P53 alterations in bladder tumors from arsenic and tobacco exposed patients.
Previous studies demonstrated that tobacco and arsenic exposure are risk factors for bladder cancer. A case-case study was conducted to compare p53 mutations in 147 bladder tumors from South American patients by tobacco and arsenic exposure. Information on residential history and lifestyle factors was collected. The prevalence of p53 mutations and protein expression was examined in relation to tumor stage, grade, patient age, gender, tobacco and arsenic exposure. Smokers were grouped as ever/never smokers and by pack years of exposure (0, 1-20, >20). Patients were also grouped into four arsenic exposure categories based on the average of the five highest years arsenic concentration in their drinking water: group 1, non-detectable to <10 microg/l (n = 50); group 2, 10-99 microg/l (n = 31); group 3, 100-299 microg/l (n = 35); group 4, >300 microg/l (n = 30). The proportion of tumor samples with p53 mutations and P53 immunopositivity increased strongly with both stage and grade, but not with arsenic exposure or smoking. The prevalence of tumors containing mutational transitions increased markedly with tumor stage (from 14 to 52%, P(trend) = 0.005) and grade (from 11 to 48%, P(trend) = 0.004) and was higher in smokers than in non-smokers (34 versus 18%, respectively, P = 0.10). An increasing trend was observed with pack years of smoking (P = 0.09). The majority of mutations in tumors from both smokers and non-smokers were G-->A transitions, however, in smokers a preference for G-->A transitions at CpG sites was observed (P = 0.07, two-tailed) and a positive trend was observed with pack years of exposure (P = 0.04). A hotspot was found at codon 273 in 12% of the tumors from smokers but was not observed in never smokers (P = 0.05) and a positive trend was observed with pack years of tobacco exposure (P = 0.001). Neither stage nor grade demonstrated a preference for CpG site mutation, suggesting that these changes may be early exposure-related events in carcinogenesis and are not related to tumor progression. Arsenic exposure was not associated with an increased prevalence of p53 mutation or P53 immunopositivity and there was no evidence of interaction between arsenic and smoking with these outcome variables.


Assessment of insulin sensitivity with minimal model: role of model assumptions.
Insulin sensitivity is frequently assessed with the minimal model (MM) and the insulin-modified intravenous glucose tolerance test (MIVGTT). To ascertain the validity of this approach, the mechanisms by which the MM estimates glucose effectiveness and insulin sensitivity (SG and SI, respectively) from the data are analyzed theoretically. Published data and new labeled MIVGTTs in normal and non-insulin-dependent diabetic (NIDDM) subjects are used as reference data. One reason for the reported difficulty in estimating SI in NIDDM is the inadequacy of the MM to describe the data. SG is a biased estimate of the fractional glucose clearance (FGC) at basal insulin, and SI is a biased estimate of the average slope of the insulin concentration-FGC curve. The monocompartmental assumption and the role of glucose production in the MM are causes of bias. The bias is fairly constant across the spectrum of glucose tolerance (SG: approximately 150% overestimate; SI: approximately 30% underestimate). Also, SI is not expected to account satisfactorily for hepatic insulin sensitivity. Finally, by the use of SG and SI, FGC at a target insulin level (FGCMM) can be estimated. FGCMM agrees well with the analogous clamp index (difference 10%; correlation: r = 0.88, P < 0.002) and, in NIDDM, has a lower coefficient of variation than SI (57 vs. 82%). In conclusion, this analysis indicates that the MM is a sufficiently reliable method for the assessment of insulin sensitivity if it is used cautiously.


Dietary manganese intake and type of lipid do not affect clinical or neuropsychological measures in healthy young women.
Because manganese (Mn) is potentially toxic, and because dietary fat type may affect Mn absorption, the objectives of the current study were to determine whether diets containing very low or very high amounts of Mn and enriched in either saturated or unsaturated fats affected measures of neuropsychological and basic metabolic function. Healthy young women were fed for 8 wk each, in a crossover design, diets that provided 0.8 or 20 mg of Mn/d. One half of the subjects received 15% of energy as cocoa butter, and one half received 15% of energy as corn oil. A meal containing (54)Mn was fed after 4 wk, and subjects underwent whole-body counting for the next 21 d. Blood draws and neuropsychological tests were administered at regular intervals during the dietary periods. When subjects consumed the diets low in Mn, compared with the high Mn diets, they absorbed a significantly higher percentage of (54)Mn, but had a significantly longer biological half-life of the absorbed (54)Mn. Manganese intake did not affect any neurological measures and only minimally affected psychologic variables. These data show that efficient mechanisms operate to maintain Mn homeostasis over the range of intakes that may be encountered in a mixed Western diet. Thus, dietary intakes of Mn from 0.8 to 20 mg for 8 wk likely do not result in Mn deficiency or toxicity signs in healthy adults.


Passive Acoustic Sampling Enhances Traditional Herpetofauna Sampling Techniques in Urban Environments.
Data are needed to assess the relationships between urbanization and biodiversity to establish conservation priorities. However, many of these relationships are difficult to fully assess using traditional research methods. To address this gap and evaluate new acoustic sensors and associated data, we conducted a multimethod analysis of biodiversity in a rapidly urbanizing county: Greenville, South Carolina, USA. We conducted audio recordings at 25 points along a development gradient. At the same locations, we used refugia tubes, visual assessments, and an online database. Analysis focused on species identification of both audio and visual data at each point along the trail to determine relationships between both herpetofauna and acoustic indices (as proxies for biodiversity) and environmental gradient of land use and land cover. Our analysis suggests the use of a multitude of different sampling methods to be conducive to the completion of a more comprehensive occupancy measure. Moving forward, this research protocol can potentially be useful in the establishment of more effective wildlife occupancy indices using acoustic sensors to move toward future conservation policies and efforts concerning urbanization, forest fragmentation, and biodiversity in natural, particularly forested, ecosystems.


Dual-Energy Computed Tomography Characterization of Urinary Calculi: Basic Principles, Applications and Concerns.
Dual-energy computed tomography (DECT) is based on obtaining 2 data sets with different peak kilovoltages from the same anatomical region, and material decomposition based on attenuation differences at different energy levels. Several DECT technologies are available such as: the dual-source CT, the fast kilovoltage-switching method, and the sandwich detectors technique. Calculi are detectable using iodine subtraction techniques. DECT also helps characterization of renal stone composition. The advanced postprocessing application enables differentiation of various renal stone types. Calculation of water content using spectral imaging is useful to diagnose urinary obstruction.


Surviving and thriving in the '90s: a formula for success.
The old role of the leader/manager giving commands and maintaining strict control is giving way to a new role of coach and facilitator. A balance of effective leadership and efficient management, plus knowing when to focus on each, is critical in order to thrive in the 1990s.


A Methodology for Determining Standard of Care Status for a New Surgical Procedure: Hand Transplantation.
Hand allotransplantation was initially criticized as unethical and unlikely to succeed. The results proved to be better than anticipated, now raising the issue of whether hand transplantation is the standard of care. The purpose of this article is to outline a reasonable methodology for determining whether a surgical procedure is the standard of care, and then to apply that methodology to hand transplantation. Publications on ethics and definitions of medical (not legal) standard of care were reviewed. All hand transplantations completed in the United States were evaluated regarding their status as experimental, standard of care, or both. Then, the stakeholders, physicians, public insurers, and regulators were examined to determine whether they accepted hand transplantation as the standard of care. Utility and incremental cost-utility ratio were determined. Hand transplantation was considered the standard of care when stakeholders were using, insuring, and regulating the procedure. The public expresses a desire for hand transplantation. A minority of surgeons consider the procedure the standard of care. Ethical committees, institutional review boards, and scholarly articles deem the procedure ethical. A series of institutions have carried out the procedure with a record of successes. Some institutions perform the surgical procedure as the standard of care. Scholarly work demonstrates beneficial outcomes. Some commercial and federal government insurers are willing to cover the cost of the procedure. Utility determination justifies the procedure. There are no incremental cost-utility ratio analysis studies that justify the procedure. Hand transplantation is moving from acceptance as an ethical surgical experiment to the standard of care.


Exoproteome analysis of Starmerella bombicola results in the discovery of an esterase required for lactonization of sophorolipids.
The yeast Starmerella bombicola secretes sophorolipids, a family of biosurfactants that find applications in green household products and cosmetics. Over the past years, a gene cluster was discovered that is responsible for the entire synthesis of the open (acidic) form of these molecules from glucose, fatty acids and acetyl-CoA building blocks. However, a significant fraction of the natural product is obtained as a ring closed form (lactonic). Both genetic and proteomic approaches hitherto failed to discover an enzyme responsible for the esterification reaction required for the ring closure step. We hypothesized that this enzyme is extracellularly secreted. Therefore, we characterized the composition of the S. bombicola exoproteome at different time points of the growth and compared it with known yeast exoproteomes. We identified 44 proteins, many of them commonly found in other fungi. Curiously, we discovered an enzyme with homology to Pseudozyma antarctica lipase A. A deletion mutation of its gene resulted in complete abolishment of the sophorolipid lactonization providing evidence that this might be the missing enzyme in the sophorolipid biosynthetic pathway. Growing concern about the impact of chemical processes on the environment increases consumers' demand for bio-based products. Lately, the household care and personal care sectors show increasing interest in naturally occurring biosurfactants, which constitute environment-friendly alternatives for chemical surfactants, typically derived from mineral oils. A particular group of biosurfactants, sophorolipids, already found their way to the market, being used in a range of household detergent products and in cosmetics. This work describes how proteomic approaches have led to the completion of our knowledge on the biosynthetic pathway of sophorolipids as performed by Starmerella bombicola, a fungus used in the industrial production of these biosurfactants. Moreover, we proved that by creating a deletion mutant in the lactone esterase discovered in this study, we can shape the biosynthesis towards custom-made sophorolipids with desired functions. Herewith, we demonstrate the potential of proteomics in industrial biotechnology.


The relationship among leadership preferences, head nurse leader style, and job satisfaction of staff nurses.
A better understanding of the effects of the relationships between staff nurses and their leaders is needed if retention of vital resources is to occur in this age of increasing need and decreasing resources in the health care industry. This study investigated the interactions among leadership preferences of staff nurses, the perceived leader behavior of their nurse managers, and their job satisfaction. Although a "match" or "mismatch" relationship was not found, one surprising finding was the high positive relationship between structuring behavior of head nurses and job satisfaction of staff nurses. Implications and recommendations for training nurse managers are offered.


Cutaneous limb inflammation produces analgesia to pressure pain in the ipsilateral forehead of healthy volunteers.
To investigate the pain-modulatory effects of a local inflammatory stimulus on pain elsewhere in the body, capsaicin was applied topically to the forearm of 14 healthy female volunteers. Pressure-pain thresholds and sensitivity to sharpness were assessed on each side of the forehead twice per day during 48 hours of capsaicin treatment, and in the treated and contralateral forearm before and at the end of treatment. Heat was applied to the treated area to rekindle pain at times of forehead assessment. Hyperalgesia to sharpness, but not pressure pain, developed in the treated area whereas sensations remained stable in the contralateral forearm. Sharpness ratings decreased bilaterally in the forehead after 6 hours of treatment, and ipsilateral analgesia to pressure pain developed in the forehead when the capsaicin site was heated after 48 hours of treatment. These findings suggest that pain modulation involves unilateral regulatory mechanisms in addition to local and generalized pain control. The dissociated changes to sharpness and pressure pain indicate distinct cutaneous and deep central pain pathways. The findings lend support to an increasing body of research which demonstrates that pain modulation involves hemilateral mechanisms in addition to local and generalized controls. Elucidation of mechanisms that modulate ipsilateral pain processing may help to clarify the pathophysiology of complex regional pain syndrome, which is characterized by hemilateral hyperalgesia.


How can we improve the assessment of safety in child and adolescent psychopharmacology?
To identify approaches to improving methods for assessing tolerability and safety of psychotropic medications in children and adolescents. Strengths and limitations of current methodology were reviewed and possible alternatives examined. Research on the validity of safety evaluation has been extremely limited. No evidence-based "gold standard" exists. Clinical trials remain the best design to establish causality, but sample size limitations prevent the detection of infrequent, though serious, adverse events. Other designs, such as cohort and case-control studies, and approaches, such as mining of large databases, must be considered. The current lack of methodological standardization across studies prevents generalizations and meta-analyses. Because the issues relevant to drug safety are diverse, a variety of methodological approaches and instruments are needed. It is, however, possible to adopt standard basic definitions of adverse events, degree of severity, ascertainment methods, and recording procedures, as a common "core," to which more specific assessment instruments can be added. Systematic empirical testing and validation of safety methodology is needed.


Tissue factor pathway inhibitor attenuates the progression of malignant pleural mesothelioma in nude mice.
Malignant pleural mesothelioma (MPM) is a rare cancer that is refractory to current treatments. It is characterized by a robust deposition of transitional fibrin that is in part promoted by tumor cells. MPM cells express tissue factor (TF) and the tissue factor pathway inhibitor (TFPI), but their contribution to the pathogenesis of MPM has been unclear. We found that REN MPM cells fail to express TFPI. Based on the tumor growth-promoting properties of TF, we hypothesized that the stable transfection of TFPI into REN MPM cells would decrease their aggressiveness. We tested our hypothesis using in vitro, in vivo, and ex vivo analyses. TFPI knock-in decreased the proliferation, invasion, and TF activity of REN cells in vitro. REN TFPI knock-in cells, empty vector, and naive control cells were next injected intrapleurally into nude mice. The expression of TFPI significantly decreased tissue invasion, inflammation, and the deposition of fibrin and collagen associated with tumor tissue, pleural effusions, and tumor burden. In ex vivo analyses, REN cells were cultured from harvested tumors. The overexpression of TFPI was maintained in cells propagated from TFPI knock-in tumors, and attenuated the activation of Factor X and the invasiveness of tumor cells. These analyses demonstrate that TFPI reduces the aggressiveness of MPM in vitro and in vivo, and that its effect involves the inhibition of TF procoagulant activity. These observations suggest that the interactions of TF and TFPI represent a novel therapeutic target in the treatment of MPM.


[Surgery in complex forms of transposition of the great vessels: long-term results in a series of 100 cases].
A series of 100 patients with complex forms of transposition of the great arteries (TGA) were operated upon over a 10 year period. Group 1 consisted of 13 TGA with pulmonary stenosis (PS), usually treated by an atrial baffle and direct repair of the stenosis. There was no operative or late mortality in this group and the long-term results were generally good (10/13). Group II comprised 29 TGA with ventricular septal defect (VSD) and PS. Seven Rastelli procedures gave 4 good results. Twenty two operations, associating atrial baffle, repair of VSD and PS (17 direct procedures, 5 left ventricle-pulmonary artery tube) were associated with a high mortality (5 operative and 4 late deaths) and 10 good long-term results. Group III comprised 58 TGA with VSD. Up to 1977 (n = 33) treatment consisted of atrial baffle + repair of VSD +/- removal of previous banding. Mortality was high (11 operative and 8 late deaths) with only 8 good long-term results. Since 1977, these patients have been treated by complete anatomical repair, the operative mortality of which is higher in the period under study (9/23) but the long-term results are much better. The surgical indications in our Department are based on the analysis of these results. In Group I only very significant PS is treated, either by left ventricle-pulmonary artery tube or direct repair depending on the form of the stenosis. In Group II, where the results based on atrial baffle are poor, a Rastelli procedure is preferred and especially its variants which avoid the use of prosthetic materials on the pulmonary trunk. In Group III, anatomical correction at the level of the great arteries is the routine procedure, the only point of discussion being the possibility of prior banding.


Physical trauma and risk of multiple sclerosis: a systematic review and meta-analysis of observational studies.
We aimed to examine physical trauma as a risk factor for the subsequent diagnosis of MS. We searched for observational studies that evaluated the risk for developing MS after physical trauma that occurred in childhood (≤20 years) or "premorbid" (>20 years). We performed a meta-analysis using a random effects model. We identified 1362 individual studies, of which 36 case-control studies and 4 cohort studies met the inclusion criteria for the review. In high quality case-control studies, there were statistically significant associations between those sustaining head trauma in childhood (OR=1.27; 95% CI, 1.12-1.44; p<0.001), premorbid head trauma (OR=1.40; 95% CI, 1.08-1.81; p=0.01), and other traumas during childhood (OR=2.31; 95% CI, 1.06-5.04; p=0.04) and the risk of being diagnosed with MS. In lesser quality studies, there was a statistical association between "other traumas" premorbid and spinal injury premorbid. No association was found between spinal injury during childhood, or fractures and burns at any age and the diagnosis of MS. The pooled OR of four cohort studies looking at premorbid head trauma was not statistically significant. The result of the meta-analyses of high quality case-control studies suggests a statistically significant association between premorbid head trauma and the risk for developing MS. However, cohort studies did not. Future prospective studies that define trauma based on validated instruments, and include frequency of traumas per study participant, are needed.


Tyrosine Phosphorylation of Caspase-8 Abrogates Its Apoptotic Activity and Promotes Activation of c-Src.
Src family tyrosine kinases (SFKs) phosphorylate caspase-8A at tyrosine (Y) 397 resulting in suppression of apoptosis. In addition, the phosphorylation of caspase-8A at other sites including Y465 has been implicated in the regulation of caspase-8 activity. However, the functional consequences of these modifications on caspase-8 processing/activity have not been elucidated. Moreover, various Src substrates are known to act as potent Src regulators, but no such role has been explored for caspase-8. We asked whether the newly identified caspase-8 phosphorylation sites might regulate caspase-8 activation and conversely, whether caspase-8 phosphorylation might affect Src activity. Here we show that Src phosphorylates caspase-8A at multiple tyrosine sites; of these, we have focused on Y397 within the linker region and Y465 within the p12 subunit of caspase-8A. We show that phosphomimetic mutation of caspase-8A at Y465 prevents its cleavage and the subsequent activation of caspase-3 and suppresses apoptosis. Furthermore, simultaneous phosphomimetic mutation of caspase-8A at Y397 and Y465 promotes the phosphorylation of c-Src at Y416 and increases c-Src activity. Finally, we demonstrate that caspase-8 activity prevents its own tyrosine phosphorylation by Src. Together these data reveal that dual phosphorylation converts caspase-8 from a pro-apoptotic to a pro-survival mediator. Specifically, tyrosine phosphorylation by Src renders caspase-8 uncleavable and thereby inactive, and at the same time converts it to a Src activator. This novel dynamic interplay between Src and caspase-8 likely acts as a potent signal-integrating switch directing the cell towards apoptosis or survival.


Type I collagen and fibromodulin enhance the tenogenic phenotype of hASCs and their potential for tendon regeneration.
Our previous work demonstrated the tendon-derived extracellular matrix (ECM) extracts as vital niches to specifically direct mesenchymal stem cells towards tenogenic differentiation. This study aims to further define the effective ECM molecules capable of teno-lineage induction on human adipose-derived stem cells (hASCs) and test their function for tendon engineering. By detecting the teno-markers expression levels in hASCs exposed to various substrate coatings, collagen I (COL1) and fibromodulin (FMOD) were identified to be the key molecules as a combination and further employed to the modification of poly(L-lactide-co-ε-caprolactone) electrospun nanoyarns, which showed advantages in inducting seeded hASCs for teno-lineage specific differentiation. Under dynamic mechanical loading, modified scaffold seeded with hASCs formed neo-tendon in vitro at the histological level and formed better tendon tissue in vivo with mature histology and enhanced mechanical properties. Primary mechanistic investigation with RNA sequencing demonstrated that the inductive mechanism of these two molecules for hASCs tenogenic differentiation was directly correlated with positive regulation of peptidase activity, regulation of cell-substrate adhesion and regulation of cytoskeletal organization. These biological processes were potentially affected by LOC101929398/has-miR-197-3p/TENM4 ceRNA regulation axis. In summary, COL1 and FMOD in combination are the major bioactive molecules in tendon ECM for likely directing tenogenic phenotype of hASCs and certainly valuable for hASCs-based tendon engineering.


Blood monocyte subsets differentially give rise to CD103+ and CD103- pulmonary dendritic cell populations.
There are two major myeloid pulmonary dendritic cell (DC) populations: CD103+ DCs and CD11bhigh DCs. In this study, we investigated in detail the origins of both myeloid DC pools using multiple experimental approaches. We show that, in resting lung, Ly-6ChighCCR2high monocytes repopulated CD103+ DCs using a CCR2-dependent mechanism, and these DCs preferentially retained residual CCR2 in the lung, whereas, conversely, Ly-6ClowCCR2low monocytes repopulated CD11bhigh DCs. CX3CR1 was required to generate normal numbers of pulmonary CD11bhigh DCs, possibly because Ly-6Clow monocytes in the circulation, which normally express high levels of CX3CR1, failed to express bcl-2 and may have diminished survival in the circulation in the absence of CX3CR1. Overall, these data demonstrate that the two circulating subsets of monocytes give rise to distinct tissue DC populations.


[Alpha 1 antitrypsin deficiency. Physiopathological consequences].
Alpha-1-antitrypsine, a glycoprotein synthesized in the liver, exists in different phenotypic variants. The Z allele, when heterozygotic, causes a diminution of protein in the blood; when homozygotic it causes an almost complete absence of blood protein. It appears that in instances of deficiency the hepatocyte is unable to secrete the protein it synthesizes, and this leads to intracellular accumulation of protein (visible on histological examination as granules of amorphic P.A.S.-positive material). The deficiency is accompanied by pulmonary manifestations of the destructive emphysematic type. The lesions are probably related to the absence of anti-protease activity in the lung tissues: proteolysis of the lung in animals reproduces the lesions observed in man. Studies on large populations have shown that, in people exhibiting a total or intermediate deficiency in alpha-1-antitrypsine, cigarette smoking represents a significant risk factor in that it increases the probability of parenchylmal destruction.


A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells.
Arginase 1 (Arg1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunoregulatory enzymes catalyzing the degradation of l-arginine and l-tryptophan, respectively, resulting in local amino acid deprivation. In addition, unlike Arg1, IDO1 is also endowed with non-enzymatic signaling activity in dendritic cells (DCs). Despite considerable knowledge of their individual biology, no integrated functions of Arg1 and IDO1 have been reported yet. We found that IDO1 phosphorylation and consequent activation of IDO1 signaling in DCs was strictly dependent on prior expression of Arg1 and Arg1-dependent production of polyamines. Polyamines, either produced by DCs or released by bystander Arg1+ myeloid-derived suppressor cells, conditioned DCs toward an IDO1-dependent, immunosuppressive phenotype via activation of the Src kinase, which has IDO1-phosphorylating activity. Thus our data indicate that Arg1 and IDO1 are linked by an entwined pathway in immunometabolism and that their joint modulation could represent an important target for effective immunotherapy in several disease settings.


Who Australasians trusted during COVID-19: lessons from the pandemic response.
Public trust in authoritative information sources is a key element of a successful public health response to a pandemic. This study investigated which sources of COVID-19 advice were most trusted by a primarily New Zealand-based cohort and considers implications for policy and practice regarding future pandemics. Data were from a COVID-19 vaccine intention survey presented to Australia- and New Zealand-based members of the longitudinal Dunedin Study (n=832) between ages 48 and 49, immediately before vaccines became available for the general population within New Zealand. We assessed participants' trust in specific sources of COVID-19 advice and investigated whether the pattern of responses differed by sex, socio-economic status (SES) or education. Doctors and healthcare providers were the most trusted source of COVID-19 advice, over and above other institutional sources. This pattern was consistent across sex, SES and education. Institutional experts were trusted significantly more by those with higher SES compared to those with lower SES, and by those with formal qualifications compared to those without formal qualifications. Our findings suggest that it is important to empower healthcare providers early in a pandemic to share advice with the public alongside other trusted sources, such as the government.


Spectrum of complications associated with Plasmodium vivax infection in a tertiary hospital in South-Western India.
To determine the range and incidence of complications associated with Plasmodium vivax (P. vivax) malaria. A retrospective analysis was performed of all patients of P. vivax malaria admitted in Kasturba Medical College, Manipal between January and December, 2010. Patients with mixed malarial infection were excluded by appropriate tests. Clinical presentation and laboratory parameters were studied. Medical records of 213 individuals who satisfied the inclusion criteria were reviewed. Anaemia was seen in 65 (30.5%), leucopenia in 38 (17.8%) and thrombocytopenia in 184 (86.4%) patients. Aspartate and alanine aminotransferases were elevated in 86 (40.4%), and 89 (41.9%) patients respectively. Hypoalbuminemia was observed in 157 (73.6%) cases. Elevated serum creatinine was noted in in 59 (27.5%) patients. Creatine kinase was elevated in 30 out of 59 patients (50.8%). Overall, 107 (50.2%) patients fulfilled WHO criteria for severe malaria. None of the patients succumbed to the disease. P. vivax malaria is a potentially severe disease, and the term "benign" tertian malaria is a misnomer. Despite significant morbidity, with timely and appropriate treatment P. vivax malaria has an excellent outcome.


A high resolution A-to-I editing map in the mouse identifies editing events controlled by pre-mRNA splicing.
Pre-mRNA-splicing and adenosine to inosine (A-to-I) RNA-editing occur mostly cotranscriptionally. During A-to-I editing, a genomically encoded adenosine is deaminated to inosine by adenosine deaminases acting on RNA (ADARs). Editing-competent stems are frequently formed between exons and introns. Consistently, studies using reporter assays have shown that splicing efficiency can affect editing levels. Here, we use Nascent-seq and identify ∼90,000 novel A-to-I editing events in the mouse brain transcriptome. Most novel sites are located in intronic regions. Unlike previously assumed, we show that both ADAR (ADAR1) and ADARB1 (ADAR2) can edit repeat elements and regular transcripts to the same extent. We find that inhibition of splicing primarily increases editing levels at hundreds of sites, suggesting that reduced splicing efficiency extends the exposure of intronic and exonic sequences to ADAR enzymes. Lack of splicing factors NOVA1 or NOVA2 changes global editing levels, demonstrating that alternative splicing factors can modulate RNA editing. Finally, we show that intron retention rates correlate with editing levels across different brain tissues. We therefore demonstrate that splicing efficiency is a major factor controlling tissue-specific differences in editing levels.


Reliability and concurrent validity of the BROM II for measuring lumbar mobility.
To establish the reliability of the BROM II device for measuring lumbar mobility in the sagittal, coronal and transverse planes and its validity against the double inclinometer method. Blind intra- and interexaminer reliability and concurrent validity. Interexaminer reliability was determined between two examiners. Chiropractice teaching college. Forty-seven asymptomatic chiropractic students (27 men and 20 women, age range 18 to 38 yr). Lumbar mobility measurement in degrees using the BROM II and double inclinometer techniques. Intraclass correlation coefficients (ICC) showed good intra- and interexaminer reliability of the BROM II for flexion (0.91 and 0.77, respectively) and lateral flexion (0.91 and 0.85 respectively). Less support was given to the reliability of the instrument in extension (0.63 and 0.35, respectively) and rotation (0.57 and 0.36 respectively). Concurrent validity of the BROM II and double inclinometer methods was partially supported (ICC in all planes range from 0.27 to 0.75). The BROM II was found to be a reliable instrument in the measurement of lumbar mobility in the sagittal (flexion) and coronal planes. However, before this device can be recommended as an assessment tool in clinical practice or clinical trials, further investigation into its reliability in a symptomatic group of patients is required. (J Manipulative Physiol Ther 1995; 18:497-502).


Effect of estimated plasma volume reduction on renal function for acute heart failure differs between patients with preserved and reduced ejection fraction.
The prognostic relevance of plasma volume reduction (PVR) in acute heart failure patients remains unclear because of the confounding hemodynamic effect of left ventricular ejection fraction impairment on kidney function. Subjects enrolled in the West Tokyo Heart Failure Registry were examined. The PV at admission and discharge was estimated from the subjects' body weight and its deviation from the ideal body weight. Patients in the top tertile of estimated PVR were classified as PVR+. Of the 381 patients with acute heart failure, 181 (47.5%) had heart failure with preserved ejection fraction (HFpEF). Estimated PVR was associated with worsening renal function in the HFpEF (odds ratio, 3.28; 95% confidence interval, 1.55-6.96; P=0.002) but not in the heart failure with reduced ejection fraction cohort (odds ratio, 1.22; 95% confidence interval, 0.61-2.42; P=0.57). This association in the HFpEF cohort remained significant after adjusting for a history of hypertension and diabetes mellitus and the estimated glomerular filtration rate (odds ratio, 3.34; 95% confidence interval, 1.52-7.33; P=0.003). The use of intravenous diuretics was a significant predictor of PVR in the HFpEF and heart failure with reduced ejection fraction groups. The effect of estimated PVR differs by HF type, and the estimated PVR during hospitalization is a predictor of worsening renal function in patients with HFpEF but not in heart failure with reduced ejection fraction. URL: http://www.umin.ac.jp/ctr/index-j.html. Unique identifier: UMIN000001549.


Metal-Backed Tibial Components Do Not Reduce Risk of Early Aseptic Loosening in Unicompartmental Knee Arthroplasty: A Systematic Review and Meta-Analysis.
Long-term results of unicompartmental knee arthroplasty (UKA) have shown a slightly higher revision rate than total knee arthroplasty (TKA), and implant fixation geometry seems to affect prosthetic survivorship. Whether metal-backed tibial component leads to superior performance over the all-polyethylene design is unclear, and a lack of evidence exists in literature. Our purpose was to demonstrate which implant design of UKA (all-polyethylene or metal-backed tibial component) is clinically superior regarding revision rates and clinical functioning, and investigate the role of potential factors that could affect the revision rate. A systematic review was conducted for clinical studies comparing all-polyethylene and metal-backed tibial components used in primary UKAs in terms of revision rates and clinical scores. Meta-regression techniques were used to explore factors modifying the observed effect. All causes of revision were extracted and analyzed, to find statistically significant differences between the two groups. Our research strategy generated a systematic review of nine studies comprising 1,101 UKAs in 1,088 patients with 87 revisions for any reason. Meta-analysis showed a higher, but not statistically significant, risk of aseptic revision in the all-polyethylene group. Studies with a smaller sample size and higher percentage of female patients were correlated to a higher relative risk of revision in favor of all-polyethylene UKAs. Differently, patients' age and duration of follow-up did not influence the risk ratio. The main cause for revision was aseptic loosening in both implants' component, with no statistically differences in the two groups examined. Our results do not show a superiority of the metal-backed tibial component in UKAs in terms of survivorship, although extreme care must be given for patients with high risk of early failure, such as female patients. However, surgical experience, in combination with careful patient selection, remains paramount and may lead to better long-term outcomes in patients requiring UKA. This is a Level III, therapeutic study.


Heparin-Induced Thrombocytopenia After Cardiac Surgery-A Statewide Review of Health Care Utilization.
Despite its severe consequences, clinical and economic impacts of heparin-induced thrombocytopenia (HIT) after cardiac operations have not been well characterized. This study assessed statewide incidence, outcomes, and resource consumption associated with HIT after cardiac operations. This was a retrospective investigation of cardiac surgery patients using the Maryland Health Services Cost Review Commission's database from 2012 to 2020. Health care costs, utilization, and outcomes for those who experienced postoperative HIT were compared with propensity score-matched controls. Of 33 583 cardiac surgery patients, 184 (0.55%) were diagnosed with postoperative HIT. Compared with non-HIT patients, HIT patients were significantly more likely to be in the oldest age group (>80 years; P < .001) and to have greater severity of illness at admission (P < .001). HIT was associated with a longer hospitalization (21 vs 7 days; P < .001), greater mortality (13.6% vs 2.3%; P < .001), and greater hospital charges ($123 160 vs $45 303; P < .001), even after propensity score matching. Readmission rates were not significantly different, however, and readmission hospital charges did not significantly differ between HIT and non-HIT patients. In addition to worse outcomes, HIT was associated with higher costs during index admissions but not during readmissions of cardiac surgery patients. Strategies to minimize HIT could yield better outcomes and reduced costs, particularly relevant for health care systems seeking improved value-based care while reducing unnecessary hospitalizations.


Karyotype of Rhodnius montenegrensis (Hemiptera, Triatominae).
The Triatominae subfamily comprises 6 tribes. The tribe Rhodniini comprises 2 genera and 22 nominal species. Rhodnius montenegrensis (Hemiptera, Triatominae) was recently described as evolutionarily related to R. robustus. Therefore, in order to contribute to karyosystematic study of the tribe Rhodniini, this report describes the number of chromosomes and compares the karyotype of R. montenegrensis to that of all other species in the tribe, in order to determine the karyotypic evolution of the tribe Rhodniini. The seminiferous tubules of adult males, after being removed and fixated on a cover slip, were processed with lacto-aceto-orcein for cytogenetic analysis. R. montenegrensis, as well as all other species of the tribe Rhodniini showed 22 chromosomes (20 autosomes + XY). Thus, we hereby describe the karyotype of the species R. montenegrensis and mainly highlight that the tribe Rhodniini displays karyotypic homogeneity, demonstrating itself as a derived group to a lesser extent when compared to the number of chromosomes of the common ancestors of the subfamily Triatominae.


Daikenchuto improved perioperative nutritional status of the patients with colorectal cancer: A prospective open-labeled randomized exploratory study.
The aim of this study is to exploratively evaluate the effect of Tsumura Daikenchuto Extract Granules (DKT, TJ-100) on abdominal symptoms, body weight, and nutritional function following colorectal cancer surgery. The subjects included 20 patients for curative resection of colorectal cancer. A TJ-100 administration group (n = 10) and non-administration group (n = 10) were randomized and compared. In the administration group, TJ-100 was administered from 2 days prior to surgery up to 12 weeks following surgery. The endpoints included body weight gain, Gastrointestinal Symptom Rating Scale (GSRS), and blood biochemical factors. For the purpose of observing safety, drug adverse events were evaluated including liver function tests. Excluding one patient, we compared 9 cases in the administration group and 10 cases in the non-administration group. No obvious adverse events were observed in any of the cases. In the comparison of body weight gain, the TJ-100 administration group showed significantly higher values at 2, 4, and 12 weeks following the surgery. There was a tendency for lower stable GSRS scores in the administration group overall, with no statistically significant difference. It is suggested that TJ-100 can be safely administered in the perioperative period for cases undergoing colorectal cancer surgery, potentially preventing weight loss during the early postoperative period.


Targeting cancer-specific mutations by T cell receptor gene therapy.
The ease of sequencing the cancer genome, identifying all somatic mutations and grafting mutation-specific T cell receptor (TCR) genes into T cells for adoptive transfer allow, for the first time, a truly tumor-specific and effective therapy. Mutation-specific TCR gene therapy might achieve optimal efficacy with least possible toxicity. Recent clinical data confirm the long-standing evidence from experimental cancer models that antigens encoded by the tumor-specific somatic mutations are potentially the best targets for adoptive T cell therapy. Open questions are, how many somatic mutations create suitable epitopes, whether only individual-specific or also recurrent somatic mutations qualify as suitable epitopes and how neoantigen-specific TCRs are most efficiently obtained. Tumor heterogeneity needs to be considered; therefore, it will be important to identify immunogenic driver mutations that occurred early, are essential for cancer cell survival and present in all cancer cells.


Genotype-limited changes in platelet and erythroid kinetics in Friend-virus-infected allophenic mice.
We report here results suggesting that cells of the megakaryocytic lineage or uncommitted precursor cells may be targets for Friend-virus-induced proliferation, and that genetic differences (other than Fv-2) between strains C57BL/6 and DBA/2 affect the susceptibility of these cells to Friend virus. The evidence suggesting this was derived from experiments with C57BL/6 in equilibrium DBA/2 allophenic mice. Within the first few weeks following infection of these mice with the polycythemic NB-tropic strain of Friend virus (FV-P), we observed a rapid shift in the genotypic composition of both red cells and platelets in favor of those of the DBA/2 genotype. Infection with the anemia-inducing strain of Friend virus (FV-A) also resulted in preferential production of DBA/2 strain erythrocytes, but its effect on platelet kinetics was nil. The FV-P- and FV-A-induced change in red cell composition is consistent with the view that erythroid precursors are target cells for Friend virus and that viral infection preferentially stimulates proliferation of susceptible strain (DBA/2) erythroid precursors. As for the platelet shifts induced by FV-P (and not FV-A), we believe the changes in platelet mosaicism also could be caused by viral-induced proliferation of DBA/2 platelet precursors, or more primitive progenitors, over the C57BL/6 ones. Thus, these results implicate the existence of nonerythroid target cells for FV-P-induced proliferation, as well as the existence of genetic differences between strains C57BL/6 and DBA/2 that modulate the responsiveness of such cells to infection.


Actin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane.
Vesicle fusion is executed via formation of an Ω-shaped structure (Ω-profile), followed by closure (kiss-and-run) or merging of the Ω-profile into the plasma membrane (full fusion). Although Ω-profile closure limits release but recycles vesicles economically, Ω-profile merging facilitates release but couples to classical endocytosis for recycling. Despite its crucial role in determining exocytosis/endocytosis modes, how Ω-profile merging is mediated is poorly understood in endocrine cells and neurons containing small ∼30-300 nm vesicles. Here, using confocal and super-resolution STED imaging, force measurements, pharmacology and gene knockout, we show that dynamic assembly of filamentous actin, involving ATP hydrolysis, N-WASP and formin, mediates Ω-profile merging by providing sufficient plasma membrane tension to shrink the Ω-profile in neuroendocrine chromaffin cells containing ∼300 nm vesicles. Actin-directed compounds also induce Ω-profile accumulation at lamprey synaptic active zones, suggesting that actin may mediate Ω-profile merging at synapses. These results uncover molecular and biophysical mechanisms underlying Ω-profile merging.


Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study.
This study assessed the efficacy and safety of canakinumab, a fully human anti-interleukin 1β monoclonal antibody, for prophylaxis against acute gouty arthritis flares in patients initiating urate-lowering treatment. In this double-blind, double-dummy, dose-ranging study, 432 patients with gouty arthritis initiating allopurinol treatment were randomised 1:1:1:1:1:1:2 to receive: a single dose of canakinumab, 25, 50, 100, 200, or 300 mg subcutaneously; 4×4-weekly doses of canakinumab (50+50+25+25 mg subcutaneously); or daily colchicine 0.5 mg orally for 16 weeks. Patients recorded details of flares in diaries. The study aimed to determine the canakinumab dose having equivalent efficacy to colchicine 0.5 mg at 16 weeks. A dose-response for canakinumab was not apparent with any of the four predefined dose-response models. The estimated canakinumab dose with equivalent efficacy to colchicine was below the range of doses tested. At 16 weeks, there was a 62% to 72% reduction in the mean number of flares per patient for canakinumab doses ≥50 mg versus colchicine based on a negative binomial model (rate ratio: 0.28-0.38, p≤0.0083), and the percentage of patients experiencing ≥1 flare was significantly lower for all canakinumab doses (15% to 27%) versus colchicine (44%, p<0.05). There was a 64% to 72% reduction in the risk of experiencing ≥1 flare for canakinumab doses ≥50 mg versus colchicine at 16 weeks (hazard ratio (HR): 0.28-0.36, p≤0.05). The incidence of adverse events was similar across treatment groups. Single canakinumab doses ≥50 mg or four 4-weekly doses provided superior prophylaxis against flares compared with daily colchicine 0.5 mg.


Determination of additivity of apparent and standardized ileal digestibility of amino acids in diets containing multiple protein sources fed to growing pigs.
An experiment was conducted in growing pigs to investigate the additivity of apparent ileal digestibility (AID) or standardized ileal digestibility (SID) of CP and AA in mixed diets containing multiple protein sources. Using the determined AID or SID for CP and AA in corn, soybean meal (SBM), corn distillers' dried grains with solubles (DDGS), or canola meal (CM), the AID or SID for 4 mixed diets based on corn-SBM, corn-SBM-DDGS, corn-SBM-CM, or corn-SBM-DDGS-CM were predicted and compared with determined AID or SID, respectively. Eighteen growing pigs (initial BW = 61.3 ± 5.5 kg) were surgically fitted with T-cannulas and assigned to a duplicated 9 × 4 incomplete Latin square design with 9 diets and 4 periods. The 9 experimental diets consisted of a nitrogen-free diet (NFD) to estimate basal ileal endogenous loss (BEL) of AA, 4 semipurified diets to determine the AID and SID of CP and AA in the 4 ingredients, and 4 mixed diets to test the additivity of AID and SID. Chromic oxide was added as an indigestible marker. Pigs were fed 1 of the 9 diets during each 7-d period, and ileal digesta were collected on d 6 and 7, from 0800 to 1800 h. The analyzed AA levels for the mixed diets were close to the calculated values based on the AA composition of each ingredient. The results revealed that the predicted SID were consistent with determined values, except for Leu, Thr, Asp, Cys, Pro, and Ser in the corn-SBM diet and Met and Cys in the corn-SBM-DDGS diet. The determined AID for total AA and Arg, His, Trp, Gly, and Pro in the corn-SBM diet were greater (P < 0.05) than predicted. For the corn-SBM-DDGS diet, the determined AID were greater (P < 0.05) than predicted AID for CP, total AA, and all AA except for Arg, Leu, and Pro. In the corn-SBM-CM diet, the determined AID were greater (P < 0.05) than predicted AID for Arg, Cys, and Gly. When compared with determined values, predicted AID in the corn-SBM-DDGS-CM diet were lower (P < 0.05) for total AA and Arg, Met, Cys, and Pro. In conclusion, the results substantiate the notion that SID of AA are more accurate than AID for predicting ileal digestibility of AA in mixed diets containing multiple protein sources. In addition, the lack of additivity of AID in mixed diets could be attributed to the intrinsic characteristics of the feed ingredient, especially its AA content.


Can subjective well-being and body concern in adolescence predict prescribed medication in adulthood? Findings from the Nord-Trøndelag Health Study and the Norwegian Prescription Database.
Aim: To examine whether subjective well-being (SW) and body concern among adolescents aged 15-19 years has an impact on adult health, measured by medications dispensed on average 18 years later. Methods: Data collected in the Nord-Trøndelag Health Study (HUNT) was paired with data from the Norwegian Prescription database (NorPD). We investigated the effects of adolescent SW and body concern on total number of medications, on use of anti-infectives (ATC-group J), medication for the musculo-skeletal system (ATC-group M), anxiolytics, hypnotics and sedatives (ATC-groups N05B and N05C), and finally antipsychotics, antidepressants and psychostimulants, agents used for attention-deficit/hyperactivity disorder and nootropics (ATC-groups N05A, N06A and N06B). We used multi-variable models where we entered body dissatisfaction and SW simultaneously in the models in order to adjust for the associations between the predictors, and also adjusted for possible confounders in the models. Results: Both body concern (dieting and dieting desire) and impaired SW predicted drug use 17-18 years after the participants were surveyed in adolescence. The impact was disease specific as body concern was the most influential predictor for drugs used for somatic diseases and complaints, whereas impaired SW was more strongly associated with drug use for mental health diseases and complaints. Conclusions: SW and body concern are important health determinants in the transition between adolescence and adulthood.


Highly Responsive Fluorescent Assemblies Allow for Unique, Multiparametric Sensing of the Phospholipid Membrane Environment.
Despite decades-long extensive research, probes that provide a comprehensive description of the lipid membrane microenvironment are still lacking. Here, a "smart" pyrene-terpyridine probe for multiparametric sensing of lipid membranes is reported. The complexity of the associated local microenvironment can be described by the distinct features of the probe fluorescence. The self-assembly of the probe molecules in phospholipid bilayers was sensitive to membrane order and phase state. The self-assembled probes showed a unique emission, influenced by dye-dye interactions and excited-state charge transfer. Moreover, this emission was sensitive to interfacial hydration, with very specific changes in emission wavelengths and fluorescence lifetimes upon variation of lipid compositions and properties. In parallel, changes in the lipid order and hydration affected the ground-state interactions in the dye aggregates and, thus, could be measured through ratiometric changes in the excitation and emission readouts. In addition, fluorescence anisotropy measurements provided another way to study the nature of dye aggregates in lipid bilayers. Overall, this report demonstrates how multiple aspects of the membrane microenvironment can be sensed through the unique fluorescence signatures of this "smart" probe in lipid membranes, and it establishes a new paradigm in lipid-membrane sensing.


Impact of transposable elements on genome structure and evolution in bread wheat.
Transposable elements (TEs) are major components of large plant genomes and main drivers of genome evolution. The most recent assembly of hexaploid bread wheat recovered the highly repetitive TE space in an almost complete chromosomal context and enabled a detailed view into the dynamics of TEs in the A, B, and D subgenomes. The overall TE content is very similar between the A, B, and D subgenomes, although we find no evidence for bursts of TE amplification after the polyploidization events. Despite the near-complete turnover of TEs since the subgenome lineages diverged from a common ancestor, 76% of TE families are still present in similar proportions in each subgenome. Moreover, spacing between syntenic genes is also conserved, even though syntenic TEs have been replaced by new insertions over time, suggesting that distances between genes, but not sequences, are under evolutionary constraints. The TE composition of the immediate gene vicinity differs from the core intergenic regions. We find the same TE families to be enriched or depleted near genes in all three subgenomes. Evaluations at the subfamily level of timed long terminal repeat-retrotransposon insertions highlight the independent evolution of the diploid A, B, and D lineages before polyploidization and cases of concerted proliferation in the AB tetraploid. Even though the intergenic space is changed by the TE turnover, an unexpected preservation is observed between the A, B, and D subgenomes for features like TE family proportions, gene spacing, and TE enrichment near genes.


Evaluation of the antibody response to the EBV proteome in EBV-associated classical Hodgkin lymphoma.
The humoral immune response to Epstein-Barr virus (EBV) in classical Hodgkin lymphoma (cHL) stratified by EBV tumor status is unclear. We examined IgG and IgA antibody responses against 202 protein sequences representing 86 EBV proteins using a microarray and sera from 139 EBV-positive cHL cases, 70 EBV-negative cHL cases and 141 population-based controls frequency matched to EBV-positive cHL cases on sex and age by area (UK, Denmark and Sweden). We leveraged existing data on the proportion of circulating B-cells infected by EBV and levels of serum CCL17, a chemokine secreted by cHL tumor cells, from a subset of the cHL cases in the UK. Total IgG but not IgA response level was significantly different between EBV-positive cHL cases and controls. The distinct serological response included significant elevations in 16 IgG antibodies and 2 IgA antibodies, with odds ratioshighest vs. lowest tertile > 3 observed for the following EBV proteins: LMP1 (oncogene), BcLF1 (VCAp160, two variants) and BBLF1 (two variants). Our cHL IgG signature correlated with the proportion of circulating EBV-infected B-cells, but not serum CCL17 levels. We observed no differences in the anti-EBV antibody profile between EBV-negative cHL cases and controls. BdRF1(VCAp40)-IgG and BZLF1(Zta)-IgG were identified as the serological markers best able to distinguish EBV-positive from EBV-negative cHL tumors. Our results support the hypothesis that differences in the EBV antibody profile are specific to patients with EBV-positive cHL and are not universally observed as part of a systematically dysregulated immune response present in all cHL cases.


Covalent immobilization of luminescent oxygen indicators reduces cytotoxicity.
Luminescence-based oxygen sensing is a widely used tool in cell culture applications. In a typical configuration, the luminescent oxygen indicators are embedded in a solid, oxygen-permeable matrix in contact with the culture medium. However, in sensitive cell cultures even minimal leaching of the potentially cytotoxic indicators can become an issue. One way to prevent the leaching is to immobilize the indicators covalently into the supporting matrix. In this paper, we report on a method where platinum(II)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorphenyl)-porphyrin (PtTFPP) oxygen indicators are covalently immobilized into a polymer matrix consisting of polystyrene and poly(pentafluorostyrene). We study how the covalent immobilization influences the sensing material's cytotoxicity to human induced pluripotent stem cell-derived (hiPSC-derived) neurons and cardiomyocytes (CMs) through 7-13 days culturing experiments and various viability analyses. Furthermore, we study the effect of the covalent immobilization on the indicator leaching and the oxygen sensing properties of the material. In addition, we demonstrate the use of the covalently linked oxygen sensing material in real time oxygen tension monitoring in functional hypoxia studies of the hiPSC-derived CMs. The results show that the covalently immobilized indicators substantially reduce indicator leaching and the cytotoxicity of the oxygen sensing material, while the influence on the oxygen sensing properties remains small or nonexistent.


Paleodemography of the libben site, Ottawa county, ohio.
The Libben site, a Late Woodland ossuary and occupation site from the Great Black Swamp of northern Ohio has yielded a well-preserved skeletal sample of 1327 articulated individuals. The outstanding preservation and completeness of the site and the utilization of an exhaustive aging methodology make this the largest and most comprehensively censused North American prehistoric cemetery. Survivorship data indicate a robust, successful population. Life expectancy at birth was 20 years. Among adults, male mortality was consistently higher than female, a condition possibly related to high interpersonal and intergroup aggression. Infant mortality was generally low, and a general hypothesis concerning the elevation of infant mortality and the simultaneous depression of adult mortality among aboriginal peoples after European contact is suggested.


[CME: Fusobacterium nucleatum/naviforme - a Rare but Serious Cause for Pyogenic Liver Abscesses].
CME: Fusobacterium nucleatum/naviforme - a Rare but Serious Cause for Pyogenic Liver Abscesses Abstract. Pyogenic liver abscesses belong to the most common abdominal infections. Beside the most common pathogens, also rare forms like Fusobacteria, which can also be part of the natural oropharyngeal and enteral microbiome, may be considered to cause severe forms of abscesses of the liver. Since they may be more difficult to detect, they could become a challenge during diagnosis and therapy.


Chromosomal locus for cadmium resistance in Pseudomonas putida consisting of a cadmium-transporting ATPase and a MerR family response regulator.
Pseudomonads from environmental sources vary widely in their sensitivity to cadmium, but the basis for this resistance is largely uncharacterized. A chromosomal fragment encoding cadmium resistance was cloned from Pseudomonas putida 06909, a rhizosphere bacterium, and sequence analysis revealed two divergently transcribed genes, cadA and cadR. CadA was similar to cadmium-transporting ATPases known mostly from gram-positive bacteria, and to ZntA, a lead-, zinc-, and cadmium-transporting ATPase from Escherichia coli. CadR was related to the MerR family of response regulators that normally control mercury detoxification in other bacterial systems. A related gene, zntR, regulates zntA in E. coli, but it is not contiguous with zntA in the E. coli genome as cadA and cadR were in P. putida. In addition, unlike ZntA and other CadA homologs, but similar to the predicted product of gene PA3690 in the P. aeruginosa genome, the P. putida CadA sequence had a histidine-rich N-terminal extension. CadR and the product of PA3689 of P. aeruginosa also had histidine-rich C-terminal extensions not found in other MerR family response regulators. Mutational analysis indicated that cadA and cadR are fully responsible for cadmium resistance and partially for zinc resistance. However, unlike zntA, they did not confer significant levels of lead resistance. The cadA promoter was responsive to Cd(II), Pb(II), and Zn(II), while the cadR promoter was only induced by Cd(II). CadR apparently represses its own expression at the transcriptional level. However, CadR apparently does not repress cadA. Homologs of the cadmium-transporting ATPase were detected in many other Pseudomonas species.


Reproductive plasticity and landscape heterogeneity benefit a ground-nesting bird in a fire-prone ecosystem.
Disturbance is critical for the conservation of rangeland ecosystems worldwide and many of these systems are fire dependent. Although it is well established that restoring fire as an ecological process can lead to increased biodiversity in grasslands and shrublands, the underlying mechanisms driving community patterns are poorly understood for fauna in fire-prone landscapes. Much of this uncertainty stems from the paucity of studies that examine the effects of fire at scales relevant to organism life histories. We assessed the response of a non-migratory ground-dwelling bird to disturbance (i.e., prescribed fire) and environmental stochasticity over the course of a 4-yr period, which spanned years of historic drought and record rainfall. Specifically, we investigated the nesting ecology of Northern Bobwhite (Colinus virginianus; hereafter Bobwhite) to illuminate possible avenues by which individuals respond to dynamic landscape patterns during a critical reproductive stage (i.e., nesting) in a mixed-grass shrubland in western Oklahoma, USA. We found that Bobwhites exhibited extreme plasticity in nest substrate use among time since fire categories (TSF) and subsequently maintained high nest survival (e.g., 57-70%). Bobwhites were opportunistic in nest substrate use among TSF categories (i.e., 72% of nest sites in shrubs in 0-12 months post fire compared to 71% in herbaceous vegetation in >36 months post fire), yet nesting decisions were first filtered by similar structural components (i.e., vertical and horizontal cover) within the vicinity of nest sites regardless of TSF category. Despite being a non-migratory and comparatively less mobile ground-nesting bird species, Bobwhites adjusted to dynamic vegetation mosaics on a fire-prone landscape under stochastic climatic conditions that culminated in stable and high nest survival. Broadly, our findings provide a unique depiction of organism response strategies to fire at scales relevant to a critical life-stage, a topic that has been previously understudied and poorly understood. We also demonstrate how doing so can better inform conservation practices aimed at restoring fire regimes on grassland and shrubland landscapes.


Solution structure of the C-terminal antiparallel coiled-coil domain from Escherichia coli osmosensor ProP.
Bacteria respond to increasing medium osmolality by accumulating organic solutes that are compatible with cellular functions. Transporter ProP of Escherichia coli, a proton symporter and a member of the major facilitator superfamily, senses osmotic shifts and responds by importing osmolytes such as glycine betaine. ProP contains a cytoplasmic, C-terminal extension that is essential for its activity. A peptide corresponding to the C-terminal extension of ProP forms a homodimeric alpha-helical coiled-coil even though some of its heptad a positions are not occupied by hydrophobic amino acid residues. Unexpectedly, amino acid replacement R488I, occurring at a heptad a position, destabilized the coiled-coil formed by the ProP peptide and attenuated the response of the intact transporter to osmotic upshifts in vivo. Thus, ProP was proposed to dimerize via an antiparallel coiled-coil. We used nuclear magnetic resonance (NMR) spectroscopy to determine the structure of the synthetic peptide corresponding to residues 468-497 of ProP. This region did form an antiparallel coil-coil in which critical residue R488 specifies the antiparallel coiled-coil orientation by forming stabilizing salt-bridges. Charged residues (both acidic and basic) are clustered on the c/g surface of the coiled-coil whereas polar residues are distributed on the b/e surface. This causes the structure to be bent, in contrast to other known antiparallel coiled-coils (those from the hepatitis delta antigen (PDB ID code 1A92) and the bovine F(1) ATPase inhibitor protein (PDB ID code 1HF9)). The coiled-coil and its possible importance for osmosensing are discussed.


[Non-enzymatic DNA methylation by S-adenosylmethionine results in the formation of minor thymine residues and 5-methylcytosine from cytosine].
It was found that nonenzymatic DNA methylation proceeds in water solution in the presence of S-adenosylmethionine (AdoMet). The main reaction products are thymine and 5-methylcytosine residues. It was shown that labelled thymine residues are formed also upon DNA incubation in the presence of [methyl-14C]methionine as well as [methyl-14C]cobalamine. Only cytosine reacts with AdoMet resulting in thymine production. AdoMet may be a potential mutagen that induces GC----AT transitions during DNA replication in the cell.


Loci and candidate gene identification for resistance to Sclerotinia sclerotiorum in soybean (Glycine max L. Merr.) via association and linkage maps.
Soybean white mold (SWM), caused by Sclerotinia sclerotiorum ((Lib.) W. Phillips), is currently considered to be the second most important cause of soybean yield loss due to disease. Research is needed to identify SWM-resistant germplasm and gain a better understanding of the genetic and molecular basis of SWM resistance in soybean. Stem pigmentation after treatment with oxaloacetic acid is an effective indicator of resistance to SWM. A total of 128 recombinant inbred lines (RILs) derived from a cross of 'Maple Arrow' (partial resistant to SWM) and 'Hefeng 25' (susceptible) and 330 diverse soybean cultivars were screened for the soluble pigment concentration of their stems, which were treated with oxalic acid. Four quantitative trait loci (QTLs) underlying soluble pigment concentration were detected by linkage mapping of the RILs. Three hundred and thirty soybean cultivars were sequenced using the whole-genome encompassing approach and 25 179 single-nucleotide polymorphisms (SNPs) were detected for the fine mapping of SWM resistance genes by genome-wide association studies. Three out of five SNP markers representing a linkage disequilibrium (LD) block and a single locus on chromosome 13 (Gm13) were significantly associated with the soluble pigment content of stems. Three more SNPs that represented three minor QTLs for the soluble pigment content of stems were identified on another three chromosomes by association mapping. A major locus with the largest effect on Gm13 was found both by linkage and association mapping. Four potential candidate genes involved in disease response or the anthocyanin biosynthesis pathway were identified at the locus near the significant SNPs (<60 kbp). The beneficial allele and candidate genes should be useful in soybean breeding for improving resistance to SWM.


Balloon expulsion from the rectum in constipation of different types.
The defaecatory mechanism using a balloon model with simultaneous measurement of intrarectal pressure has been studied in 15 control subjects with normal bowel habit and in 39 patients with chronic constipation; 31 with a normal barium enema and eight with idiopathic megarectum. Fourteen of those with a normal barium enema had prolonged whole gut transit times as measured by radio-opaque shapes. The ability of the patient to expel a rectal balloon containing 50, 100, and 150 ml of water, lying on their side in the left lateral position was tested and if unsuccessful, in the sitting position with the knees raised. All but one of the control subjects could expel balloons in the left lateral position. Only five of 17 constipated patients with normal barium enemas and transit times could expel balloons lying on their side although a further three could do so when sitting. None of 14 patients with slow transit and normal barium enemas could expel balloons in left lateral position although three could do so when sitting. Patients with megarectum could not expel balloons in either position. Levels of intrarectal pressure with straining were not significantly different between controls, who were able to expel balloons, and constipated patients with a normal barium enema, but were greater (p less than 0.01) in patients with megacolon than in control subjects. Using the balloon model a disorder of the defaecatory mechanism is present in patients with constipation of different types, but this is not because of an inability to raise intrarectal pressure.


Monoclonal antibodies reactive with hairy cell leukemia.
Monoclonal antibodies reactive with hairy cell leukemia were developed to aid in the diagnosis of this subtype of B cell chronic lymphocytic leukemia and to gain better insight into the origin of hairy cells. Three antibodies were found to be of value in the diagnosis of hairy cell leukemia. Antibody B-ly 2 can be considered a pan-B cell reagent and generally reacts similar to CD22 antibodies. Antibody B-ly 6 is reactive with the same antigen as CD11c (p150/95), an antigen that is present on hairy cell leukemia, macrophages, and a minor subpopulation of lymphocytes. Antibody B-ly 7 is a unique antibody reactive with 144 Kd antigen present only on hairy cell leukemia and a very small population of normal B lymphocytes. This subpopulation may be the counterpart of hairy cells.


Effects of MDMA and related analogs on plasma 5-HT: relevance to 5-HT transporters in blood and brain.
(±)-3,4-Methylenedioxymethamphetamine (MDMA) is an illicit drug that evokes transporter-mediated release of serotonin (5-HT) in the brain. 5-HT transporter (SERT) proteins are also expressed in non-neural tissues (e.g., blood), and evidence suggests that MDMA targets platelet SERT to increase plasma 5-HT. Here we tested two hypotheses related to the effects of MDMA on circulating 5-HT. First, to determine if MDMA metabolites might contribute to actions of the drug in vivo, we used in vitro microdialysis in rat blood specimens to examine the effects of MDMA and its metabolites on plasma 5-HT. Second, to determine whether effects of MDMA on plasma 5-HT might be used as an index of central SERT activity, we carried out in vivo microdialysis in blood and brain after intravenous MDMA administration. The in vitro results show that test drugs evoke dose-related increases in plasma 5-HT ranging from two- to sevenfold above baseline, with MDMA and its metabolite, (±)-3,4-methylenedioxyamphetamine (MDA), producing the largest effects. The ability of MDMA and related analogs to elevate plasma 5-HT is correlated with their potency as SERT substrates in rat brain synaptosomes. The in vivo results reveal that MDMA causes concurrent increases in extracellular 5-HT in blood and brain, but there are substantial individual differences in responsiveness to the drug. Collectively, our findings indicate that MDMA and its metabolites increase plasma 5-HT by a SERT-dependent mechanism, and suggest the possibility that measures of evoked 5-HT release in blood may reflect central SERT activity.


Phosphorylation of receptor-like cytoplasmic kinases by bacterial flagellin.
Molecular mechanisms that distinguish self and non-self are fundamental in innate immunity to prevent infections in plants and animals. Recognition of the conserved microbial components triggers immune responses against a broad spectrum of potential pathogens. In Arabidopsis, bacterial flagellin was perceived by a leucine-rich repeat-receptor-like kinase (LRR-RLK) FLS2. Upon flagellin perception, FLS2 forms a complex with another LRR-RLK BAK1. The intracellular signaling events downstream of FLS2/BAK1 receptor complex are still poorly understood. We recently identified a receptor-like cytoplasmic kinase (RLCK) BIK1 that associates with flagellin receptor complex to initiate plant innate immunity. BIK1 is rapidly phosphorylated upon flagellin perception in an FLS2- and BAK1-dependent manner. BAK1 directly phosphorylates BIK1 with an in vitro kinase assay. Plants have evolved a large number of RLCK genes involved in a wide range of biological processes. We provided evidence here that additional RLCKs could also be phosphorylated by flagellin and may play redundant role with BIK1 in plant innate immunity.


Adolescent sexual aggression: risk and protective factors.
Little research addresses the correlates of sexual aggression in nonclinical populations of adolescents. The purpose of this study was to identify risk and protective factors associated with sexual violence among male and female adolescents. We analyzed data on 71,594 students in the 9th and 12th grades responding to the 1992 Minnesota Student Survey, an anonymous, self-report survey examining an array of risk environments, health-compromising behaviors, and protective factors. The responses of students reporting a history of forcing someone into a sexual act were compared with those who reported that they had never forced someone into a sexual act. Separate analyses were conducted for males and females. A history of sexual violence perpetration was reported by 4.8% of male and 1.3% of female adolescents. Using a logistic regression model, sexual aggression was associated with experiencing intrafamilial or extrafamilial sexual abuse, witnessing family violence, frequent use of illegal drugs, anabolic steroid use, daily alcohol use, gang membership, high levels of suicide risk behavior, and excessive time spent "hanging out." Emotional health and connectedness with friends and adults in the community were protective factors for male adolescents against sexually aggressive behavior, and academic achievement was a protective factor for female adolescents. A history of forcing someone into a sexual act was associated with several risk and protective factors. Efforts to prevent adolescent sexual violence should target individuals at increased risk. Through their psychosocial assessment of young people, health care professionals can play a role in identifying, counseling, and making appropriate referrals for adolescents at risk for sexually aggressive behavior.


Action Intention-based and Stimulus Regularity-based Predictions: Same or Different?
We act on the environment to produce desired effects, but we also adapt to the environmental demands by learning what to expect next, based on experience: How do action-based predictions and sensory predictions relate to each other? We explore this by implementing a self-generation oddball paradigm, where participants performed random sequences of left and right button presses to produce frequent standard and rare deviant tones. By manipulating the action-tone association as well as the likelihood of a button press over the other one, we compare ERP effects evoked by the intention to produce a specific tone, tone regularity, and both intention and regularity. We show that the N1b and Tb components of the N1 response are modulated by violations of tone regularity only. However, violations of action intention as well as of regularity elicit MMN responses, which occur similarly in all three conditions. Regardless of whether the predictions at sensory levels were based on either intention, regularity, or both, the tone deviance was further and equally well detected at hierarchically higher processing level, as reflected in similar P3a effects between conditions. We did not observe additive prediction errors when intention and regularity were violated concurrently, suggesting the two integrate despite presumably having independent generators. Even though they are often discussed as individual prediction sources in the literature, this study represents to our knowledge the first to directly compare them. Finally, these results show how, in the context of action, our brain can easily switch between top-down intention-based expectations and bottom-up regularity cues to efficiently predict future events.


COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs
In the Wuhan Province of China, in December 2019, the novel coronavirus 2019 (COVID-19) has caused a severe involvement of the lower respiratory tract leading to an acute respiratory syndrome. Subsequently, coronavirus 2 (SARS-CoV-2) provoked a pandemic which is considered a life-threatening disease. The SARS-CoV-2, a family member of betacoronaviruses, possesses single-stranded positive-sense RNA with typical structural proteins, involving the envelope, membrane, nucleocapsid and spike proteins that are responsible for the viral infectivity, and nonstructural proteins. The effectual host immune response including innate and adaptive immunity against SARS-Cov-2 seems crucial to control and resolve the viral infection. However, the severity and outcome of the COVID-19 might be associated with the excessive production of proinflammatory cytokines "cytokine storm" leading to an acute respiratory distress syndrome. Regretfully, the exact pathophysiology and treatment, especially for the severe COVID-19, is still uncertain. The results of preliminary studies have shown that immune-modulatory or immune-suppressive treatments such as hydroxychloroquine, interleukin (IL)-6 and IL-1 antagonists, commonly used in rheumatology, might be considered as treatment choices for COVID-19, particularly in severe disease. In this review, to gain better information about appropriate anti-inflammatory treatments, mostly used in rheumatology for COVID-19, we have focused the attention on the structural features of SARS-CoV-2, the host immune response against SARS-CoV-2 and its association with the cytokine storm.


Children's experienced and imaginary stories about lunch packs and lunch breaks: Associations and perceptions of school lunch among primary school students in Norway.
This article examined Norwegian students' associations with lunch packs and lunch breaks in primary schools, highlighting the Norwegian school meal system. Empathy-based stories were used; that is, participants were asked to write on a story about a good or a bad school lunch, either based on actual experiences or imagination. The data included stories from 181 fifth graders (105 girls and 76 boys) aged 10-11 years. Additionally, this study employed a social-constructivist approach. The analysis of the stories on the lunch packs resulted in four sub-themes: food and sensory properties of food; food norms and the violation of the norms; physical and psychological consequences of (not) eating lunch; and expressions of peer-relations and family bonds. The analysis of the stories on lunch breaks resulted in two sub-themes: social interaction and simultaneous activity, and contextual factors. In the stories the lunch pack was found to evoke both enthusiasm and discontent. Students' associations and perceptions of the food were often related to how it looked, smelled, and tasted. Furthermore, a clear feature of the stories concerning lunch break in the classroom was that the students were concerned with the social aspects of the eating situation, such as interacting with classmates by chatting, watching television, or listening to music together. This study can contribute to a deeper understanding of children's experiences with a school meal system used in countries within and outside the Nordic region.


Mitigating Herding in Hierarchical Crowdsourcing Networks.
Hierarchical crowdsourcing networks (HCNs) provide a useful mechanism for social mobilization. However, spontaneous evolution of the complex resource allocation dynamics can lead to undesirable herding behaviours in which a small group of reputable workers are overloaded while leaving other workers idle. Existing herding control mechanisms designed for typical crowdsourcing systems are not effective in HCNs. In order to bridge this gap, we investigate the herding dynamics in HCNs and propose a Lyapunov optimization based decision support approach - the Reputation-aware Task Sub-delegation approach with dynamic worker effort Pricing (RTS-P) - with objective functions aiming to achieve superlinear time-averaged collective productivity in an HCN. By considering the workers' current reputation, workload, eagerness to work, and trust relationships, RTS-P provides a systematic approach to mitigate herding by helping workers make joint decisions on task sub-delegation, task acceptance, and effort pricing in a distributed manner. It is an individual-level decision support approach which results in the emergence of productive and robust collective patterns in HCNs. High resolution simulations demonstrate that RTS-P mitigates herding more effectively than state-of-the-art approaches.


Integrin cytoplasmic domain-binding proteins.
Integrins are a large family of cell surface receptors that mediate cell adhesion and influence migration, signal transduction, and gene expression. The cytoplasmic domains of integrins play a pivotal role in these integrin-mediated cellular functions. Through interaction with the cytoskeleton, signaling molecules, and other cellular proteins, integrin cytoplasmic domains transduce signals from both the outside and inside of the cell and regulate integrin-mediated biological functions. Identification and functional analyses of integrin cytoplasmic domain-binding proteins have been pursued intensively. In recent years, more cellular proteins have been reported to directly interact with integrin cytoplasmic domains and some of these interactions may play important roles in integrin-mediated biological responses. Integrin (&bgr;) chains, for example, interact with actin-binding proteins (e.g. talin and filamin), which form mechanical links to the cytoskeleton. These and other proteins (e.g. FAK, ILK and novel proteins such as TAP20) might also link integrins to signaling mechanisms and, in some cases (e.g. JAB1) mediate integrin-dependent gene regulation.


A favorable response to lithium carbonate in a "schizo-affective" father and son.
It has recently been suggested that patients with mania are often misdiagnosed as having schizophrenia. The authors report a favorable clinical response to lithium carbonate in a father and son with an apparent schizo-affective syndromes may respond favorably to lithium but caution that a favorable response in such cases does not absolutely confirm a diagnosis of mania.


Function of Akkermansia muciniphila in Obesity: Interactions With Lipid Metabolism, Immune Response and Gut Systems.
Obesity and its metabolic syndrome, including liver disorders and type 2 diabetes, are a worldwide epidemic and are intimately linked to diet. The gut microbiota interaction has been pointed to as a hot topic of research in the treatment of obesity and related metabolic diseases by influencing energy metabolism and the immune system. In terms of the novel beneficial microbes identified, Akkermansia muciniphila (A. muciniphila) colonizes the mucosa layer of the gut and modulates basal metabolism. A. muciniphila is consistently correlated with obesity. The causal beneficial impact of A. muciniphila treatment on obesity is coming to light, having been proved by a variety of animal models and human studies. A. muciniphila has been characterized as a beneficial player in body metabolism and has great prospects for treatments of the metabolic disorders associated with obesity, as well as being considered for next-generation therapeutic agents. This paper aimed to investigate the basic mechanism underlying the relation of A. muciniphila to obesity and its host interactions, as identified in recent discoveries, facilitating the establishment of the causal relationship in A. muciniphila-associated therapeutic supplement in humans.


Monoclonal antibody PD41 recognizes an antigen restricted to prostate adenocarcinomas.
A monoclonal antibody (MAb) designated PD41 (IgG1k) was generated by hyperimmunizing BALB/c mice with a membrane preparation prepared from a moderately to poorly differentiated prostate carcinoma surgical specimen. The immunohistochemical reactivity of MAb PD41 was shown to be highly restricted to the ductal epithelia and secretions of prostate adenocarcinoma tissues. Sixty-five % of the prostate tumor specimens were stained with MAb PD41, whereas no staining of the fetal or benign prostate specimens was observed. PD41 reacted minimally with normal prostate tissues, with less than 1% of the epithelial cells staining. This MAb did not react with nonprostate carcinomas or to a variety of normal human tissues. Using both radioimmunoassay and immunofluorescent procedures, several cultured human tumor cell lines, human blood cells, and purified antigens to prostate-specific antigen and prostatic acid phosphatase also were found not to express the PD41 antigen. MAb PD41 also was shown to bind to the target antigen present in seminal plasma obtained from prostate carcinoma patients but not to seminal plasma from normal donors. Immunoblots of gel-separated components of prostate carcinoma tissue extracts indicate that the molecular weight of the proteins carrying the PD41 antigenic determinant can differ among individual tumors, ranging from Mr 90,000 to greater than 400,000. However, in seminal plasma from prostate cancer patients, the predominant component recognized by PD41 is the diffuse Mr greater than 400,000 band. It appears that this monoclonal antibody may recognize a prostate carcinoma-associated mucin-like antigen, which is preferentially expressed on prostate carcinomas, and therefore, may be a useful marker to distinguish benign prostate hyperplasia from prostate carcinoma.


Early Detection and Reversal of Cell Apoptosis Induced by Focused Ultrasound-Mediated Blood-Brain Barrier Opening.
Focused ultrasound (FUS) combined with microbubbles (MBs) has recently emerged as a potential approach to open the blood-brain barrier (BBB) for delivering drugs into the brain. However, appropriate approaches are still lacking to monitor the sublethal damage during FUS-mediated BBB opening in vivo, especially the early stage cell apoptotic events. Here, we developed a kind of nanoprobe-loaded MBs (AV-ICG-NPs@MBs) which can monitor the apoptotic cells that occur during FUS-mediated BBB opening through encapsulating the annexin V-targeted nanoprobes AV-ICG-NPs into the cavity of lipid-PLGA hybrid MBs. When irradiated by FUS, AV-ICG-NPs@MBs in the cerebral blood vessels would produce cavitation, favoring the BBB opening. Meanwhile, AV-ICG-NPs@MBs would be destroyed and release their AV-ICG-NPs payload. These released AV-ICG-NPs can be further delivered into the brain via the destructed BBB and bind with the phosphatidylserine externalized on the membrane of apoptotic cells if this occurs, leading to the prolonged detention of fluorescent signals in the brain. Furthermore, we also provided an effective strategy to inhibit or reverse the possible damage to the brain from a FUS-mediated BBB opening technology, through developing AV-ICG-NPs/GAS@MBs that encapsulate the antioxidant gastrodin (GAS) into AV-ICG-NPs@MBs. Accompanied by FUS irradiation and bubble cavitation, GAS was released and delivered into the brain, where they scavenged the oxygen free radicals produced from cavitation, leading to significantly lower fluorescence signals in the brain due to the absence of externalized phosphatidylserine. In conclusion, our study provides an approach to monitor and inhibit cell apoptotic events during FUS-mediated BBB opening.


Impact of community-based support services on antiretroviral treatment programme delivery and outcomes in resource-limited countries: a synthetic review.
Task-shifting to lay community health providers is increasingly suggested as a potential strategy to overcome the barriers to sustainable antiretroviral treatment (ART) scale-up in high-HIV-prevalence, resource-limited settings. The dearth of systematic scientific evidence on the contributory role and function of these forms of community mobilisation has rendered a formal evaluation of the published results of existing community support programmes a research priority. We reviewed the relevant published work for the period from November 2003 to December 2011 in accordance with the guidelines for a synthetic review. ISI Web of Knowledge, Science Direct, BioMed Central, OVID Medline, PubMed, Social Services Abstracts, and Sociological Abstracts and a number of relevant websites were searched. The reviewed literature reported an unambiguous positive impact of community support on a wide range of aspects, including access, coverage, adherence, virological and immunological outcomes, patient retention and survival. Looking at the mechanisms through which community support can impact ART programmes, the review indicates that community support initiatives are a promising strategy to address five often cited challenges to ART scale-up, namely (1) the lack of integration of ART services into the general health system; (2) the growing need for comprehensive care, (3) patient empowerment, (4) and defaulter tracing; and (5) the crippling shortage in human resources for health. The literature indicates that by linking HIV/AIDS-care to other primary health care programmes, by providing psychosocial care in addition to the technical-medical care from nurses and doctors, by empowering patients towards self-management and by tracing defaulters, well-organised community support initiatives are a vital part of any sustainable public-sector ART programme. The review demonstrates that community support initiatives are a potentially effective strategy to address the growing shortage of health workers, and to broaden care to accommodate the needs associated with chronic HIV/AIDS. The existing evidence suggests that community support programmes, although not necessarily cheap or easy, remain a good investment to improve coverage of communities with much needed health services, such as ART. For this reason, health policy makers, managers, and providers must acknowledge and strengthen the role of community support in the fight against HIV/AIDS.


Interventions for drug-using offenders with co-occurring mental health problems.
This review represents one from a family of three reviews focusing on interventions for drug-using offenders. Many people under the care of the criminal justice system have co-occurring mental health problems and drug misuse problems; it is important to identify the most effective treatments for this vulnerable population. To assess the effectiveness of interventions for drug-using offenders with co-occurring mental health problems in reducing criminal activity or drug use, or both.This review addresses the following questions.• Does any treatment for drug-using offenders with co-occurring mental health problems reduce drug use?• Does any treatment for drug-using offenders with co-occurring mental health problems reduce criminal activity?• Does the treatment setting (court, community, prison/secure establishment) affect intervention outcome(s)?• Does the type of treatment affect treatment outcome(s)? We searched 12 databases up to February 2019 and checked the reference lists of included studies. We contacted experts in the field for further information. We included randomised controlled trials designed to prevent relapse of drug use and/or criminal activity among drug-using offenders with co-occurring mental health problems. We used standard methodological procedures as expected by Cochrane . We included 13 studies with a total of 2606 participants. Interventions were delivered in prison (eight studies; 61%), in court (two studies; 15%), in the community (two studies; 15%), or at a medium secure hospital (one study; 8%). Main sources of bias were unclear risk of selection bias and high risk of detection bias.Four studies compared a therapeutic community intervention versus (1) treatment as usual (two studies; 266 participants), providing moderate-certainty evidence that participants who received the intervention were less likely to be involved in subsequent criminal activity (risk ratio (RR) 0.67, 95% confidence interval (CI) 0.53 to 0.84) or returned to prison (RR 0.40, 95% CI 0.24 to 0.67); (2) a cognitive-behavioural therapy (one study; 314 participants), reporting no significant reduction in self-reported drug use (RR 0.78, 95% CI 0.46 to 1.32), re-arrest for any type of crime (RR 0.69, 95% CI 0.44 to 1.09), criminal activity (RR 0.74, 95% CI 0.52 to 1.05), or drug-related crime (RR 0.87, 95% CI 0.56 to 1.36), yielding low-certainty evidence; and (3) a waiting list control (one study; 478 participants), showing a significant reduction in return to prison for those people engaging in the therapeutic community (RR 0.60, 95% CI 0.46 to 0.79), providing moderate-certainty evidence.One study (235 participants) compared a mental health treatment court with an assertive case management model versus treatment as usual, showing no significant reduction at 12 months' follow-up on an Addictive Severity Index (ASI) self-report of drug use (mean difference (MD) 0.00, 95% CI -0.03 to 0.03), conviction for a new crime (RR 1.05, 95% CI 0.90 to 1.22), or re-incarceration to jail (RR 0.79, 95% CI 0.62 to 1.01), providing low-certainty evidence.Four studies compared motivational interviewing/mindfulness and cognitive skills with relaxation therapy (one study), a waiting list control (one study), or treatment as usual (two studies). In comparison to relaxation training, one study reported narrative information on marijuana use at three-month follow-up assessment. Researchers reported a main effect < .007 with participants in the motivational interviewing group, showing fewer problems than participants in the relaxation training group, with moderate-certainty evidence. In comparison to a waiting list control, one study reported no significant reduction in self-reported drug use based on the ASI (MD -0.04, 95% CI -0.37 to 0.29) and on abstinence from drug use (RR 2.89, 95% CI 0.73 to 11.43), presenting low-certainty evidence at six months (31 participants). In comparison to treatment as usual, two studies (with 40 participants) found no significant reduction in frequency of marijuana use at three months post release (MD -1.05, 95% CI -2.39 to 0.29) nor time to first arrest (MD 0.87, 95% CI -0.12 to 1.86), along with a small reduction in frequency of re-arrest (MD -0.66, 95% CI -1.31 to -0.01) up to 36 months, yielding low-certainty evidence; the other study with 80 participants found no significant reduction in positive drug screens at 12 months (MD -0.7, 95% CI -3.5 to 2.1), providing very low-certainty evidence.Two studies reported on the use of multi-systemic therapy involving juveniles and families versus treatment as usual and adolescent substance abuse therapy. In comparing treatment as usual, researchers found no significant reduction up to seven months in drug dependence on the Drug Use Disorders Identification Test (DUDIT) score (MD -0.22, 95% CI -2.51 to 2.07) nor in arrests (RR 0.97, 95% CI 0.70 to 1.36), providing low-certainty evidence (156 participants). In comparison to an adolescent substance abuse therapy, one study (112 participants) found significant reduction in re-arrests up to 24 months (MD 0.24, 95% CI 0.76 to 0.28), based on low-certainty evidence.One study (38 participants) reported on the use of interpersonal psychotherapy in comparison to a psychoeducational intervention. Investigators found no significant reduction in self-reported drug use at three months (RR 0.67, 95% CI 0.30 to 1.50), providing very low-certainty evidence. The final study (29 participants) compared legal defence service and wrap-around social work services versus legal defence service only and found no significant reductions in the number of new offences committed at 12 months (RR 0.64, 95% CI 0.07 to 6.01), yielding very low-certainty evidence. Therapeutic community interventions and mental health treatment courts may help people to reduce subsequent drug use and/or criminal activity. For other interventions such as interpersonal psychotherapy, multi-systemic therapy, legal defence wrap-around services, and motivational interviewing, the evidence is more uncertain. Studies showed a high degree of variation, warranting a degree of caution in interpreting the magnitude of effect and the direction of benefit for treatment outcomes.


Does the longevity of the Sardinian population date back to Roman times? A comprehensive review of the available evidence.
The discovery early in this century of the exceptional longevity of the Sardinian population has given new impetus to demographic studies of this phenomenon during the classical period. In the 1970s, it was hypothesised that the average mortality rate in Roman Sardinia was lower than in metropolitan Rome itself, postulating an ancient precedent for the remarkable longevity observable nowadays in the island's population. In the present study, the available evidence was examined in order to test this hypothesis. Literary, juridical, epigraphic, papyrological, anthropological and archaeological sources regarding the population of the Roman Empire, including Sardinia, were retrieved by accessing Science Direct, PubMed, Scopus and Google Scholar databases, as well as regional libraries, regardless of time limitation, and were independently reviewed by the authors. For Roman Sardinia, only funerary epitaphs were retrieved, in contrast with the numerous sources available for the whole Roman Empire. Inscriptions revealing the existence of three alleged nonagenarians, two centenarians, two ultracentenarians and one supercentenarian were found, corresponding to 2% in a total of 381 inscriptions. The majority were located in a highly Romanised rural area of central-western Sardinia. However, the ages reported in the epitaphs may be inaccurate because of the influence of confounders such as age rounding, approximations and/or amplifications, and are unrelated to the total number of inhabitants. In conclusion, the funerary evidence, the only available data from Roman Sardinia, is too weak to estimate the life expectancy of the local ancient population and cannot offer valuable arguments to support the hypothesis that exceptional longevity has been a Sardinian trait since Roman times.