been found near the ends of the genomic DNA that may be due to the presence of similar phiOL and phiOR promoters. Probably, such promoters can be found in the genomes of other bacteriophages. Thus, for the promoters of bacteriophages, we have a confirmation of the relationship of SIDD as a DNA duplex parameter and the DNA replication initiation on promoters, serving as secondary OR.


First Report of Fusarium temperatum Causing Fusarium Ear Rot on Maize in Northern China.
In China, several diseases of maize (Zea mays L.) including ear rot are caused by Fusarium spp., leading to significant yield losses and potential risk of mycotoxin contamination (2,3). In 2013, a survey was conducted to determine the population composition of Fusarium species on maize ears in Jilin Province. Symptomatic maize ears with pink or white mold were collected and surface disinfested with 70% ethanol and 10% sodium hypochlorite, followed by three rinses with sterile distilled water and placed onto potato dextrose agar (PDA). After 3 days of incubation at 25°C in the dark, newly grown-out mycelia were transferred onto fresh medium and purified by the single-spore isolation method (4). Fusarium spp. were identified by morphological characteristics (2) and sequence analysis of translation elongation factor-1α (TEF) gene (1). A large number of Fusarium spp. were found including F. graminearum species complex and F. verticillioides. In addition, a new species, F. temperatum, recently described in Belgium (2), was also identified. F. temperatum was originally described as F. subglutinans, but a robust polyphasic approach proved it to be a new biological species closely related to F. subglutinans (2). Previous studies had reported ~15% of Fusarium maize ear rot in Jilin was F. subglutinans. In this study, we found both F. subglutinans s. str. and F. temperatum in the proportion of 16.3% and 9.2%, respectively. Similar to previous studies (2), colonies of our strains on PDA were initially white cottony mycelium that become pinkish white. Conidiophores formed abundantly on SNA that were erect, branched, and terminated in 1 to 3 phialides. Microconidia were abundant, hyaline, 0 to 2 septa, obovoid to oval, and not produced in chains. Chlamydospores were absent. Typically macroconidia were falcate, 3 to 5 septate (mostly 4 septate), hyaline with a curved and blunt apical cell and a distinct foot-shaped basal cell. In order to validate this result, partial translation elongation factor (TEF-1α, 629 bp) gene sequences of isolates were generated (GenBank Accession No. KJ137018) (1). BLASTn analysis revealed 100% sequence identity to F. temperatum (HM067690). A pathogenicity test was performed on maize cv. Zhengdan958. Four days after silk emergence, 2 ml conidial suspension (105 macroconidia/ml) of each isolate was injected into each of 10 maize ears through silk channel. Control plants were inoculated with sterile distilled water. Twenty days after inoculation, typical Fusarium ear rot symptoms (reddish-white mold) was observed on inoculated ears and no symptoms were observed on water controls. Koch's postulates were fulfilled by re-isolating the same fungus from the infected seeds. Although F. temperatum was reported to attack maize kernels in southern China where the annual average temperatures are moderately high (3), to our knowledge, this is the first report of F. temperatum causing Fusarium ear rot in northern China, where the winter is long and very cold, the annual average temperature is 4 to 5°C, and the lowest temperature is lower than -35°C. This indicated that F. temperatum was widely distributed in different ecological regions in China. Furthermore, the northeast spring corn region that includes Jinlin is the most important corn belt, with corn production of this region accounting for 42% of the total corn production in China. Therefore, we should pay more attention to the new species in this region and consider them in the development of maize cultivars with broad-based resistance to the pathogens. References: (1) D. M. Geiser et al. Eur. J. Plant Pathol. 110:473, 2004. (2) J. Scauflaire et al. Mycologia 103:586, 2011. (3) J. H. Wang et al. J. Phytopathol. 162:147, 2014. (4) L. Yang et al. Phytopathology 98:719, 2008.


[A microradiographic and histological study of a case of dentinogenesis imperfecta type I].
Four temporary teeth, extracted for periodontal infection reasons, from a 53-months-old child with osteogenesis imperfecta, have been coated in methyl metacrylate and prepared for microradiographic analysis and light microscopic study. The enamel and dentin of three teeth (51, 65 and 85) don't show any particularity, some how the cementum is remarkably thin. Pulp chambers was large and contain a great number of calcifications. Some of them present a radial striation around a radio-transparent center, and when coloured with blue of methylen, they revealed inflammatory or fibroblastic cells. The fourth tooth (55) shows a dentinogenetic overproduction which closed the major part of the pulp chamber. The dentin presents two rows of different aspect, separated with a calcified bond. The mantle dentin contains sinuous tubules with a type I arrangement of SIAR classification (1986). But, in the deepest dentin, they are very little size and joined together while approaching the center of the tooth and coast along cellular inclusions, pathognomonic sign of dentinogenesis imperfecta. The pulpal space not obliterated contains a calcification with radial and microlacunary aspect.


Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice.
MicroRNAs (miRNAs) have the potential to regulate cellular differentiation programs; however, miRNA deficiency in primary hematopoietic stem cells (HSCs) results in HSC depletion in mice, leaving the question of whether miRNAs play a role in early-lineage decisions un-answered. To address this issue, we deleted Dicer1, which encodes an essential RNase III enzyme for miRNA biogenesis, in murine CCAAT/enhancer-binding protein α (C/EBPA)-positive myeloid-committed progenitors in vivo. In contrast to the results in HSCs, we found that miRNA depletion affected neither the number of myeloid progenitors nor the percentage of C/EBPA-positive progenitor cells. Analysis of gene-expression profiles from wild-type and Dicer1-deficient granulocyte-macrophage progenitors (GMPs) revealed that 20 miRNA families were active in GMPs. Of the derepressed miRNA targets in Dicer1-null GMPs, 27% are normally exclusively expressed in HSCs or are specific for multipotent progenitors and erythropoiesis, indicating an altered gene-expression landscape. Dicer1-deficient GMPs were defective in myeloid development in vitro and exhibited an increased replating capacity, indicating the regained self-renewal potential of these cells. In mice, Dicer1 deletion blocked monocytic differentiation, depleted macrophages, and caused myeloid dysplasia with morphologic features of Pelger-Huët anomaly. These results provide evidence for a miRNA-controlled switch for a cellular program of self-renewal and expansion toward myeloid differentiation in GMPs.


Distribution of circulation-derived endothelial progenitors following systemic delivery.
Cells with an endothelial phenotype can be cultured from peripheral blood. These cells include cells of a monocytic origin with endothelial features (culture-modified mononuclear cells, CMMCs) and, at later time points, blood outgrowth endothelial cells (BOECs). Both are promising candidates for systemic cell-based cardiovascular therapies and each may have unique capabilities. Indeed, the combined use of both cell types has been shown to have synergistic therapeutic features requiring simultaneous delivery. However, the majority of preclinical studies of cell delivery have used splenectomized animals to increase systemic distribution. The goal of this study was to directly compare the distribution of these two cell types following systemic delivery in an intact animal model. A similar pattern of delivery was seen following delivery of both cell types with detection in the lung, liver, bone marrow, and spleen. Taken together, the data suggest that strategies using systemic delivery of circulation-derived cells must consider the distribution and efficiency of delivery in intact animals.


Morphology of Liquid-Liquid Phase Separated Aerosols.
The morphology of liquid-liquid phase separated aerosols has a strong impact on their rate of gas and water uptake, and the type and rate of heterogeneous reactions in the atmosphere. However, it is extremely challenging to experimentally distinguish different morphologies (core-shell or partial wetting) of aerosols and to quantify the extent of wetting between the two phases. The aim of this work is to quantitatively predict the morphology of liquid-liquid aerosols from fundamental physical properties of the aerosol phases. We determine the equilibrium structure of liquid-liquid phase separated aerosols through free energy minimization and predict that the contact angle between the two liquids in the aerosol depends on the composition but not the amount of each phase. We demonstrate that for aerosols of diameter larger than ∼100 nm, the equilibrium contact angle can be accurately predicted from the surface tensions of each liquid with the vapor and between the two liquids through an expression that is identical to Young's equation. The internal structure of smaller, ultrafine aerosols depends also on the value of the line tension between the two liquids and the vapor. The thermodynamic model accurately predicts the experimental morphology, core-shell or partial wetting, of all aerosols for which surface tensions are provided in the literature, and provides contact angles that cannot be accurately determined with state of the art experimental methods. We find that the contact angle of model atmospheric aerosols is rarely higher than 30°. We validate the thermodynamic predictions through molecular simulations of nonane-water droplets, and use the simulation data to compute line tension values that are in good agreement with theory and the analysis from experimental data in water-nonane droplets. Our finding of a simple analytical equation to compute the contact angle of liquid-liquid droplets should have broad application for the prediction of the morphology of two-phase atmospheric aerosols and its impact in their chemistry.


Impact of multisite artery disease on clinical outcomes after percutaneous coronary intervention: an analysis from the e-Ultimaster registry.
Multisite artery disease is considered a 'malignant' type of atherosclerotic disease associated with an increased cardiovascular risk, but the impact of multisite artery disease on clinical outcomes after percutaneous coronary intervention (PCI) is unknown. Patients enrolled in the large, prospective e-Ultimaster study were grouped into (1) those without known prior vascular disease, (2) those with known single-territory vascular disease, and (3) those with known two to three territories (i.e coronary, cerebrovascular, or peripheral) vascular disease (multisite artery disease). The primary outcome was coronary target lesion failure (TLF), defined as the composite of cardiac death, target vessel-related myocardial infarction, and clinically driven target lesion revascularization at 1-year. Inverse propensity score weighted (IPSW) analysis was performed to address differences in baseline patient and lesion characteristics. Of the 37 198 patients included in the study, 62.3% had no prior known vascular disease, 32.6% had single-territory vascular disease, and 5.1% had multisite artery disease. Patients with known vascular disease were older and were more likely to be men and to have more co-morbidities. After IPSW, the TLF rate incrementally increased with the number of diseased vascular beds (3.16%, 4.44%, and 6.42% for no, single, and multisite artery disease, respectively, P < 0.01 for all comparisons). This was also true for all-cause death (2.22%, 3.28%, and 5.29%, P < 0.01 for all comparisons) and cardiac mortality (1.26%, 1.91%, and 3.62%, P ≤ 0.01 for all comparisons). Patients with previously known vascular disease experienced an increased risk of adverse cardiovascular events and mortality post-PCI. This risk is highest among patients with multisite artery disease. Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02188355.


Implementing Smoking Cessation Interventions for Tobacco Users Within Oncology Settings: A Systematic Review.
Patients with cancer who continue to smoke tobacco experience greater treatment-related complications, higher risk of secondary cancers, and greater mortality. Despite research to improve smoking cessation care within clinical oncology, implementation of proposed interventions within routine care remains challenging. To identify and recommend implementation strategies for smoking cessation interventions associated with improved screening, advice-giving, and referral for tobacco users recently diagnosed with cancer, as well as shifting smoking behaviors and attitudes in this patient population. MEDLINE, CINAHL, Embase, and PsycINFO databases, as well as Google Scholar, were searched for articles published before September 7, 2020, using terms related to cancer, smoking cessation, and implementation science. Outcomes of interest were study characteristics, implementation strategies, and outcome measures (screening, advice, referral, abstinence rates, and attitudes). The Cochrane Risk of Bias Tool for randomized and nonrandomized studies was used to assess bias. The review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and Synthesis Without Meta-analysis (SWiM) guideline. Implementation strategies were categorized according to Expert Recommendations for Implementing Change (ERIC) study taxonomy. A systematic analysis was conducted focusing on studies with low or moderate risk of bias due to high heterogeneity in outcome measurement. In total, 6047 records were screened, yielding 43 articles (10 randomized clinical trials and 33 nonrandomized studies). Four strategies were associated with improved screening, advice-giving, and referral: (1) supporting clinicians, (2) training implementation stakeholders (including clinicians), (3) changing the infrastructure, and (4) developing stakeholder interrelationships. In this systematic review, supporting clinicians by providing cessation care through a trained tobacco specialist was identified as important for achieving short-term abstinence and changing attitudes among patients with cancer. Combined with a theoretical framework and stakeholder involvement, these strategies provide the basis for successful implementation of cessation support; this systematic review serves as an illustration of the methodological application and synthesis of implementation studies and other medical conditions more generally.


Kinetics of Severity Biomarkers and Immunological Features of Methylprednisolone Therapy for Severe COVID-19 Patients.
In contrast to dexamethasone, the clinical efficacy of methylprednisolone (MP) remains controversial, and a systems biology study on its mechanism is lacking. In this study, a total of 38 severe COVID-19 patients were included. The demographics, clinical characteristics, and severity biomarkers including C-reactive protein (CRP), d-dimer, albumin, and Krebs von den Lungen 6 of patients receiving MP (n=26, 40 mg or 80 mg daily for 3-5 days) and supportive therapy (n=12) were compared. Longitudinal measurements of 92 cytokines in MP group from admission to over six months after discharge were performed by multiplex Proximity Extension Assay. The results showed that demographics, baseline clinical characteristics were similar in MP and non-MP groups. No death occurred and the hospital stays between the two groups were similar. Kinetics studies showed that MP was not better than supportive therapy at improving the four severity biomarkers. Cytokines in MP group were characterized by five clusters according to their baseline levels and responses to MP. The immunological feature of severe COVID-19 could be defined by the "core signature" cytokines in cluster 2: MCP-3, IL-6, IFN-γ, and CXCL10, which strongly correlated with each other and CRP, and are involved in cytokine release storm. The "core signature" cytokines were significantly upregulated at baseline and remained markedly elevated after MP treatment. Our work showed a short course of MP therapy could not rapidly improve the immune disorders among severe COVID-19 patients or clinical outcomes, also confirmed "core signature" cytokines, as severity biomarkers similar to CRP, could be applied to evaluate clinical treatment effect.


[Meningoradiculitis caused by herpes simplex virus type 2].
A 24-year-old immune-competent woman was admitted to hospital with a three-day history of fever and headache. On examination bilateral facial nerve palsy, lumbosacral radicular pain, reduced sacral sensibility and urinary retention were found. Open perianal lesions were suspect for genital herpes. The symptoms were compatible with a meningoradiculitis including a sacral polyradiculitis. On testing, cerebrospinal fluid was found to be abnormal with a lymphocytic cell reaction. Polymerase chain reaction (PCR) of cerebrospinal fluid and of the perianal lesions was positive for herpes simplex virus type 2 (HSV-2). An MRI scan showed colouration of part of the cauda equina. The patient was treated by intravenous injections of acyclovir 10 mg/kg t.i.d. for 21 days, after which she completely recovered. HSV-2 infection of the nervous system can cause lymphocytic, and sometimes recurrent meningitis as well as sacral polyradiculitis. It may also occur without any symptomatic genital herpes infection. A positive result from a PCR test of the cerebrospinal fluid confirms this diagnosis. Treatment with acyclovir should be started as soon as possible.


Development and Validation of an Observational Game Analysis Tool with Artificial Intelligence for Handball: Handball.ai.
Performance analysis based on artificial intelligence together with game-related statistical models aims to provide relevant information before, during and after a competition. Due to the evaluation of handball performance focusing mainly on the result and not on the analysis of the dynamics of the game pace through artificial intelligence, the aim of this study was to design and validate a specific handball instrument based on real-time observational methodology capable of identifying, quantifying, classifying and relating individual and collective tactical behaviours during the game. First, an instrument validation by an expert panel was performed. Ten experts answered a questionnaire regarding the relevance and appropriateness of each variable presented. Subsequently, data were validated by two observers (1.5 and 2 years of handball observational analysis experience) recruited to analyse a Champions League match. Instrument validity showed a high accordance degree among experts (Cohen's kappa index (k) = 0.889). For both automatic and manual variables, a very good intra- ((automatic: Cronbach's alpha (α) = 0.984; intra-class correlation coefficient (ICC) = 0.970; k = 0.917) (manual: α = 0.959; ICC = 0.923; k = 0.858)) and inter-observer ((automatic: α = 0.976; ICC = 0.961; k = 0.874) (manual: α = 0.959; ICC = 0.923; k = 0.831) consistency and reliability was found. These results show a high degree of instrument validity, reliability and accuracy providing handball coaches, analysts, and researchers a novel tool to improve handball performance.


What POST-COVID-19 lifestyles may look like? Identifying scenarios and their implications for sustainability.
The COVID-19 pandemic has deeply disrupted society´s priorities and individuals' lifestyles with major implications for sustainable development. Economic shutdown and social isolation reduced society's ecological footprint by lowering transportation and industrial activity while prompting families to engage in non-commercialized modes of leisure and social relations. Yet economic recession has intensified problems of under-consumption and poverty, while social isolation has worsened physical and mental illness. The pandemic's short-term effects are visible to everyone experiencing it, yet the global health crisis will also have long-term effects which are presently unknown but whose configurations can be spotted by identifying scenarios based upon individual relations with their material, symbolic and social environments. This perspective article reviews changes in two critical domains of practice: consumption and social relations, based on a theory of scarcity, and proposes an approach to foresee post-COVID-19 scenarios across several areas of social practice. The experience of scarcity in consumption and socializing redefines priorities and values yielding two ideal-types of responses for each domain: the assimilation of reduced levels of material wellbeing and social interactions or the drive for self-indulgence to compensate sacrifices in those areas. Four different lifestyle scenarios are thereby generated based on that analytical framework, enabling the identification of long-term scenarios, beyond the simplistic old normal versus new normal dichotomy. Grounded in available secondary data and relying on the recent Brazilian experience, which can be generalized to other Global South contexts, this proposed framework illustrates distinctive behavioral patterns for each lifestyle across ten areas of practice.