Legionellosis --- United States, 2000-2009.
Legionnaires disease (LD), a serious, sometimes lethal pneumonia, and Pontiac fever (PF), an influenza-like, self-limited illness, are the two most common forms of legionellosis, which is caused by Legionella bacteria. Legionellosis cases are reported to CDC through the National Notifiable Disease Surveillance System (NNDSS) and a Supplemental Legionnaires Disease Surveillance System (SLDSS) designed to manage surveillance data on travel-related cases and enhance outbreak detection. For this report, cases reported to NNDSS during 2000-2009 from the 50 states and the District of Columbia (DC) were assessed, and crude and age-adjusted incidence rates per 100,000 persons were calculated. U.S. legionellosis cases reported annually increased 217%, from 1,110 in 2000 to 3,522 in 2009, and the crude national incidence rate increased 192%, from 0.39 per 100,000 persons in 2000 to 1.15 in 2009. Because NNDSS is a passive surveillance system dependent on health-care providers and laboratories reporting cases, the actual incidence of legionellosis in the United States likely is higher. Although NNDSS does not record legionellosis cases by type, 99.5% of the legionellosis cases reported to SLDSS during 2005-2009 were classified as LD and 0.5% as PF. Legionellosis surveillance was added to the population-based Active Bacterial Core surveillance (ABCs) system in January 2011 to assess reasons for these increases in numbers of reported cases. The rise in reported cases reinforces the need for health-care providers in all parts of the United States to test and treat adults with severe community-acquired pneumonia for LD, to be vigilant for health-care--associated LD, and to report legionellosis cases to public health authorities.


Posterior parahepatic cyst as an incidental finding--review of 40 cases.
To describe the characteristic imaging features of the incidental, isolated posterior parahepatic cyst. Out of 150 patients previously identified on computed tomography (CT) to have an incidental, isolated posterior parahepatic cyst, 40 patients had lesions that were large enough to be assessed for enhancement on CT and/or magnetic resonance imaging (MRI) and had at least 1 year of imaging follow-up. All available CT, MRI, and 2- [(18)F]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) examinations for these 40 patients were reviewed, and the lesions were assessed for size, attenuation, and location relative to the spine and right kidney. For the 40 patients reviewed, all parahepatic lesions were shown to be cysts by absence of identifiable enhancement on CT or MRI. Cysts ranged in size from 3mm to 2.5cm. Hounsfield unit (HU) measurements ranged from 12HU to 83HU. In the transverse plane, all cysts were located lateral to the lateral margin of the right kidney. In the craniocaudal dimension, all cysts were at or above the level of the right kidney, and all were located between the T11-12 and L1-2 vertebral levels. All cysts were stable on follow-up imaging with a mean duration of follow-up of 41 months. Isolated, indolent posterior parahepatic cysts have a characteristic appearance and location and demonstrate benign behaviour with stability on follow-up imaging. These cysts should be considered in the differential diagnosis for isolated parahepatic lesions, and the imaging features described here aid in the distinction of these cysts from other entities such as metastatic disease.


Impulsivity Symptoms as Core to the Developmental Externalizing Spectrum.
Impulsivity is posited to be a key part of the externalizing spectrum during childhood, but this idea has received minimal empirical attention. The goal of the present investigation was to utilize network analysis to determine whether behavioral impulsivity symptoms are key components of the externalizing network across several developmental periods from preschool into adolescence. Participants were 109 preschoolers (64 % male) ages 3 to 6, 237 children (59 % male) ages 6 to 9, 372 children (59 % male) ages 10 to 13, and 357 adolescents (59 % male) ages 13 to 17 and their parents. Parents completed ratings of Attention-Deficit/Hyperactivity Disorder (ADHD) and Oppositional Defiant Disorder (ODD) symptoms on a well-validated rating scale. Network analyses indicated that ADHD and ODD were somewhat differentiated in preschool, becoming united by behavioral impulsivity symptoms during early childhood, and then differentiating into inattention versus externalizing clusters later during childhood and in adolescence. Behavioral impulsivity symptoms were core to the externalizing spectrum across most developmental periods, but core inattentive and ODD symptoms were also identified in line with progressive differentiation. These results suggest the increasing importance of impulsivity symptoms across development, explaining externalizing comorbidity and potentially serving as a viable target for childhood interventions for externalizing problems.


[Low back pain in pregnant women].
Pain of lumbosacral segment of the vertebral column and the pelvis concerns about 45% of all pregnant women. The change of the body posture during pregnancy is the result of gravity centre relocation, which affects the musculosceletal system. Development of the joint, ligament and myofascial dysfunctions, as well as the pain in the lumbosacral segment and the pelvis, are the most common reasons of spine pain. The aim of this review is to present the current state of knowledge about lumbar spine pain in pregnant women with special focus on the pain connected with muscular, joint and ligament disorders. Pregnancy is a serious burden for the female osteo-skeletal system. Lumbar pain with different location and intensification is the negative consequence of the position changes during pregnancy. Pharmacotherapy could be useful only in cases of intensive low back pain, with possible application of small spectrum of drugs that are safe during pregnancy. Physical therapy including manual therapy exercises, massage and techniques of local anesthesia are alternative methods in case of low back pain in pregnant women.


[Psychiatric nursing program for nurses in clinicai setting].
Because education is one of the means to bring about the process of change, a process extremely necessary in psychiatric nursing, the authors decided to find out the opinion of nurses in psychiatric hospitals about the recommended contents of a program of specialization on the subject, to be based on the difficulties found in their work.


Desymmetrization and Parallel Kinetic Resolution of 1-Ethynylcyclobutanols via Asymmetric Cooperative Gold Catalysis.
Enantioselective gold catalysis remains a challenging area of research. By harnessing gold-ligand cooperation in the presence of a chiral bifunctional phosphine ligand featuring a novel 3'-phosphine oxide moiety, highly enantioselective desymmetrization of 1-ethynylcyclobutanols is achieved, permitting access to chiral α-methylenecyclopentanones featuring a diverse array of chiral quaternary and tertiary centers. This cooperative gold catalysis also enables parallel kinetic resolution in gold catalysis, delivering cyclopentanone regioisomers with excellent enantiomeric excesses. DFT calculations of the transition states support the distinct mechanism of asymmetric induction via controlling the conformation of the bound substrate and hence dictating the ring bond undergoing migration.


The design of matching pursuit filters.
This paper presents a new technique for creating efficient and compact models from data, called matching pursuit filters. The design of a matching pursuit filter is based on an adapted wavelet expansion, where the expansion is adapted to both the data and the pattern recognition problem being addressed. This contrasts with most adaptation schemes, where the representation is a function of the data, but not of the problem to be solved. This approach does not decompose the images in the training set individually, but rather determines the expansion by simultaneously decomposing all the images. Because it uses two-dimensional wavelets as the building blocks for the decomposition, the representation is explicitly two-dimensional and is composed of local information. Matching pursuit filters can be trained to detect, recognize, or identify objects and have been applied to recognizing faces and detecting objects in infrared imagery.


Modern Outcomes Following Treatment of Hepatocellular Carcinoma in Hereditary Hemochromatosis: A Matched Cohort Study.
Hepatocellular carcinoma (HCC) is a complication of the common genetic condition hereditary hemochromatosis (HH). It is unknown whether HH as an etiology of liver disease impacts the outcome. We compared the results of liver transplantation (LT), surgical resection and locoregional therapies in a matched cohort study and investigated whether HH as an etiology has an impact on survival. Consecutive patients with HH and HCC (2000 to 2015) were compared with age, sex and Barcelona Clinic Liver Cancer (BCLC) stage-matched non-HH HCC cases. Patients were offered curative or noncurative treatment according to BCLC stage and Milan criteria. The primary endpoint was all-cause mortality. A total of 102 patients (52 HH; total cohort median age: 67 [44 to 78] y, 97% male, Model for End-stage Liver Disease: 9 [5 to 31]) were studied with a median follow-up of 22 (3 to 126) months. Of the HH cases, the median serum ferritin at diagnosis of HCC was 326 (27 to 5718) μg/L and α-fetoprotein 33 (2 to 197,926) kIU/L. Five-year survival for HH patients receiving curative therapy was 77% (80% for LT, 67% for resection/radiofrequency ablation), and 15% (23% for transarterial chemoembolization) for those undergoing noncurative therapy. Survival for HH patients compared with controls was similar (hazard ratio=0.949; P=0.839). On multivariate Cox regression survival analysis, BCLC stage, and diagnosis of ischemic heart disease (but not HH diagnosis) were independently associated with reduced survival. Patients with HCC and HH can achieve comparable survival rates following curative or LRT modalities to other liver diseases. The BCLC staging system accurately stratifies survival and excellent 5-year survival is possible following LT in selected patients.


Improvements in colorectal cancer screening programmes - quantitative immunochemical faecal occult blood testing - how to set the cut-off for a particular population.
The aim of the study was to determine the optimum cut-off value of the quantitative immunochemical test (q-FIT) OC-Sensor for colorectal cancer and advanced adenomatous polyps in a particular population. 815 patients were referred for colonoscopy and were offered two q-FIT examinations at two different colonoscopy centers. The patients were classified according to the colonoscopic findings. Test sensitivity, specificity, and accuracy were statistically evaluated using one test and two tests at the levels of 50, 75, 100, 125, and 150 ng/mL of faecal hemoglobin in those patients with advanced polyps and colorectal cancer. The optimum cut-off test level for clinically significant neoplasia was determined using one test. The optimum cut-off value of q-FIT OC-Sensor for the detection of clinically significant neoplasia in our particular population was determined as 75 ng/mL using one test. This value provides an optimum proportion of 73% sensitivity (±95% CI 60.3% - 83.4%) and 90% specificity (±95% CI 86.8% - 92.8%), PPV and NPV were determined as 54.76% and 95.43% respectively. The first step in the implementation of q-FIT test in the screening program in our country is to determine the optimum cut-off level for a population, and to estimate the number of tests performed with respect to the optimum cost effectiveness and economical climate. Using one test, the optimum level of q-FIT OC-Sensor® in the Czech Republic was determined as 75 ng/mL. This study could serve as a model for further studies in other countries, where screening does not yet exist.


The Use of Somatosensory Evoked Potentials to Determine the Relationship Between Intraoperative Arterial Blood Pressure and Intraoperative Upper Extremity Position-Related Neurapraxia in the Prone Surrender Position During Spine Surgery: A Retrospective Analysis.
Peripheral nerve injury is a significant perioperative problem. Intraoperative position-related neurapraxia may indicate impending peripheral nerve injury and can be detected by changes in somatosensory evoked potentials (SSEP). The purpose of this retrospective analysis of spine surgeries performed under general anesthesia with SSEP monitoring was to determine the relationship between intraoperative mean arterial blood pressure (MAP) and intraoperative upper extremity position-related neurapraxia in the prone surrender (superman) position. We reviewed a computerized database of spine surgeries performed on adult patients in the prone surrender position. The authors reviewed intraoperative SSEP monitoring reports to identify the patients who developed intraoperative upper extremity position-related neurapraxia (case group) and patients who did not (control group). Propensity matching was performed to derive 2 demographically matched groups. Preoperative and intraoperative variables were included in the univariate Cox regression analysis of risk factors associated with neurapraxia. Multivariate Cox regression models were used to identify the independent risk factors. One hundred fifty-two patients were included in the analysis. The case group included 32 patients, whereas the control group included 120 matched patients. Intraoperative MAP <55 mm Hg for a total duration of ≥5 minutes was an independent risk factor associated with a greater incidence of upper extremity position-related neurapraxia compared with a duration of <5 minutes with MAP <55 mm Hg (hazard ratio, 3.43; confidence interval, 1.445-8.148; P = 0.0052). Intraoperative MAP >80 mm Hg for a total duration of >55 minutes was an independent predictor associated with a lower incidence of neurapraxia compared with a total duration ≤55 minutes (hazard ratio, 0.341; confidence interval, 0.163-0.717; P = 0.0045). In this study, we identified the changes in intraoperative MAP as independent predictors associated with upper extremity position-related neurapraxia in the prone surrender position under general anesthesia.


Biology of SNU cell lines.
SNU (Seoul National University) cell lines have been established from Korean cancer patients since 1982. Of these 109 cell lines have been characterized and reported, i.e., 17 colorectal carcinoma, 12 hepatocellular carcinoma, 11 gastric carcinoma, 12 uterine cervical carcinoma, 17 B-lymphoblastoid cell lines derived from cancer patients, 5 ovarian carcinoma, 3 malignant mixed Mllerian tumor, 6 laryngeal squamous cell carcinoma, 7 renal cell carcinoma, 9 brain tumor, 6 biliary tract, and 4 pancreatic carcinoma cell lines. These SNU cell lines have been distributed to biomedical researchers domestic and worldwide through the KCLB (Korean Cell Line Bank), and have proven to be of value in various scientific research fields. The characteristics of these cell lines have been reported in over 180 international journals by our laboratory and by many other researchers from 1987. In this paper, the cellular and molecular characteristics of SNU human cancer cell lines are summarized according to their genetic and epigenetic alterations and functional analysis.


Use of Genetically Modified Organism (GMO)-Containing Food Products in Children.
Families increasingly raise questions about the use of genetically modified organism (GMO)-containing food products. These products are widely found in the US food supply but originate from a narrow list of crops. Although GMO technology could be used to increase the micronutrient content of foods, this does not occur in the United States; instead, GMO technology has been used to make crops resistant to chemical herbicides. As a result, herbicide use has increased exponentially. The World Health Organization's International Agency on Research for Cancer has determined that glyphosate, an herbicide widely used in producing GMO food crops, is a probable human carcinogen. Measurable quantities of glyphosate are detected in some GMO foods. Families who wish to minimize GMO food products can do so by focusing on a dietary pattern of primarily whole, plant-based foods while minimizing ultra-processed foods. Pediatricians play a vital role in their efforts to minimize fear-based messaging and support families through shared decision-making. Pediatrician awareness of GMO labeling can guide individualized conversations, particularly that non-GMO labeling does not indicate organic status and that increased cost of some non-GMO foods, especially if also organic, may limit this choice for many families.


Will it ever become possible to prevent dopaminergic neuronal degeneration?
Parkinson's disease (PD) is the second leading age-related degenerative brain disease in the world affecting millions of people. This neurological disorder disrupts the quality of life of patients and their families, exerts an enormous emotional and physical strain on caregivers, and has a large cost for society. Moreover, the increasing numbers of elderly people in the population will result in a sharp increase in the prevalence of PD. The understanding of its pathophysiology and treatment has advanced at a very impressive rate during past decades. Nevertheless, PD is still fatal and there is at present no cure for it. Furthermore, there are no proven therapies for prevention of PD and although evidence exists of risk and protective factors, this is not strong enough to warrant specific measures in an attempt to diminish risk or enhance protection. Drug development programmes are engaged in finding neuroprotective and neurorestorative therapies or, even better, discovering drugs able to rejuvenate the dopaminergic neurons. The latest developments in this promising field will be discussed with reference to the current literature together with the advantages and pitfalls of suggested drugs. Finally, an analysis of the role of various dietary recommendations, lifestyle, environmental and other factors in reducing the risk of PD is carried out.


Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial.
Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC. This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0-1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m2 intravenously followed by 250 mg/m2 intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov, NCT03082534, and remains open as the three additional cohorts are actively accruing participants. Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9-10·9). By 6 months, the overall response rate was 45% (95% CI 28-62), with 15 of 33 participants achieving a partial response. The most common grade 3-4 treatment-related adverse event was oral mucositis (three [9%] of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred. Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation. Merck Sharp & Dohme.


Transitional Twin Block.
When FJO is integrated with fixed orthodontic treatment possibilities are greater than with one system only. Given proper case selection and patient corroboration consistent results are achieved. The Comfort Twin Block design enhances patient acceptance and compliance. Transitional Twin Block Methods to encourage active eruption of teeth result in faster case completion. The Twin Block is a versatile and effective appliance in the correction of Class II malocclusions.


UV cross-linking/immunoprecipitation assay: glucocorticoid receptor-adrenergic receptor gene sequence interaction.
The rat beta 1-adrenergic receptor (beta 1-AR) gene contains glucocorticoid response element (GRE) half-sites at positions -2767 and -945. In electrophoretic mobility shift assay (EMSA) experiments, neither beta 1-AR GRE half-site recognized glucocorticoid receptors (GRs) obtained from baculovirus high-level expression systems or from mammalian cells. We have developed a sensitive UV cross-linking/immunoprecipitation assay, using a 524-bp fragment containing the prototypical GRE obtained from the rat tyrosine aminotransferase promoter sequence and using antibodies recognizing mammalian GR. Using this assay, we provide evidence that rat beta 1-AR gene sequences recognize mammalian GRs expressed in mouse 3T3 cells and that the site of GR interaction does not appear to specifically contain the beta 1-AR GRE half-sites. This represents one of the first reports demonstrating the utility of a UV cross-linking/immunoprecipitation assay in the detection of mammalian GR interaction with beta 1-AR sequences, is consistent with the lack of specific DNA-GR protein complexes observed in EMSA experiments using oligonucleotide probes containing the beta 1-AR GRE half-sites, and provides evidence that mammalian GR interaction occurs at complex rate beta 1-AR gene sequences.


The "Warrior" COMT Val/Met Genotype Occurs in Greater Frequencies in Mixed Martial Arts Fighters Relative to Controls.
A functional single-nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene (rs4680) is a gene variant that has been shown to predict the ability to maintain cognitive agility during combat and competition. Critically, COMT Met (low-activity; high dopamine) allele carriers outperform Val (high-activity; low dopamine) homozygotes on a variety of cognitive tasks. However, the relationship between genotype and cognitive performance appears to reverse under stressful conditions. Stress increases pre-frontal cortex dopamine (PFC DA) levels, and Met allele carriers (with higher DA) show performance deficits relative to Val allele carriers. This pattern reflects the inverted U-shaped function of DA activity where too little (Val allele) or too much (Met allele carriers under stress) DA is associated with poor cognitive performance. The Val allele advantage for stress resiliency is referred to as the COMT "warrior/ worrier" model. In line with this model, we predicted that elite level mixed martial arts (MMA) fighters would be more likely than athlete controls to carry the GG (warrior) genotype compared to an athlete group and a non-athlete group. Based on findings in our previous studies, we also assessed the stress biomarkers cortisol and salivary alpha-amylase (sAA). There was an overall significant difference in genotype frequencies between groups (p =0.01) and the MMA group showed a significantly greater GG (warrior) genotype frequency than the non-athlete control group (p = 0.003). There was not a significant group x genotype interaction for the cortisol or sAA; however, the non-athlete GG group had significantly higher cortisol than the A/- group (p = 0.038). Combined, our findings suggest that the "warrior" genotype may play a participation role in combat sports.


Antioxidative meroterpenoids from the brown alga Cystoseira crinita.
Six new tetraprenyltoluquinol derivatives (1-6), two new triprenyltoluquinol derivatives (7 and 8), and two new tetraprenyltoluquinone derivatives (9 and 10) were isolated from the brown alga Cystoseira crinita Duby together with four known tetraprenyltoluquinol derivatives (11-14). All structures were elucidated by employing spectroscopic techniques (NMR, MS, UV, and IR). Each compound was evaluated for its antioxidative properties in the TBARS and DPPH assay, and compounds 1, 2, 6, and 10-14 were additionally assessed in the TEAC and PCL assay. Hydroquinones were found to have powerful antioxidant activity.


Interferometer for optical coherence tomography.
We describe a new interferometer setup for optical coherence tomography (OCT). The interferometer is based on a fiber arrangement similar to Young's two-pinhole interference experiment with spatial coherent and temporal incoherent light. Depth gating is achieved detection of the interference signal on a linear CCD array. Therefore no reference optical delay scanning is needed. The interference signal, the modulation of the signal, the axial resolution, and the depth range are derived theoretically and compared with experiments. The dynamic range of the setup is compared with OCT sensors in the time domain. To our knowledge, the first images of porcine brain and heart tissue and human skin are presented.


Direct imaging and manipulation of ionic diffusion in mixed electronic-ionic conductors.
Next generation Li-ion batteries require improved energy densities, power output and safety to satisfy the demands of emerging technologies. All solid state 3D thin-film batteries (ASB) based on nanoionics are considered as frontrunners to enable all this. In order to facilitate the introduction of this new architecture, a homogeneous electrochemical activity and a high ionic diffusivity of the electrodes is key. However, nanometer-resolved techniques to probe structural, electrical and electrochemical properties of the battery components are still limited. Here we propose a study that combines conductive atomic force microscopy (C-AFM) and secondary ion mass spectrometry (SIMS) for structural and electrical characterization. In addition, a novel concept called ion-modulated C-AFM (imC-AFM) is introduced to also sense the electrochemical activity of ions in confined volumes. Using the aforementioned methodologies, LixMn2O4 thin film cathodes are studied observing: (1) a direct correlation between electrical conductivity and local chemistry. (2) A non-uniform Li-ion electrochemical activity (i.e. ionic conductivity) on the cathode's surface with a clear enhancement in grain boundaries (GBs). Finally, (3) imC-AFM observes a high volume expansion associated with high Li incorporation. This work introduces a novel pathway for the rapid analysis of materials to be used in ASB.


Future trends in antimicrobial chemotherapy: expert opinion on the 43rd ICAAC.
The current document bestows an expert synopsis of key new information presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in 2003. Data is presented on the socio-political aspects of and policies on antimicrobial prescribing, novel mechanisms of resistance in Streptococcus pneumoniae, and current epidemiological trends in global resistance. Novel information on new (and existing) antimicrobial agents--new penicillins, cephalosporins, monobactams and oxipenem inhibitors, ketolides, glycopeptides, fluoroquinolones (and hybrids), peptides, daptomycin, aminomethylcyclines, glycylcyclines, and newer formulations of agents such as amoxycillin-clavulanate--provides renewed hope that resistant pathogens can be controlled through use of more potent agents. Improved strategies for the use of existing antimicrobial agents, such as the use of high-dose regimens, short-course therapy, also may delay or reduce the development of resistance and preserve the value of our antibiotic armamentarium.


[Ultrastructural study on membranoproliferative glomerulonephritis with special reference to subepithelial deposits].
The distribution of electron dense deposits in the glomerulus was scrutinized by electron microscopy in 34 cases of membranoproliferative glomerulonephritis (MPGN). Seven cases underwent serial biopsies. Results are summarized as follows. (1) Mesangial deposits (MD) and subendothelial deposits (SEND) were demonstrated in nearly all biopsy specimens. Intramembranous deposits (IMD) and subepithelial deposits (SEPD), which had hitherto been considered uncommon in MPGN, were also seen in over three- fourths of the specimens. (2) According to these findings, Burkholder's Type III MPGN, characterized by the frequent presence of SEPD, seems not to be essential in the classification of MPGN. In contrast, Strife's type III MPGN, defined by the disruption of the glomerular basement membrane (GBM), appears to be appropriate for the classification, because the cases diagnosed as Strife's type III showed quite peculiar histology among the MPGN. (3) In most cases having undergone serial biopsies, cellular proliferation in the glomeruli was more improved at the second biopsy than at the first, which probably resulted from intensive medications such as the combined therapy of corticosteroids, immunosuppressants, and anticoagulants. On electron microscopy, however, electron dense deposits were not decreased, and SEPD was rather increased. Furthermore, the GBM was more thickened and showed more irregular structure in the second biopsy. (4) Humps were observed in 14 out of 41 biopsy specimens of MPGN. They were seen not only in the acute but also in the chronic stage of the disease, especially in the cases with persistent hypocomplementemia. These results suggest that the subepithelial deposits are more common in MPGN than considered previously, and are more closely related to the morphological changes and the progression of MPGN. In particular, humps should be a marker indicating the activity of the disease associated with hypocomplementemia, whether it is acute or chronic.


KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.
Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.


Structural organization of chloroplast coupling factor.
Fluorescence resonance energy transfer measurements have been used to construct spatial maps for the accessible sulfhydryl of the gamma subunit (dark site) and the essential tyrosine residue of the beta subunits relative to previously mapped sites on the H+-ATPase from chloroplasts. The extent of energy transfer was measured between a coumarinylmaleimide derivative reacted covalently at the dark site and acceptor species selectively bound at the gamma-disulfide and the three nucleotide binding sites of the solubilized coupling factor complex. The nucleotide energy acceptor was 2'(3')-(trinitrophenyl)adenosine triphosphate, and the gamma-disulfide site was labeled with fluoresceinylmaleimide. The dark-site sulfhydryl also was labeled with pyrenylmaleimide which served as an energy donor for 7-chloro-4-nitro-2,1,3-benzoxadiazole reacted at the beta-tyrosine sites. Similar measurements were also made with pyrenylmaleimide covalently attached to the gamma-sulfhydryl accessible only under energized conditions on the thylakoid membrane surface (light site). The observed transfer efficiencies indicate that the dark-site sulfhydryl is approximately 45 A from all three nucleotide sites and 41-46 A from the gamma-disulfide site. The average distances separating the essential beta-tyrosines and the light- and dark-site sulfhydryls are 38 and 42 A, respectively. (In calculating these distances, random orientation of the donor-acceptor dipoles was assumed.) The results are consistent with a previously described structural model of the intact enzyme and can be used to gain insight into the overall structural organization or alpha-, beta-, and gamma-polypeptides within the coupling factor.


Pathogenesis of Rift Valley fever in rhesus monkeys: role of interferon response.
Rhesus monkeys inoculated intravenously with Rift Valley fever (RVF) virus presented clinical disease syndromes similar to human cases of RVF. All 17 infected monkeys had high-titered viremias but disease ranged from clinically inapparent to death. Three (18%) RVF virus-infected monkeys developed signs of hemorrhagic fever characterized by epistaxis, petechial to purpuric cutaneous lesions, anorexia, and vomiting prior to death. The 14 remaining monkeys survived RVF viral infection but, 7 showed clinical signs of illness characterized by diminished food intake, cutaneous petechiae, and occasional vomiting. The other 7 monkeys showed no evidence of clinical disease. All monkeys had detectable serum interferon 24-30 h after infection, but 4 of 7 monkeys that did not develop clinical illness had serum interferon titers within 12 h after infection. In lethally infected macaques, indices of hepatic function and blood coagulation were abnormal within 2 days, implicating early pathogenetic events as critical determinants of survival. Serum transferase values were elevated in proportion to severity of clinical disease and outcome of infection. Both myocardial damage and laboratory evidence consistent with disseminated intravascular coagulation were present in fatal infections. All surviving monkeys developed neutralizing antibodies to RVF virus 4-7 days after infection, and this coincided with termination of viremia. Two fatally infected monkeys were viremic until death on days 6 and 8, and the third cleared viremia on day 5 and developed antibody on day 6 but died on day 15. There was a significant correlation between a delayed interferon response and mortality, suggesting that the early appearance of interferon was influential in limiting the severity of disease.


Nitroglycerin tolerance in caveolin-1 deficient mice.
Nitrate tolerance developed after persistent nitroglycerin (GTN) exposure limits its clinical utility. Previously, we have shown that the vasodilatory action of GTN is dependent on endothelial nitric oxide synthase (eNOS/NOS3) activity. Caveolin-1 (Cav-1) is known to interact with NOS3 on the cytoplasmic side of cholesterol-enriched plasma membrane microdomains (caveolae) and to inhibit NOS3 activity. Loss of Cav-1 expression results in NOS3 hyperactivation and uncoupling, converting NOS3 into a source of superoxide radicals, peroxynitrite, and oxidative stress. Therefore, we hypothesized that nitrate tolerance induced by persistent GTN treatment results from NOS3 dysfunction and vascular toxicity. Exposure to GTN for 48-72 h resulted in nitrosation and depletion (>50%) of Cav-1, NOS3 uncoupling as measured by an increase in peroxynitrite production (>100%), and endothelial toxicity in cultured cells. In the Cav-1 deficient mice, NOS3 dysfunction was accompanied by GTN tolerance (>50% dilation inhibition at low GTN concentrations). In conclusion, GTN tolerance results from Cav-1 modification and depletion by GTN that causes persistent NOS3 activation and uncoupling, preventing it from participating in GTN-medicated vasodilation.


Management of Tinnitus In Covid-19 Outbreak- A Comparative Study Between Mindfulness Based Tinnitus Stress Reduction And Tinnitus Retraining Therapy.
Covid-19 pandemic has caused a profound impact on the lives of people and has given rise to many mental health issues like anxiety and stress which eventually has given rise to bothersome tinnitus. In case of people having pre-existing tinnitus, the pandemic has raised the problem of tinnitus and the co-morbid issues related to tinnitus and severely affected the overall quality of life. Hence, we need to find a mean for home-based management of tinnitus and its associated problems. To understand the mechanism of mental health and to compare between the mindfulness-based tinnitus reduction and tinnitus retraining therapy on android-based application. Comparative and Experimental design. The study was conducted on 60 participants and was divided into two groups. Detailed audiological assessment, tinnitus assessment and Tinnitus Handicap Inventory (THI) and Tinnitus Cognitions Questionnaire (TCQ) were administered. Group-I was provided with tinnitus retraining therapy and group-II was provided with mindfulness based tinnitus stress reduction. After the post therapy evaluation the data were compiled for statistical analysis in SPSS software 20.0. Results: It was found that there were significant difference between the pre and post therapy scores of TRT and MBTSR in both THI and TCQ (p<0.001). Home-based management of tinnitus during the COVID-19 pandemic using both TRT and MBTSR were highly successful and had similar results MBTSR was found to be more useful as it had better outcome in reducing the tinnitus related annoyance and shown better improvement in QOL examination.


Equine infectious anemia virus resists the antiretroviral activity of equine APOBEC3 proteins through a packaging-independent mechanism.
Equine infectious anemia virus (EIAV), uniquely among lentiviruses, does not encode a vif gene product. Other lentiviruses, including human immunodeficiency virus type 1 (HIV-1), use Vif to neutralize members of the APOBEC3 (A3) family of intrinsic immunity factors that would otherwise inhibit viral infectivity. This suggests either that equine cells infected by EIAV in vivo do not express active A3 proteins or that EIAV has developed a novel mechanism to avoid inhibition by equine A3 (eA3). Here, we demonstrate that horses encode six distinct A3 proteins, four of which contain a single copy of the cytidine deaminase (CDA) consensus active site and two of which contain two CDA motifs. This represents a level of complexity previously seen only in primates. Phylogenetic analysis of equine single-CDA A3 proteins revealed two proteins related to human A3A (hA3A), one related to hA3C, and one related to hA3H. Both equine double-CDA proteins are similar to hA3F and were named eA3F1 and eA3F2. Analysis of eA3F1 and eA3F2 expression in vivo shows that the mRNAs encoding these proteins are widely expressed, including in cells that are natural EIAV targets. Both eA3F1 and eA3F2 inhibit retrotransposon mobility, while eA3F1 is a potent inhibitor of a Vif-deficient HIV-1 mutant and induces extensive editing of HIV-1 reverse transcripts. However, both eA3F1 and eA3F2 are weak inhibitors of EIAV. Surprisingly, eA3F1 and eA3F2 were packaged into EIAV and HIV-1 virions as effectively as hA3G, although only the latter inhibited EIAV infectivity. Moreover, all three proteins bound both the HIV-1 and EIAV nucleocapsid protein specifically in vitro. It therefore appears that EIAV has evolved a novel mechanism to specifically neutralize the biological activities of the cognate eA3F1 and eA3F2 proteins at a step subsequent to virion incorporation.


Top-Down Inference in the Auditory System: Potential Roles for Corticofugal Projections.
It has become widely accepted that humans use contextual information to infer the meaning of ambiguous acoustic signals. In speech, for example, high-level semantic, syntactic, or lexical information shape our understanding of a phoneme buried in noise. Most current theories to explain this phenomenon rely on hierarchical predictive coding models involving a set of Bayesian priors emanating from high-level brain regions (e.g., prefrontal cortex) that are used to influence processing at lower-levels of the cortical sensory hierarchy (e.g., auditory cortex). As such, virtually all proposed models to explain top-down facilitation are focused on intracortical connections, and consequently, subcortical nuclei have scarcely been discussed in this context. However, subcortical auditory nuclei receive massive, heterogeneous, and cascading descending projections at every level of the sensory hierarchy, and activation of these systems has been shown to improve speech recognition. It is not yet clear whether or how top-down modulation to resolve ambiguous sounds calls upon these corticofugal projections. Here, we review the literature on top-down modulation in the auditory system, primarily focused on humans and cortical imaging/recording methods, and attempt to relate these findings to a growing animal literature, which has primarily been focused on corticofugal projections. We argue that corticofugal pathways contain the requisite circuitry to implement predictive coding mechanisms to facilitate perception of complex sounds and that top-down modulation at early (i.e., subcortical) stages of processing complement modulation at later (i.e., cortical) stages of processing. Finally, we suggest experimental approaches for future studies on this topic.


Effects of an activator on the masseter and anterior temporal muscle activities in Class II malocclusions.
Effects of an activator on the temporal and masseter muscles activities were investigated in subjects with an Angle Class II division 1 malocclusions in this study. The measurements were done on 21 subjects. Twelve of these subjects were in the treatment group and 9 were in the control group. Average ages of treatment group was 11.42 +/- 0.29 years and average ages of control group was 10.68 +/- 0.52 years. Muscle activities were investigated at the beginning and at the end of this research, both with and without the activator. The increase of activities in the rest position and decrease of activities in maximum biting of both muscles with activator were found to be statistically significant at the beginning of the treatment. Activities of both muscles with the activator decreased in the rest position at the end of treatment when compared to the beginning of the treatment. No change has been observed between the activities of masseter and temporal muscles recorded at the beginning and at the end of this investigation without the activator.


Genome-wide association study of antidepressant response: involvement of the inorganic cation transmembrane transporter activity pathway.
Genome-wide association studies (GWAS) represent the current frontier in pharmacogenomics. Thousands of subjects of Caucasian ancestry have been included in previous GWAS investigating antidepressant response. GWAS focused on this phenotype are lacking in Asian populations. A sample of 109 major depressive disorder (MDD) patients of Korean origin in antidepressant treatment was collected. Phenotypes were response and remission according to the Hamilton Rating Scale for Depression (HRSD). Genome-wide genotyping was performed using the Illumina Human Omni2.5-8 platform. The same phenotypes were used in the STAR*D level 1 (n = 1677) for independent replication. In order to corroborate findings and increase the comparability between the two datasets, three levels of analysis (SNPs, genes and pathways) were carried out. Bonferroni correction, permutations, and replication across samples were used to reduce the risk of false positives. Among the genes replicated across the two samples (permutated p < 0.05 in both of them), CTNNA3 appeared promising. The inorganic cation transmembrane transporter activity pathway (GO:0022890) was associated with antidepressant response in both samples (p = 2.9e-5 and p = 0.001 in the Korean and STAR*D samples, respectively) and this pathway included CACNA1A, CACNA1C, and CACNB2 genes. The present study supported the involvement of genes coding for subunits of L-type voltage-gated calcium channel in antidepressant efficacy across different ethnicities but replication of findings is required before any definitive statement.


Comparison of 2 canal preparation techniques in the induction of microcracks: a pilot study with cadaver mandibles.
The purpose of this pilot study in a cadaver model was to compare 2 different shaping techniques regarding the induction of dentinal microcracks. Three lower incisors from each of 6 adult human cadaver skulls were randomly distributed into 3 groups: the control group (CG, no instrumentation), the GT group (GT Profile hand files; Dentsply Tulsa Dental, Tulsa, OK), and the WO group (WaveOne; Dentsply Tulsa Dental). In the GT group, manual shaping in a crown-down sequence with GT Profile hand files was performed. In the WO group, Primary WaveOne files were used to the working length. Teeth were separated from the mandibles by careful removal of soft tissue and bone under magnification. Roots were sectioned horizontally at 3, 6, and 9 mm from the apex using a low-speed saw. Color photographs at 2 magnifications (25× and 40×) were obtained. Three blinded examiners registered the presence of microcracks (yes/no), extension (incomplete/complete), direction (buccolingual/mesiodistal), and location. Data were analyzed with chi-square tests at P < .05. Microcracks were found in 50% (CG and GT) and 66% (WO) of teeth at 3 mm, 16.6% (CG) and 33.3% (GT and WO) at 6 mm, and 16.6% in all 3 groups at 9 mm from the apex. There were no significant differences in the incidence of microcracks between all groups at 3 (P = .8), 6 (P = .8), or 9 mm (P = 1). All microcracks were incomplete, started at the pulpal wall, and had a buccolingual direction. Within the limitations of this pilot study, a relationship between the shaping techniques (GT hand and WaveOne) and the incidence of microcracks could not be shown compared with uninstrumented controls.


Predictive value of colony-forming unit assays for engraftment and leukemia-free survival after transplantation of chemopurged syngeneic bone marrow in rats.
We evaluated the efficacy of in vitro clonogenic assays for acute myeloid leukemia (AML) (CFU-Leuk) and granulocyte-macrophage progenitor cells derived from normal bone marrow (BM) (CFU-GM) to predict hematopoietic engraftment, median survival time (MST) and leukemia-free survival (LFS) in LBN rats that received injections of untreated or drug-treated AML and/or normal BM cells. Injection of untreated AML cells resulted in a log-linear relationship between AML cell dose and time of death from leukemia; LBN rats given 10(6) cells died with AML (MST, 24 days; range, 19-28) after injection. A minimum of 0.5-1.0 X 10(6) untreated normal BM cells was needed to insure satisfactory hematopoietic reconstitution in at least 50% of lethally irradiated LBN rats. After ex vivo incubation with graded concentrations of 4-hydroperoxycyclophosphamide (4HC) or bleomycin (BLEO), LBN AML or normal BM cells were cultured for CFU-Leuk or CFU-GM and injected into untreated or lethally irradiated syngeneic recipients. Over a variety of drug concentrations (4HC, 3-30 micrograms/ml; BLEO, 100-10,000 mU/ml) and cell doses (10(6)-10(7)/animal) examined, the log-kill estimates derived from in vitro CFU-Leuk assays correlated with the observed MST or LFS. Recovery of greater than 1% CFU-GM from 4HC- or BLEO-treated suspensions of normal BM was associated with satisfactory engraftment in lethally irradiated LBN rats. Clonogenic assays also predicted for engraftment and LFS in animals that received mixtures of AML and normal BM cells (1:10) treated with 4HC and/or BLEO. We conclude that CFU-Leuk and CFU-GM assays are useful screening techniques to develop and evaluate strategies for ex vivo purging with chemotherapeutic agents in this preclinical model of autologous marrow transplantation for AML.


Health disparities and health equity: the issue is justice.
Eliminating health disparities is a Healthy People goal. Given the diverse and sometimes broad definitions of health disparities commonly used, a subcommittee convened by the Secretary's Advisory Committee for Healthy People 2020 proposed an operational definition for use in developing objectives and targets, determining resource allocation priorities, and assessing progress. Based on that subcommittee's work, we propose that health disparities are systematic, plausibly avoidable health differences adversely affecting socially disadvantaged groups; they may reflect social disadvantage, but causality need not be established. This definition, grounded in ethical and human rights principles, focuses on the subset of health differences reflecting social injustice, distinguishing health disparities from other health differences also warranting concerted attention, and from health differences in general. We explain the definition, its underlying concepts, the challenges it addresses, and the rationale for applying it to United States public health policy.


Dumpy-30 family members as determinants of male fertility and interaction partners of metal-responsive transcription factor 1 (MTF-1) in Drosophila.
Metal-responsive transcription factor 1 (MTF-1), which binds to metal response elements (MREs), plays a central role in transition metal detoxification and homeostasis. A Drosophila interactome analysis revealed two candidate dMTF-1 interactors, both of which are related to the small regulatory protein Dumpy-30 (Dpy-30) of the worm C. elegans. Dpy-30 is the founding member of a protein family involved in chromatin modifications, notably histone methylation. Mutants affect mating type in yeast and male mating in C. elegans. Constitutive expression of the stronger interactor, Dpy-30L1 (CG6444), in transgenic flies inhibits MTF-1 activity and results in elevated sensitivity to Cd(II) and Zn(II), an effect that could be rescued by co-overexpression of dMTF-1. Electrophoretic mobility shift assays (EMSA) suggest that Dpy-30L1 interferes with the binding of MTF-1 to its cognate MRE binding site. Dpy-30L1 is expressed in the larval brain, gonads, imaginal discs, salivary glands and in the brain, testes, ovaries and salivary glands of adult flies. Expression of the second interactor, Dpy-30L2 (CG11591), is restricted to larval male gonads, and to the testes of adult males. Consistent with these findings, dpy-30-like transcripts are also prominently expressed in mouse testes. Targeted gene disruption by homologous recombination revealed that dpy-30L1 knockout flies are viable and show no overt disruption of metal homeostasis. In contrast, the knockout of the male-specific dpy-30L2 gene results in male sterility, as does the double knockout of dpy-30L1 and dpy-30L2. A closer inspection showed that Dpy-30L2 is expressed in elongated spermatids but not in early or mature sperm. Mutant sperm had impaired motility and failed to accumulate in sperm storage organs of females. Our studies help to elucidate the physiological roles of the Dumpy-30 proteins, which are conserved from yeast to humans and typically act in concert with other nuclear proteins to modify chromatin structure and gene expression. The results from these studies reveal an inhibitory effect of Dpy-30L1 on MTF-1 and an essential role for Dpy-30L2 in male fertility.


Quantitative Microplate Assay for Real-Time Nuclease Kinetics.
Utilizing the phenomenon of nucleases exposing oligonucleotide phosphate backbones to phosphatases we present a novel quantitative method for kinetics of nuclease catalysis. Inorganic phosphate released from nuclease products by phosphatases could be quantified in real-time by a fluorescent sensor of inorganic phosphate. Two different nucleases were employed, showing the versatility of this assay for multiple turnover label-free nuclease studies.


Clinical Characteristics and Prognosis of Penicilliosis Among Human Immunodeficiency Virus-Infected Patients in Eastern China.
AbstractTalaromyces marneffei infection is increasingly observed in people living with human immunodeficiency virus (HIV) in eastern China, a nonendemic area. This study aimed to draw the clinician's attention to this disease by presenting the clinical characteristics and prognosis of penicilliosis among HIV-infected patients from this region. We retrospectively analyzed HIV-infected patients with culture-proven T. marneffei infection admitted during January 1, 2014-December 31, 2015, at the Shanghai Public Health Clinical Center. A total of 48 patients with confirmed HIV infection and penicilliosis were enrolled, which accounted for a mean of 3.2% (95% confidence interval: 2.4-4.2%) of yearly HIV infection admissions among patients from eastern China. Symptoms included fever, cough, and gastrointestinal complaints, whereas the most common sign was skin lesions. Anemia occurred in 87.5% (42/48) of the patients. The overall mortality rate was 16.7%. Low CD4 T-cell count and hemoglobin level were correlated with mortality. Based on these results, we concluded that penicilliosis should be considered in HIV-infected patients from eastern China who present with fever, cutaneous lesions, and anemia. The clinical characters and the prognosis of patients with penicilliosis are similar to those in endemic areas. More attention should be paid to penicilliosis patients with low CD4 T-cell count and/or low hemoglobin level.


Understanding unmet need: history, theory, and measurement.
During the past two decades, estimates of unmet need have become an influential measure for assessing population policies and programs. This article recounts the evolution of the concept of unmet need, describes how demographic survey data have been used to generate estimates of its prevalence, and tests the sensitivity of these estimates to various assumptions in the unmet need algorithm. The algorithm uses a complex set of assumptions to identify women: who are sexually active, who are infecund, whose most recent pregnancy was unwanted, who wish to postpone their next birth, and who are postpartum amenorrheic. The sensitivity tests suggest that defensible alternative criteria for identifying four out of five of these subgroups of women would increase the estimated prevalence of unmet need. The exception is identification of married women who are sexually active; more accurate measurement of this subgroup would reduce the estimated prevalence of unmet need in most settings.


Simulation modeling of change to breast cancer detection age eligibility recommendations in Ontario, 2002-2021.
The purpose of this project was to demonstrate the development and use of a decision support tool based on simulation modeling of breast cancer screening to evaluate the implications for the provision of health services and the economic impact of extending routine radiographic screening for breast cancer to women in the 40-49 age group between 2002 and 2021. The main method was computer simulation with a Markov model that used published estimates of population size by age group, breast cancer prevalence and incidence, screening program participation rate, sensitivity and specificity of the screening test and diagnostic test, stage transition probabilities, directed diagnosis rates and costs. The model predicted that changes to age eligibility requirements would result in the detection of an additional 6610 women with breast cancer in Ontario requiring treatment, at an additional cost of 795 Canadian per case. These costs include those related to screening, diagnosis and initial treatment and apply to the 20-year period. The model provided a useful decision support tool for those planning and implementing breast cancer screening programs.


The impact of finite-depth cylindrical and conical holes in lithium niobate photonic crystals.
The performance of lithium niobate (LN) photonic crystals (PhCs) is theoretically analyzed with transmission spectra and band diagrams as calculated by the 3-D Finite-Difference Time Domain (FDTD) method. For a square lattice of holes fabricated in the top surface of an Annealed Proton-Exchange (APE) waveguide, we investigate the influence of both finite hole depth and non-cylindrical hole shape, using a full treatment of the birefringent gradient index profile. As expected, cylindrical holes which are sufficiently deep to overlap the APE waveguide mode (centered at 2.5microm below the surface) produce transmission spectra closely resembling those predicted by simple 2-D modeling. As the hole depth decreases without any change in the cylindrical shape, the contrast between the photonic pass- and stop-bands and the sharpness of the band-edge are slowly lost. We show that this loss of contrast is due to the portion of the buried APE waveguide mode that passes under the holes. However, conical holes of any depth fail to produce well-defined stop-bands in either the transmission spectra or band diagrams. Deep conical holes act as a broad-band attenuator due to refraction of the mode out of the APE region down into the bulk. Experimental results confirming this observation are shown. The impact of holes which are cylindrical at the top and conical at their bottom is also investigated. Given the difficulty of fabricating high aspect-ratio cylindrical holes in lithium niobate, we propose a partial solution to improve the overlap between shallow holes and the buried mode, in which the PhC holes are fabricated at the bottom of a wide, shallow trench previously introduced into the APE waveguide surface.


Early Use of Remdesivir in Patients Hospitalized With COVID-19 Improves Clinical Outcomes: A Retrospective Observational Study.
Remdesivir treatment, like most antiviral drugs, is likely to be most effective when used early in the course of coronavirus disease 2019 (COVID-19). Optimal timing of remdesivir for the treatment of COVID-19 remains unclear. The aim of this study was to determine whether early treatment with remdesivir improves clinical outcomes: length of stay, need for mechanical ventilation, and death. We conducted a retrospective observational study of patients hospitalized with COVID-19 who received remdesivir therapy within 10 days of symptom onset at a large health system in Georgia, United States. We identified a total of 475 patients. Initiation of therapy 3 days or less from first positive SARS-CoV-2 improved length of stay (15.7 days) compared with those started on therapy more than 3 days after a positive test (19.3 days) (P = 0.03). In the ≤3 day group, further reduction in length of stay was seen in those with lower oxygen requirement at baseline (P < 0.0001). Length of stay was lower in the ≤3 day group both with and without the use of corticosteroids (P = 0.0003). The odds of requiring mechanical ventilation were higher for the >3 day group compared with the ≤3 day group (odds ratio, 1.5; 95% confidence interval, 0.8-2.7), and the odds of death were higher for the >3 day group versus the ≤3 day group (odds ratio, 1.74; 95% confidence interval, 0.9-3.2). Our data show that early treatment with remdesivir in patients hospitalized with COVID-19 shortened length of stay.


The metabolomic signature of weight loss and remission in the Diabetes Remission Clinical Trial (DiRECT).
High-throughput metabolomics technologies in a variety of study designs have demonstrated a consistent metabolomic signature of overweight and type 2 diabetes. However, the extent to which these metabolomic patterns can be reversed with weight loss and diabetes remission has been weakly investigated. We aimed to characterise the metabolomic consequences of a weight-loss intervention in individuals with type 2 diabetes. We analysed 574 fasted serum samples collected within an existing RCT (the Diabetes Remission Clinical Trial [DiRECT]) (N=298). In the trial, participating primary care practices were randomly assigned (1:1) to provide either a weight management programme (intervention) or best-practice care by guidelines (control) treatment to individuals with type 2 diabetes. Here, metabolomics analysis was performed on samples collected at baseline and 12 months using both untargeted MS and targeted 1H-NMR spectroscopy. Multivariable regression models were fitted to evaluate the effect of the intervention on metabolite levels. Decreases in branched-chain amino acids, sugars and LDL triglycerides, and increases in sphingolipids, plasmalogens and metabolites related to fatty acid metabolism were associated with the intervention (Holm-corrected p<0.05). In individuals who lost more than 9 kg between baseline and 12 months, those who achieved diabetes remission saw greater reductions in glucose, fructose and mannose, compared with those who did not achieve remission. We have characterised the metabolomic effects of an integrated weight management programme previously shown to deliver weight loss and diabetes remission. A large proportion of the metabolome appears to be modifiable. Patterns of change were largely and strikingly opposite to perturbances previously documented with the development of type 2 diabetes. The data used for analysis are available on a research data repository ( https://researchdata.gla.ac.uk/ ) with access given to researchers subject to appropriate data sharing agreements. Metabolite data preparation, data pre-processing, statistical analyses and figure generation were performed in R Studio v.1.0.143 using R v.4.0.2. The R code for this study has been made publicly available on GitHub at: https://github.com/lauracorbin/metabolomics_of_direct .


Statistical learning of target and distractor spatial probability shape a common attentional priority computation.
Converging evidence recently put forward the notion that dedicated neurocognitive mechanisms do exist for the suppression of salient, but irrelevant distractors. Along this line, it is plausible to hypothesize that, in appropriate contexts, experience-dependent forms of attentional learning might selectively induce plastic changes within this dedicated circuitry, thus allowing an independent shaping of priorities at the service of attentional filtering. Conversely, previous work suggested that statistical learning (SL) of both target and distractor spatial probability distributions converge in adjusting only the overall attentional priority of locations: in fact, in the presence of an independent manipulation, either related to the target or to the distractor only, SL induces indirect effects (e.g., changes in filtering efficiency due to an uneven distribution of targets), suggesting that SL-induced plastic changes affect a shared neural substrate. Here we tested whether, when (conflicting) target- and distractor-related manipulations are concurrently applied to the very same locations, dedicated mechanisms might support the selective encoding of spatial priority in relation to the specific attentional operation involved. In three related experiments, human healthy participants discriminated the direction of a target arrow, while ignoring a salient distractor, if present; both target and distractor spatial probability distributions were concurrently manipulated in relation to each single location. Critically, the selection bias produced by the target-related SL was marginally reduced by an adverse distractor contingency, and the suppression bias generated by the distractor-related SL was erased, or even reversed, by an adverse target contingency. Our results suggest that even conflicting target- and distractor-related SL manipulations result in the adjustment of a unique spatial priority computation, likely because the process directly relies on direct plastic alterations of shared spatial priority map(s).


Subcutaneous ovarian tissue transplantation in nonhuman primates: duration of endocrine function and normalcy of subsequent offspring as demonstrated by reproductive competence, oocyte production, and telomere length.
The main purposes of the study were to investigate the endocrine function of ovarian tissue transplanted to heterotopic subcutaneous sites and the reproductive competence and telomere length of a nonhuman primate originating from transplanted tissue. Ovarian cortex pieces were transplanted into the original rhesus macaques in the arm subcutaneously, in the abdomen next to muscles, or in the kidney. Serum estradiol (E2) and progesterone (P4) concentrations were measured weekly for up to 8 years following tissue transplantation. A monkey derived from an oocyte in transplanted ovarian tissue entered time-mated breeding and underwent controlled ovarian stimulation. Pregnancy and offspring were evaluated. Telomere lengths and oocytes obtained following controlled ovarian stimulation were assessed. Monkeys with transplants in the arm and abdomen had cyclic E2 of 100 pg/ml, while an animal with arm transplants had E2 of 50 pg/ml. One monkey with transplants in the abdomen and kidney had ovulatory cycles for 3 years. A monkey derived from an oocyte in transplanted tissue conceived and had a normal gestation until intrapartum fetal demise. She conceived again and delivered a healthy offspring at term. Controlled ovarian stimulations of this monkey yielded mature oocytes comparable to controls. Her telomere length was long relative to controls. Heterotopic ovarian tissue transplants yielded long-term endocrine function in macaques. A monkey derived from an oocyte in transplanted tissue was reproductively competent. Her telomere length did not show epigenetically induced premature cellular aging. Ovarian tissue transplantation to heterotopic sites for fertility preservation should move forward cautiously, yet optimistically.


Donor-site morbidity with use of vascularized autogenous fibular grafts.
One hundred and ninety-eight consecutive patients (247 vascularized fibular grafts) were studied to determine the prevalence of morbidity at the donor site after the grafts had been obtained. Objective motor weakness, subjective discomfort in the ankle and other sites in the leg, and sensory abnormalities in the lower limb (or limbs) from which the graft had been obtained were recorded. The average duration of follow-up was forty-seven months (range, twenty-four to 144 months). Kaplan-Meier analysis was used to estimate the prevalence of each finding for the entire cohort over time. Forty-seven (19.0 per cent) of the 247 lower limbs had at least one of the findings, and eighteen(24.3 percent) of the seventy-four limbs for which data were available at five years or more had findings at that time. Twenty-five (10.1 per cent) of the 247 limbs had evidence of motor weakness at three months postoperatively, although no limb had this finding subsequently. At five years or more postoperatively, the prevalence had decreased to two (2.7 per cent) of the seventy-four limbs. Twelve (4.9 per cent) of the 247 limbs had sensory deficits at three months; this increased to 11.8 per cent (95 per cent confidence interval, 7.7 to 17.7 per cent), according to the Kaplan-Meier analysis, at five years. Pain at sites other than the ankle was noted in nine (3.6 per cent) of the 247 limbs at three months and in 8.9 per cent (95 per cent confidence interval, 5.5 to 14.1 per cent), according to the Kaplan-Meier analysis, at five years. The prevalence of pain in the ankle also increased with time, from four (1.6 per cent) of the 247 limbs at three months to 11.5 per cent (95 per cent confidence interval, 7.4 to 17.6 per cent), according to the Kaplan-Meier analysis, at five years. Removal of a vascularized portion of the fibula is associated with a low prevalence of motor weakness and sensory deficits in the foot. The prevalence of pain in the ankle and lower limb increases with time, with some patients having a late onset of the symptoms. While free vascularized fibular grafts remain ideal for many applications, the morbidity must be weighed against the benefits.


Interaction between two mitogen-activated protein kinases during tobacco defense signaling.
Plant mitogen-activated protein kinases (MAPKs) represented by tobacco wounding-induced protein kinase (WIPK) have unique regulation at the level of transcription in response to stresses. By using transcriptional and translational inhibitors, it has been shown previously that WIPK gene expression and de novo protein synthesis are required for the high-level activity of WIPK in cells treated with elicitins from Phytophthora spp. However, regulation of WIPK expression and the role(s) of WIPK in plant disease resistance are unknown. In this report, we demonstrate that WIPK gene transcription is regulated by phosphorylation and de-phosphorylation events. Interestingly, salicylic acid-induced protein kinase (SIPK) was identified as the kinase involved in regulating WIPK gene expression based on both gain-of-function and loss-of-function analyses. This finding revealed an additional level of interaction between SIPK and WIPK, which share an upstream MAPKK, NtMEK2. Depending on whether WIPK shares its downstream targets with SIPK, it could either function as a positive feed-forward regulator of SIPK or initiate a new pathway. Consistent with the first scenario, co-expression of WIPK with the active mutant of NtMEK2 leads to accelerated hypersensitive response (HR)-like cell death in which SIPK also plays a role. Mutagenesis analysis revealed that the conserved common docking domain in WIPK is required for its function. Together with prior reports that (i) WIPK is activated in NN tobacco infected with tobacco mosaic virus, and (ii) PVX virus-induced gene silencing of WIPK attenuated N gene-mediated resistance, we concluded that WIPK plays a positive role in plant disease resistance, possibly through accelerating the pathogen-induced HR cell death.


Development of a novel rapid non-invasive screening test for coeliac disease.
Coeliac disease is one of the commonest underdiagnosed diseases in general practice. The autoantigen recognised by the sera of patients with coeliac disease has recently been identified as tissue transglutaminase. We evaluated a simple non-invasive immunological dot blot assay for coeliac disease, suitable for use by the general physician in the ambulatory setting. The sensitivity and specificity of this dot blot assay based on recognition of recombinant human transglutaminase were compared with those of antiendomysial antibodies and an enzyme linked immunosorbent assay. Serum samples were analysed from 64 healthy controls, 58 first degree relatives of coeliacs, 74 diseased controls, and 70 biopsy confirmed untreated patients with coeliac disease. Dot blot assay and enzyme linked immunosorbent assay were performed using recombinant human transglutaminase as antigen. The dot blot assay, which can be performed in 20 minutes, was positive in all 70 untreated coeliacs (sensitivity 100%). Among the three control groups, there were three false positive tests by dot blot (specificity 98%), all belonging to the group of healthy subjects. The antiendomysial antibodies test missed five untreated coeliac patients (sensitivity 93%) and was negative in all three control groups (specificity 100%). The specificity of the immunosorbent assay was 99% for IgA and 98% for IgG, while sensitivity was 93% for IgA, 47% for IgG, and 100% for IgA and IgG combined. The dot blot assay is highly accurate in detecting untreated subjects with coeliac disease and can be performed in the general physician's medical office during the course of a routine examination. This innovative test is a practical, reliable alternative to both the immunofluorescent based antiendomysial test and immunosorbent assay for detection of transglutaminase antibodies for the diagnosis of coeliac disease.


Coupled electronic and structural relaxation pathways in the postexcitation dynamics of Rydberg states of BaArN clusters.
We investigate, theoretically, the joint relaxation of orbital and structure in postexcitation dynamics of Rydberg states of cluster BaArN (N=250). Mixed quantum-classical dynamics is used to account for the nonadiabatic transitions among more than 160 electronic states, represented via a diatomics-in-molecules Hamiltonian. The simulation illustrates the complex multistep relaxation processes and provides detailed insight in the mechanisms contributing to the final-time experimental photoelectron spectrum.


Fc gamma receptor III on human neutrophils. Allelic variants have functionally distinct capacities.
As a model system to explore the functional consequences of structural variants of human Fc gamma receptors (Fc gamma R), we have investigated Fc gamma R-mediated phagocytosis in relation to the NA1-NA2 polymorphism of Fc gamma RIII (CD16) on neutrophils (Fc gamma RIIIPMN). The neutrophil-specific NA antigen system is a biallelic polymorphism with codominant expression demonstrating a gene dose effect with the anti-NA1 MAb CLB-gran 11 in a large donor population. To explore the impact of this allelic variation of Fc gamma RIIIPMN on phagocytosis, we used two Fc gamma RIII-dependent probes, IgG-sensitized erythrocytes (EA) and concanavalin. A-treated erythrocytes (E-ConA). Comparison of Fc gamma R-mediated phagocytosis by PMN from NA1 subjects and from NA2 subjects showed lower levels of phagocytosis of both probes by the NA2 individuals. The difference was most pronounced with lightly opsonized EA: at the lowest level of sensitization the phagocytic index was 72% lower for NA2 donors, whereas at the highest level of sensitization it was 21% lower (P less than 0.003). Blockade of Fc gamma RII with MAb IV.3 Fab amplified by threefold the difference between NA1 and NA2 donors. NA1 and NA2 individuals had identical phagocytic capacities for the non-Fc gamma RIII probes, serum-treated and heat-treated zymosan. These individuals did not show differential quantitative cell surface expression of Fc gamma RIIIPMN measured by a panel of anti-CD16 MAb (3G8, CLB FcR-gran 1, VEP13, BW209/2) and by Scatchard analysis of 125I-IgG dimer binding. The difference in Fc gamma R-mediated phagocytosis was not explicable on the basis of differential collaboration of Fc gamma RIIIPMN alleles with Fc gamma RII, since (a) the difference in phagocytic capacity between NA1 and NA2 individuals was readily apparent with the E-ConA probe (which is independent of Fc gamma RII) and (b) the difference in phagocytosis of EA was magnified by Fc gamma RII blockade. The demonstration that allelic polymorphisms in Fc gamma R can have significant consequences for physiological functions implies that within the structural complexity of human Fc gamma Rs, including both allelic forms and cell type-specific isoforms, there will be differences in quantitative, and perhaps qualitative, function with potential importance for disease processes.


Characterization of the hypercoagulable state following severe orthopedic trauma.
Acute traumatic coagulopathy develops in seriously injured patients, which is followed by a paradoxical hypercoagulable state. The hypercoagulable state contributes to venous thromboembolism, and yet, there are no sensitive tests available to detect it. The aim of this study was to characterize the hypercoagulable state caused by major orthopedic trauma using the overall hemostatic potential (OHP) assay. Major orthopedic trauma patients admitted during a 7-month period in 2012 were included in the study. Blood samples were drawn 1 hour before surgery, then 1, 7, 24 hours and 3, 5, 10, and 42 days postoperatively. The assay parameters were determined and analyzed according to injury severity (polytrauma or nonpolytrauma), type of surgical intervention, and shock status. Values were compared with 20 healthy controls. Forty-one consecutive patients were enrolled (age, 41.5 ± 2.7 years; 70% male; Injury Severity Score [ISS], 21.5 ± 2.1). Hypercoagulability based on OHP was present in the preoperative sample compared with the controls (OHP, 13.8 ± 1.4 U vs. 8.1 ± 0.5 U; p = 0.020) and then further elevated after surgery (1 hour postoperative, 17.8 ± 2.0 U vs. preoperative, 13.8 ± 1.4 U, p = 0.008). Polytrauma patients were more hypercoagulable than nonpolytrauma at the preoperative sample time (17.7 ± 2.6 U vs. 10.7 ± 1.2 U, p = 0.040) and postoperative period (24.3 ± 3.4 U vs. 11.9 ± 1.4 U, p = 0.006). The OHP for patients undergoing open pelvic surgery (28.3 ± 3.0 U) was higher than both intramedullary nailing (16.2 ± 2.0 U) and percutaneous pelvic surgery (17.0 ± 1.7 U) on Day 5 (p < 0.05). Patients demonstrated a higher OHP than controls did at all time points, except at 6 weeks (patients, 10.8 ± 1.7 U vs. controls, 8.1 ± 0.5 U; p = 0.400). The OHP assay detected the hypercoagulable state following major orthopedic trauma and surgical intervention, which was present for 10 days postoperatively. The extent of hypercoagulability could be associated with polytrauma and the type of surgical intervention; however, further studies are needed to confirm this. Epidemiologic study, level III.


2014 presidential address: stop diabetes--it is up to us.
This address was delivered by Elizabeth R. Seaquist, MD, President, Medicine & Science, of the American Diabetes Association (ADA) at the Association's 74th Scientific Sessions in San Francisco, CA, on 15 June 2014. Dr. Seaquist is a professor of medicine at the University of Minnesota in Minneapolis, where she holds the Pennock Family Chair in Diabetes Research. She has been an ADA volunteer since 1987 and has served on several national committees and chaired the Association's workgroup on Hypoglycemia in Diabetes. At the local level, she served a 2-year term as cochair of the ADA EXPO in Minneapolis. Dr. Seaquist is a clinical investigator interested in the complications of diabetes. Her research focuses on the effect of diabetes on brain metabolism structure and function. She directs the University of Minnesota site for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study(GRADE) trials and has an active clinical practice. She was the 2009 recipient of the ADA's Distinguished Clinical Scientist Award. Dr. Seaquist holds a Bachelor of Arts degree from Vassar College in Poughkeepsie, NY, and a doctorate in medicine from the University of Minnesota. She is board certified in internal medicine and endocrinology, diabetes, and metabolism. The ADA and Diabetes Care thank Dr. Seaquist for her outstanding leadership and service to the Association.


Mechanical arm trainer for the treatment of the severely affected arm after a stroke: a single-blinded randomized trial in two centers.
To test whether training with a new mechanical arm trainer leads to better outcomes than electrical stimulation of the paretic wrist extensors in subacute stroke patients with severe upper limb paresis. Electrical stimulation is a standard and reimbursable form of therapy in Germany. Randomized controlled trial of 54 inpatients enrolled 4-8 wks from stroke onset, mean upper-extremity subsection of Fugl-Meyer assessment (0-66) at admission less than 18. In addition to standard care, all patients practiced 20-30 mins arm trainer or electrical stimulation every workday for 6 wks, totaling 30 sessions. Primary outcome was the Fugl-Meyer assessment, secondary outcomes were the Box and Block test, the Medical Research Council and the modified Ashworth scale, blindly assessed at enrollment, after 6 wks, and at 3-mo follow-up. Both groups were homogeneous at study onset. Shoulder pain occurred in two arm trainer patients. The primary Fugl-Meyer assessment outcome improved for both groups over time (P < 0.001), but this improvement did not differ between groups. The initial (terminal) mean Fugl-Meyer assessment scores were 8.8 +/- 4.8 (19.2 +/- 14.5) for the arm trainer and 8.6 +/- 3.5 (13.6 +/- 7.9) for the electrical stimulation group. No patient could transport a block initially, but at completion significantly more arm trainer patients were able to transport at least three blocks (five vs. zero, P = 0.023). No significant differences were observed between the groups on the secondary Box and Block outcome at follow-up (eight vs. four patients). All Box and Block responders had an initial Fugl-Meyer assessment > or =10. Arm trainer training did not lead to a superior primary outcome over electrical stimulation training. However, "good performers" on the secondary outcome seemed to benefit more from the arm trainer training.


Macular Retinal Sublayer Thicknesses in G11778A Leber Hereditary Optic Neuropathy.
To determine macular retinal sublayer thickness changes in G11778A Leber hereditary optic neuropathy (LHON). The authors performed a cross-sectional study by segmenting spectral-domain Cirrus OCT (Carl Zeiss Meditec, Dublin, CA) 512 × 128 macular cube scans from a prospective, observational study of G11778A LHON. The thickness of the retinal sublayers of LHON affected subjects and asymptomatic carriers were compared to those of a normal group. The study included 20 LHON-affected subjects (13 males; age: 31 years ± 14 years, range: 10 years to 61 years; time since onset of visual loss: 5.9 years ± 8.7 years; 0.4-29.8), 31 asymptomatic LHON carriers (five males; age: 38 years ± 18 years, range: 9 years to 65 years), and 14 normal subjects (five males; age: 39 years ± 13 years, range: 23 years to 61 years). The retinal sublayer thickness parameters were not significantly correlated with age in any of the groups. There were no differences between carriers and normal subjects for thickness of total retina or any sublayer. Affected LHON retinal nerve fiber layer (RNFL) and ganglion cell layer plus inner plexiform layer (GCL+IPL) were thinner, whereas the photoreceptor outer segment (OS) layer was thicker than carriers and normal subjects (P values ranged from .042 to < .001), except for the OS layer in the inferior inner ring and temporal outer ring. Differences between groups were not significant in the inner nuclear layer plus outer plexiform layer (INL+OPL). The affected LHON outer nuclear layer plus inner segment layer was thicker in some quadrants, and the affected LHON choroid layer was generally thinner than carriers and normal subjects; however, these differences were not significant after accounting for age. LHON-affected patients have thickened photoreceptor OS layers in spite of having thinner RNFL and GCL+IPL layers. The findings indicate LHON also has an effect on the morphology of the photoreceptors. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:802-810.].


Dissemination and Refutation of Rumors During the COVID-19 Outbreak in China: Infodemiology Study.
During the outbreak of COVID-19, numerous rumors emerged on the internet in China and caused confusion among the public. However, the characteristics of these rumors in different phases of the epidemic have not been studied in depth, and the official responses to the rumors have not been systematically evaluated. The aims of this study were to evaluate the rumor epidemic and official responses during the COVID-19 outbreak in China and to provide a scientific basis for effective information communication in future public health crises. Data on internet rumors related to COVID-19 were collected via the Sina Weibo Official Account to Refute Rumors between January 20 and April 8, 2020, extracted, and analyzed. The data were divided into five periods according to the key events and disease epidemic. Different classifications of rumors were described and compared over the five periods. The trends of the epidemic and the focus of the public at different stages were plotted, and correlation analysis between the number of rumors and the number of COVID-19 cases was performed. The geographic distributions of the sources and refuters of the rumors were graphed, and analyses of the most frequently appearing words in the rumors were applied to reveal hotspots of the rumors. A total of 1943 rumors were retrieved. The median of the response interval between publication and debunking of the rumors was 1 day (IQR 1-2). Rumors in text format accounted for the majority of the 1943 rumors (n=1241, 63.9%); chat tools, particularly WeChat (n=1386, 71.3%), were the most common platform for initial publishing of the rumors (n=1412, 72.7%). In addition to text rumors, Weibo and web pages were more likely to be platforms for rumors released in multimedia formats or in a combination of formats, respectively. Local agencies played a large role in dispelling rumors among social media platforms (1537/1943, 79.1%). There were significant differences in the formats and origins of rumors over the five periods (P<.001). Hubei Province accounted for most of the country's confirmed rumors. Beijing and Wuhan City were the main centers for debunking of disinformation. The words most frequently included in the core messages of the rumors varied by period, indicating shifting in the public's concern. Chat tools, particularly WeChat, became the major sources of rumors during the COVID-19 outbreak in China, indicating a requirement to establish rumor monitoring and refuting mechanisms on these platforms. Moreover, targeted policy adjustments and timely release of official information are needed in different phases of the outbreak.


[Thromboembolic risk in atrial fibrillation: new clinical perspectives].
Prevention of embolic complications is one of the major goals of therapeutic strategy for atrial fibrillation. The embolic risk is related to the presence and nature of underlying heart disease; furthermore cerebrovascular accidents associated with atrial fibrillation occur in a higher percentage in the elderly, representing 6.7% of the total number of cerebrovascular accidents in the 50-to-59-year-old population and 36% in the 80-to-89-year-old population. Anticoagulation with oral vitamin K antagonists, such as warfarin, is highly effective in reducing ischemic stroke in these patients, but some concerns exist about its safety and tolerability, especially in older patients, because of the hemorrhagic risk. Several risk stratification schemes have been developed to evaluate the thromboembolic/hemorrhagic risk profile in the individual patient, but they have shown intrinsic limitations. In this short report we compare different risk stratification schemes to predict thromboembolic risk in atrial fibrillation patients, and we discuss the application of these schemes into clinical practice and the effects on clinical events.


Animal bites and rabies exposure in Australian travellers.
To examine the circumstances of animal exposure in a case series of Australian travellers who required rabies postexposure prophylaxis, and to assess the appropriateness of current guidelines for rabies pre-exposure vaccination. Prospective case series of 65 returned travellers who presented to four Australian travel medicine clinics between 1 April 2009 and 31 July 2010 for rabies post-exposure prophylaxis. Demographic characteristics associated with risk of injury; countries where injuries occurred; circumstances of the injuries; and travellers' experiences of obtaining postexposure prophylaxis overseas. Animal bites and scratches occurred most commonly among travellers aged 20-29 years. Most injuries occurred in Bali, Indonesia (30 [46%]) and Thailand (21 [32%]), and the most common animals responsible for the injuries to the 65 travellers were monkeys (29 travellers [45%]) and dogs (27 [42%]). Thirty-nine of the travellers (60%) initiated contact with the animal. Forty travellers (62%) were able to commence rabies vaccination overseas, but only nine (14%) were able to obtain rabies immunoglobulin overseas. Most travellers had difficulty obtaining rabies postexposure prophylaxis overseas, resulting in significant delays in appropriate treatment. We recommend that current National Health and Medical Research Council guidelines for at-risk persons be broadened, and that the risk of rabies and the option of pre-exposure vaccination be discussed with all travellers to rabies-endemic areas.


The African American Tobacco Control Leadership Council: Advocating for a menthol cigarette ban in San Francisco, California.
The African American Tobacco Control Leadership Council (AATCLC) is an advocacy group that works to inform the direction of tobacco control policy and priorities in the USA. This article narrates the AATCLC's work advocating for a comprehensive, flavoured tobacco product sales ban in San Francisco, California. Recommendations for tobacco control advocates and lessons learned from their work are provided. The article concludes by discussing conditions necessary to enact the policy. These include having a dedicated advocacy team, community support, a policy sponsor, and clear and repeated messaging that is responsive to community concerns.


Nutritional risk in early childhood and parent-reported school concerns.
To determine if nutritional risk in early childhood is associated with parent-reported school concerns. A prospective cohort study conducted through the TARGet Kids! primary care research network (2011-2018). Nutritional risk was measured between 18 months and 5 years of age using validated parent-completed NutriSTEP® questionnaires with eating behaviour and dietary intake subscores (0 = lowest and 68 = highest total nutritional risk score). Parent-reported school concerns were measured at school age (4-10 years of age) and included: speech and language; learning; attention; behaviour; social relationships; physical coordination; fine motor coordination and self-help skills and independence. The primary outcome was any parent-reported school concerns, and individual school concerns were used as secondary outcomes. Multiple logistic regression models were conducted adjusting for clinically relevant confounders to assess the relationship between nutritional risk and school concerns. Toronto, Canada. Children aged 18 months to 10 years. The study included 3655 children, 52 % were male, mean NutriSTEP® score was 14·4 (sd 6·4). Each 1 sd increase in NutriSTEP® total score was associated with a 1·18 times increased odds of school concerns (adj OR: 1·18, 95 % CI 1·07, 1·28, P = 0·0004), and high nutritional risk was associated with a 1·42 times increased odds of school concerns (adj OR: 1·42, 95 % CI 1·13, 1·78, P = 0·002). Nutritional risk in early childhood was associated with school concerns. Nutritional interventions in early childhood may reveal opportunities to enhance school outcomes.


The contribution of Escherichia coli from human and animal sources to the integron gene pool in coastal waters.
To understand the contribution of animal- and human-derived fecal pollution sources in shaping integron prevalence and diversity in beach waters, 414 Escherichia coli strains were collected from beach waters (BW, n = 166), seagull feces (SF, n = 179), and wastewaters (WW, n = 69), on the World Biosphere Reserve of the Berlenga Island, Portugal. Statistical differences were found between the prevalence of integrons in BW (21%) and WW (10%), but not between BW and SF (19%). The majority of integrase-positive (intI (+))-strains affiliated to commensal phylogroups B1 (37%), A0 (24%), and A1 (20%). Eighteen different gene cassette arrays were detected, most of them coding for resistances to aminoglycosides, trimethoprim, chloramphenicol, and quaternary ammonia compounds. Common arrays were found among strains from different sources. Multi-resistance to three or more different classes of antibiotics was observed in 89, 82, and 57% of intI (+)-strains from BW, SF and WW, respectively. Plasmids were detected in 79% of strains (60/76) revealing a high diversity of replicons in all sources, mostly belonging to IncF (Frep, FIA, and FIB subgroups), IncI1, IncN, IncY, and IncK incompatibility groups. In 20% (15/76) of strains, integrons were successfully mobilized through conjugation to E. coli CV601. Results obtained support the existence of a diverse integron pool in the E. coli strains from this coastal environment, associated with different resistance traits and plasmid incompatibility groups, mainly shaped by animal fecal pollution inputs. These findings underscore the role of wild life in dissemination of integrons and antibiotic resistance traits in natural environments.


Mechanisms regulating auxin action during fruit development.
Auxin controls many aspects of fruit development, including fruit set and growth, ripening and abscission. However, the mechanisms by which auxin regulates these processes are still poorly understood. While it is generally agreed that precise spatial and temporal control of auxin distribution and signaling are required for fruit development, the dynamics of auxin biosynthesis and the mechanisms for its transport to different fruit tissues are mostly unknown. Despite major advances in elucidating many aspects of auxin biology in vegetative tissues, until recently, the nature and importance of auxin metabolism, transport and signaling during fruit ontogeny remained obscure. In this review, we summarize recent research that has started to elucidate the molecular mechanisms by which auxin is produced and transported in the fruit and to unravel the complexity of auxin signaling during fruit development. We also discuss recent approaches used to reveal the genes and regulatory networks that mediate cell and tissue-specific control of auxin levels in the developing fruit.


Health insurance and child mortality in Costa Rica.
This study uses a natural experiment approach to evaluate the effect of health insurance on infant and child mortality. In the 1970s Costa Rica adopted national health insurance, which expanded children's insurance coverage from 42 percent in 1973 to 73 percent by 1984. Aggregate infant and child mortality rates dropped rapidly during this period, but this trend had begun prior to the insurance expansion, and may be related to other changes during this period. We use county-level vital statistics and census data to isolate the causal insurance effect on mortality using county fixed effects models. We find that insurance increases are strongly related to mortality decreases at the county level before controlling for other time-varying factors. However, after controlling for changes in other correlated maternal, household, and community characteristics, fixed effects models indicate that the insurance expansion could have explained only a small portion of the mortality change. These results question the proposition that health insurance can lead to large improvements in infant and child mortality, and that expanding insurance to the poor can substantially narrow socioeconomic differentials in mortality.


What are families for? Getting to an ethics of reproductive technology.
The standard approach to the ethics of reproductive technologies starts and ends with the parents' procreative liberty. There's much more to think about. We should start with the relationship between parents and children.


A feasibility study of the Redesigning Daily Occupations (ReDOTM-10) programme in an Irish context.
Despite high demand, mental health services in primary care in Ireland are underdeveloped. People with mild/moderate anxiety, depression and unspecified psychological distress are frequently seen in primary care settings, mostly by general practitioners (GPs). Occupational therapists have the potential to contribute to service-provision with interventions specially designed for the targeted group e.g. the Redesigning Daily Occupations programme (ReDO-10). This study aimed to explore the feasibility of a future RCT of the ReDO-10 programme in Ireland and the contextual factors that would influence future implementation. Using a multi-phase, mixed-method design, qualitative and quantitative data were gathered from key stakeholders: ReDO-10 participants (n = 10), GPs (n = 9) and occupational therapists (n = 2). Acceptability, satisfaction, cultural fit and demand were explored, as well as methodological issues such as appropriateness of recruitment methods, outcome measures and randomization. ReDO-10 was acceptable to participants who reported improvements in their occupational patterns and valued the group-based format. GPs and occupational therapists welcomed the intervention, but acknowledged the limitations of time and resources in the Irish primary care context. ReDO-10 is feasible to explore in a future RCT in Ireland and this study provides important context for future implementation and/or research.