Plasma and whole blood mefloquine concentrations during treatment of chloroquine-resistant falciparum malaria with the combination mefloquine-sulphadoxine-pyrimethamine.
Mefloquine-sulphadoxine-pyrimethamine (MSP) in combination has proved effective against multiple-drug-resistant falciparum malaria, but nothing is known about mefloquine absorption when it is given in this formulation. Nine Thai patients, aged 15-51 years with uncomplicated chloroquine-resistant falciparum malaria, took 11.2-16.7 mg of mefloquine base per kilogram bodyweight as MSP tablets. All patients responded to treatment with fever and parasite clearance times of 61 +/- 29 h (mean +/- s.d.) and 52 +/- 24 h, respectively. The mean apparent absorption half-time (t1/2abs) of mefloquine was 4.89 h (range 2.25-9.72) and mean peak plasma concentration was 1815 ng ml-1 (range 725-3368). Peak plasma mefloquine concentrations in three patients who vomited within 2 h of treatment were 725, 956 and 1972 ng ml-1. There was no significant difference between plasma and whole blood mefloquine concentrations during the first 48 h of treatment. Based on the elimination of parasitaemia, the plasma mefloquine concentrations are adequate for therapy of uncomplicated falciparum malaria although the relationship between plasma concentrations and therapeutic efficacy of mefloquine requires further study.


Targeting Hypoxia Signaling for Perioperative Organ Injury.
Perioperative organ injury has a significant impact on surgical outcomes and presents a leading cause of death in the United States. Recent research has pointed out an important role of hypoxia signaling in the protection from organ injury, including for example myocardial infarction, acute respiratory distress syndrome, acute kidney, or gut injury. Hypoxia induces the stabilization of hypoxia-inducible factors (HIFs), thereby leading to the induction of HIF target genes, which facilitates adaptive responses to low oxygen. In this review, we focus on current therapeutic strategies targeting hypoxia signaling in various organ injury models and emphasize potential clinical approaches to integrate these findings into the care of surgical patients. Conceptually, there are 2 options to target the HIF pathway for organ protection. First, drugs became recently available that promote the stabilization of HIFs, most prominently via inhibition of prolyl hydroxylase. These compounds are currently trialed in patients, for example, for anemia treatment or prevention of ischemia and reperfusion injury. Second, HIF target genes (such as adenosine receptors) could be activated directly. We hope that some of these approaches may lead to novel pharmacologic strategies to prevent or treat organ injury in surgical patients.


Core Clerkship Grading: The Illusion of Objectivity.
Core clerkship grading creates multiple challenges that produce high stress for medical students, interfere with learning, and create inequitable learning environments. Students and faculty alike succumb to the illusion of objectivity-that quantitative ratings converted to grades convey accurate measures of the complexity of clinical performance.Clerkship grading is the first high-stakes assessment within medical school and occurs just as students are newly immersed full-time in an environment in which patient care supersedes their needs as learners. Students earning high marks situate themselves to earn entry into competitive residency programs and selective specialties. However, there is no commonly accepted standard for how to assign clerkship grades, and the process is vulnerable to imprecision and bias. Rewarding learners for the speed with which they adapt inherently favors students who bring advantages acquired before medical school and discounts the goal of all learners achieving competence.The authors propose that, rather than focusing on assigning core clerkship grades, assessment of student performance should incorporate expert judgment of learning progress. Competency-based medical education is predicated on the articulation of stepwise expectations for learners, with the support and time allocated for each learner to meet those expectations. Concurrently, students should ideally review their own performance data with coaches to self-assess areas of relative strength and areas for further growth. Eliminating grades in favor of competency-based assessment for learning holds promise to engage learners in developing essential patient care and teamwork skills and to foster their development of lifelong learning habits.


Nonsense Suppression as an Approach to Treat Lysosomal Storage Diseases.
In-frame premature termination codons (PTCs) (also referred to as nonsense mutations) comprise ~10% of all disease-associated gene lesions. PTCs reduce gene expression in two ways. First, PTCs prematurely terminate translation of an mRNA, leading to the production of a truncated polypeptide that often lacks normal function and/or is unstable. Second, PTCs trigger degradation of an mRNA by activating nonsense-mediated mRNA decay (NMD), a cellular pathway that recognizes and degrades mRNAs containing a PTC. Thus, translation termination and NMD are putative therapeutic targets for the development of treatments for genetic diseases caused by PTCs. Over the past decade, significant progress has been made in the identification of compounds with the ability to suppress translation termination of PTCs (also referred to as readthrough). More recently, NMD inhibitors have also been explored as a way to enhance the efficiency of PTC suppression. Due to their relatively low threshold for correction, lysosomal storage diseases are a particularly relevant group of diseases to investigate the feasibility of nonsense suppression as a therapeutic approach. In this review, the current status of PTC suppression and NMD inhibition as potential treatments for lysosomal storage diseases will be discussed.


RESTORE: an exploratory trial of an online intervention to enhance self-efficacy to manage problems associated with cancer-related fatigue following primary cancer treatment: study protocol for a randomized controlled trial.
There are over 25 million people worldwide living with or beyond cancer and this number is increasing. Cancer survivors face a range of problems following primary treatment. One of the most frequently reported and distressing symptoms experienced by cancer survivors is fatigue. There is growing support for survivors who are experiencing problems after cancer treatment to engage in supported self-management. To date there is some evidence of effective interventions to manage fatigue in this population; however, to our knowledge there are no online resources that draw on this information to support self-management of fatigue. This paper describes the protocol for an exploratory randomized controlled trial of an online intervention to support self-management of cancer-related fatigue after primary cancer treatment. This is a parallel-group two-armed (1:1) exploratory randomized controlled trial including 125 cancer survivors experiencing fatigue (scoring ≥4 on a unidimensional 11-point numeric rating scale for fatigue intensity) within five years of primary treatment completion with curative intent. Participants will be recruited from 13 NHS Trusts across the UK and randomized to either the online intervention (RESTORE), or a leaflet comparator (Macmillan Cancer Backup, Coping with Fatigue). The primary outcome is a change in Perceived Self-Efficacy for Fatigue Self-Management (as measured by the Perceived Self-Efficacy for Fatigue Self-Management Instrument). Secondary outcomes include impact on perception and experience of fatigue (measured by the Brief Fatigue Inventory), and quality of life (measured by the Functional Assessment of Cancer Therapy - General and the Personal Wellbeing Index). Outcome measures will be collected at baseline, 6 weeks (completion of intervention), and 3 months. Process evaluation (including telephone interviews with recruiting staff and participants) will determine acceptability of the intervention and trial processes. Data from this trial will be used to refine the intervention and contribute to the design of an effectiveness trial. This intervention will be expanded to address other cancer-related problems important to cancer survivors following primary cancer treatment. ISRCTN67521059.


Preparation of diglycolamide polymer modified silica and its application as adsorbent for rare earth ions.
Three novel diglycolamide monomers were synthesized and polymerized on silica. The diglycolamide polymer grafted silica were used as adsorbents for rare earth ions. The effects of acid concentration, structure of monomer, initial solution concentration, contact time and coexisting ions on adsorption of rare earth ions were investigated in detail. It was shown that the adsorption capacity increased with increasing acid concentration. Three adsorbents exhibited selectivity for middle and heavy rare earth over light rare earth in different extent. The adsorbent prepared from the monomer having the largest alkyl substituent showed the lowest adsorption capacity but the highest selectivity for different rare earth elements (REEs). Adsorption data were well fitted to the Langmuir isotherm and pseudo-second-order models. The presence of high concentrations (100 fold) of coexisting metal ions, K(I), Cr(II), Cu(II) or Fe(III), does not decrease the adsorption for rare earth ions seriously.


mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation.
Despite its central position in oncogenic intracellular signaling networks, the role of mTORC1 in epithelial development has not been studied extensively in vivo. Here, we have used the epidermis as a model system to elucidate the cellular effects and signaling feedback sequelae of mTORC1 loss of function in epithelial tissue. In mice with conditional epidermal loss of the mTORC1 components Rheb or Rptor, mTORC1 loss of function unexpectedly resulted in a profound skin barrier defect with epidermal abrasions, blistering, and early postnatal lethality, due to a thinned epidermis with decreased desmosomal protein expression and incomplete biochemical differentiation. In mice with mTORC1 loss of function, we found that Rho kinase (ROCK) signaling was constitutively activated, resulting in increased cytoskeletal tension and impaired cell-cell adhesion. Inhibition or silencing of ROCK1 was sufficient to rescue keratinocyte adhesion and biochemical differentiation in these mice. mTORC1 loss of function also resulted in marked feedback upregulation of upstream TGF-β signaling, triggering ROCK activity and its downstream effects on desmosomal gene expression. These findings elucidate a role for mTORC1 in the regulation of epithelial barrier formation, cytoskeletal tension, and cell adhesion, underscoring the complexity of signaling feedback following mTORC1 inhibition.


Mechanisms and functions of cellular senescence.
Cellular senescence is a highly stable cell cycle arrest that is elicited in response to different stresses. By imposing a growth arrest, senescence limits the replication of old or damaged cells. Besides exiting the cell cycle, senescent cells undergo many other phenotypic alterations such as metabolic reprogramming, chromatin rearrangement, or autophagy modulation. In addition, senescent cells produce and secrete a complex combination of factors, collectively referred as the senescence-associated secretory phenotype, that mediate most of their non-cell-autonomous effects. Because senescent cells influence the outcome of a variety of physiological and pathological processes, including cancer and age-related diseases, pro-senescent and anti-senescent therapies are actively being explored. In this Review, we discuss the mechanisms regulating different aspects of the senescence phenotype and their functional implications. This knowledge is essential to improve the identification and characterization of senescent cells in vivo and will help to develop rational strategies to modulate the senescence program for therapeutic benefit.


Three distinct amine receptors operating at different levels within the locomotory circuit are each essential for the serotonergic modulation of chemosensation in Caenorhabditis elegans.
Serotonin modulates behavioral plasticity in both vertebrates and invertebrates and in Caenorhabditis elegans regulates key behaviors, including locomotion, aversive learning and olfaction through at least four different 5-HT receptors. In the present study, we examined the serotonergic stimulation of aversive responses to dilute octanol in animals containing null alleles of these 5-HT receptors. Both ser-1 and mod-1 null animals failed to increase sensitivity to dilute octanol on food/5-HT, in contrast to wild-type, ser-4 or ser-7 null animals. 5-HT sensitivity was restored by the expression of MOD-1 and SER-1 in the AIB or potentially the AIY, and RIA interneurons of mod-1 and ser-1 null animals, respectively. Because none of these 5-HT receptors appear to be expressed in the ASH sensory neurons mediating octanol sensitivity, we identified a 5-HT(6)-like receptor, F16D3.7(SER-5), that was required for food/5-HT-dependent increases in octanol sensitivity. ser-5 null animals failed to increase octanol sensitivity in the presence of food/5-HT and sensitivity could be restored by expression of SER-5 in the ASHs. Similarly, the RNAi knockdown of ser-5 expression in the ASHs of wild-type animals also abolished 5-HT-dependent increases in octanol sensitivity, suggesting that SER-5 modulates the octanol responsiveness of the ASHs directly. Together, these results suggest that multiple amine receptors, functioning at different levels within the locomotory circuit, are each essential for the serotonergic modulation of ASH-mediated aversive responses.


Reverse gyrase is not a prerequisite for hyperthermophilic life.
We disrupted the reverse gyrase gene from a hyperthermophilic archaeon, Thermococcus kodakaraensis KOD1. An apparent positive supercoiling activity that was observed in the host strain was not found in the disruptant strain. We found that a lack of reverse gyrase led to a retardation in growth that was more striking at higher temperatures. However, the disruption of the reverse gyrase gene did not lead to a lethal phenotype at 90 degrees C. This study provides experimental evidence that reverse gyrase is not a prerequisite for hyperthermophilic life.


Homicide Using an Air Weapon.
The debate over the lethality and ownership of modern, high-powered weapons has recently grabbed the headlines. High-velocity air weapons, advertised as starter guns for children, can cause lethal injuries despite non-lethal appearing wounds. Presented is a rare case of a modern, high-powered air weapon used in a homicide. A literature search yielded reports of only three previous murders by air weapon in the United States and only one involving injury to the thorax. In the current case, the killer used a diabolo pellet to penetrate the chest. The pathway tracked through the sternum, piercing the anterior pericardial sac and perforating the right ventricle, which led to a pericardial effusion. The pellet embolized to the left pulmonary artery and eventually the vasculature of the left lung. Cause of death was a penetrating gunshot wound of the chest most likely leading to cardiac tamponade. This case exemplifies several important characteristics of penetrating chest trauma from air guns: first, air rifles, with exit velocities up to 1200 feet per second, can kill and have been used in accidental deaths, homicides and suicides; secondly, diabolo pellets may embolize just as bullets can; and lastly, minor external damage may mask major internal destruction.


New frontiers in mucositis.
Mucositis is among the most debilitating side effects of radiotherapy, chemotherapy, and targeted anticancer therapy. Research continues to escalate regarding key issues such as etiopathology, incidence and severity across different mucosae, relationships between mucosal and nonmucosal toxicities, and risk factors. This approach is being translated into enhanced management strategies. Recent technology advances provide an important foundation for this continuum. For example, evolution of applied genomics is fostering development of new algorithms to rapidly screen genomewide single-nucleotide polymorphisms (SNPs) for patient-associated risk prediction. This modeling will permit individual tailoring of the most effective, least toxic treatment in the future. The evolution of novel cancer therapeutics is changing the mucositis toxicity profile. These agents can be associated with unique mechanisms of mucosal damage. Additional research is needed to optimally manage toxicity caused by agents such as mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors, without reducing antitumor effect. There has similarly been heightened attention across the health professions regarding clinical practice guidelines for mucositis management in the years following the first published guidelines in 2004. New opportunities exist to more effectively interface this collective guideline portfolio by capitalizing upon novel technologies such as an Internet-based Wiki platform. Substantive progress thus continues across many domains associated with mucosal injury in oncology patients. In addition to enhancing oncology patient care, these advances are being integrated into high-impact educational and scientific venues including the National Cancer Institute Physician Data Query (PDQ) portfolio as well as a new Gordon Research Conference on mucosal health and disease scheduled for June 2013.


Gastrojejunostomy: a simple method of treatment of gastric volvulus.
Ten patients treated for gastric volvulus over eleven years are reviewed. Nine were treated successfully by gastrojejunostomy. The advantages of this simple procedure are discussed. Changes occurring in the position of the pylorus may predispose to this condition.


Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma.
Inherited predisposition to phaeochromocytoma is seen in multiple endocrine neoplasia type 2 syndromes, von Hippel-Lindau (VHL) disease, and neuro-fibromatosis type 1. In addition familial phaeochromocytoma alone has been reported. To investigate the genetic basis for familial phaeochromocytoma alone, we screened three affected kindreds for mutations in the RET proto-oncogene and the VHL tumour suppressor gene. We did not detect MEN 2 associated RET mutations in any family, but missense VHL gene mutations (V155L and R238W) were identified in two kindreds with no clinical evidence of VHL disease. Patients with familial, multiple, or early onset phaeochromocytoma should be investigated for germline VHL and RET gene mutations as the molecular diagnosis of multisystem familial cancer syndromes enables appropriate counselling and screening to be provided.


Biosensing with electroconductive biomimetic soft materials.
The development of smart biomaterials able to quantitatively analyse the dynamics of biological systems with high temporal resolution in biomimetic environments is of paramount importance in biophysics, biology and medicine. In this context, we develop a biosensing water-based soft biomaterial with tunable mechanical properties through the generation of an electroconductive nano-element network. As a proof of concept, in order to detect glucose concentration, we fabricate an electroconductive polyacrylamide glucose oxidase (GOx) loaded hydrogel (HY) modified with a small amount of single-walled carbon nanotubes (SWNTs) (up to 0.85 wt%). MicroRaman maps and optical analysis show the nanotube distribution in the samples at different mass fractions. Electrochemical impedance spectra and their fitting with equivalent circuit models reveal electron conduction in the charged hydrogels in addition to ionic conductivity. The effective resulting resistance of the nanostructured network is comparable to that of a gold electrode. These findings were also confirmed by cyclic voltammetry. Interestingly, heterogeneous clustering of SWNTs shows double electric mechanisms and efficiencies. GOx-SWNT doped hydrogels show a linear glucose concentration response in the range between 0.1 mM and 1.6 mM; taken together these results show high detection limits for glucose (down to 15 μM) and a sensitivity of 0.63 μA mM-1. In the perspective of monitoring cell dynamics, hydrogel functionalization allows cell adhesion and long-term cell culture, and atomic force microscopy is used for mapping the doped hydrogel stiffness. Myoblasts, cells sensitive to mechanical substrate properties, show proper differentiation of phenotype in the SWNT-HYs with nominal physiological stiffness.


Screening for hepatocellular carcinoma in chronic liver disease: a systematic review.
Guidelines recommend routine screening for hepatocellular carcinoma (HCC) in high-risk patients, but the strength of evidence supporting these recommendations is unclear. To review the benefits and harms of HCC screening in patients with chronic liver disease. MEDLINE, PsycINFO, and ClinicalTrials.gov from inception to April 2014; Cochrane databases to June 2013; reference lists; and technical advisors. English-language trials and observational studies comparing screening versus no screening, studies of harms, and trials comparing different screening intervals. Mortality and adverse events were the outcomes of interest. Individual-study quality and the overall strength of evidence were dual-reviewed using published criteria. Of 13,801 citations, 22 studies met inclusion criteria. The overall strength of evidence on the effects of screening was very low. One large trial of patients with hepatitis B found decreased HCC mortality with periodic ultrasonographic screening (rate ratio, 0.63 [95% CI, 0.41 to 0.98]), but the study was limited by methodological flaws. Another trial in patients with hepatitis B found no survival benefit with periodic α-fetoprotein screening. In 18 observational studies, screened patients had earlier-stage HCC than clinically diagnosed patients, but lead- and length-time biases confounded the effects on mortality. Two trials found no survival differences between shorter (3- to 4-month) and longer (6- to 12-month) screening intervals. Harms of screening were not well-studied. Only English-language studies were included. The evidence base is limited by methodological issues and a paucity of trials. There is very-low-strength evidence about the effects of HCC screening on mortality in patients with chronic liver disease. Screening tests can identify early-stage HCC, but whether systematic screening leads to a survival advantage over clinical diagnosis is uncertain. U.S. Department of Veterans Affairs Quality Enhancement Research Initiative.


Effectiveness of Covid-19 Vaccines over a 9-Month Period in North Carolina.
The duration of protection afforded by coronavirus disease 2019 (Covid-19) vaccines in the United States is unclear. Whether the increase in postvaccination infections during the summer of 2021 was caused by declining immunity over time, the emergence of the B.1.617.2 (delta) variant, or both is unknown. We extracted data regarding Covid-19-related vaccination and outcomes during a 9-month period (December 11, 2020, to September 8, 2021) for approximately 10.6 million North Carolina residents by linking data from the North Carolina Covid-19 Surveillance System and the Covid-19 Vaccine Management System. We used a Cox regression model to estimate the effectiveness of the BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Johnson & Johnson-Janssen) vaccines in reducing the current risks of Covid-19, hospitalization, and death, as a function of time elapsed since vaccination. For the two-dose regimens of messenger RNA (mRNA) vaccines BNT162b2 (30 μg per dose) and mRNA-1273 (100 μg per dose), vaccine effectiveness against Covid-19 was 94.5% (95% confidence interval [CI], 94.1 to 94.9) and 95.9% (95% CI, 95.5 to 96.2), respectively, at 2 months after the first dose and decreased to 66.6% (95% CI, 65.2 to 67.8) and 80.3% (95% CI, 79.3 to 81.2), respectively, at 7 months. Among early recipients of BNT162b2 and mRNA-1273, effectiveness decreased by approximately 15 and 10 percentage points, respectively, from mid-June to mid-July, when the delta variant became dominant. For the one-dose regimen of Ad26.COV2.S (5 × 1010 viral particles), effectiveness against Covid-19 was 74.8% (95% CI, 72.5 to 76.9) at 1 month and decreased to 59.4% (95% CI, 57.2 to 61.5) at 5 months. All three vaccines maintained better effectiveness in preventing hospitalization and death than in preventing infection over time, although the two mRNA vaccines provided higher levels of protection than Ad26.COV2.S. All three Covid-19 vaccines had durable effectiveness in reducing the risks of hospitalization and death. Waning protection against infection over time was due to both declining immunity and the emergence of the delta variant. (Funded by a Dennis Gillings Distinguished Professorship and the National Institutes of Health.).


MRI texture analysis predicts p53 status in head and neck squamous cell carcinoma.
Head and neck cancer is common, and understanding the prognosis is an important part of patient management. In addition to the Tumor, Node, Metastasis staging system, tumor biomarkers are becoming more useful in understanding prognosis and directing treatment. We assessed whether MR imaging texture analysis would correctly classify oropharyngeal squamous cell carcinoma according to p53 status. A cohort of 16 patients with oropharyngeal squamous cell carcinoma was prospectively evaluated by using standard clinical, histopathologic, and imaging techniques. Tumors were stained for p53 and scored by an anatomic pathologist. Regions of interest on MR imaging were selected by a neuroradiologist and then analyzed by using our 2D fast time-frequency transform tool. The quantified textures were assessed by using the subset-size forward-selection algorithm in the Waikato Environment for Knowledge Analysis. Features found to be significant were used to create a statistical model to predict p53 status. The model was tested by using a Bayesian network classifier with 10-fold stratified cross-validation. Feature selection identified 7 significant texture variables that were used in a predictive model. The resulting model predicted p53 status with 81.3% accuracy (P < .05). Cross-validation showed a moderate level of agreement (κ = 0.625). This study shows that MR imaging texture analysis correctly predicts p53 status in oropharyngeal squamous cell carcinoma with ∼80% accuracy. As our knowledge of and dependence on tumor biomarkers expand, MR imaging texture analysis warrants further study in oropharyngeal squamous cell carcinoma and other head and neck tumors.


Spatial and temporal variation in fungal endophyte communities isolated from cultivated cotton (Gossypium hirsutum).
Studies of fungi in upland cotton (Gossypium hirsutum) cultivated in the United States have largely focused on monitoring and controlling plant pathogens. Given increasing interest in asymptomatic fungal endophytes as potential biological control agents, surveys are needed to better characterize their diversity, distribution patterns and possible applications in integrated pest management. We sampled multiple varieties of cotton in Texas, USA and tested for temporal and spatial variation in fungal endophyte diversity and community composition, as well as for differences associated with organic and conventional farming practices. Fungal isolates were identified by morphological and DNA identification methods. We found members of the genera Alternaria, Colletotrichum and Phomopsis, previously isolated as endophytes from other plant species. Other recovered species such as Drechslerella dactyloides (formerly Arthrobotrys dactyloides) and Exserohilum rostratum have not, to our knowledge, been previously reported as endophytes in cotton. We also isolated many latent pathogens, but some species such as Alternaria tennuissima, Epicoccum nigrum, Acremonium alternatum, Cladosporium cladosporioides, Chaetomium globosum and Paecilomyces sp., are known to be antagonists against plant pathogens, insects and nematode pests. We found no differences in endophyte species richness or diversity among different cotton varieties, but did detect differences over time and in different plant tissues. No consistent patterns of community similarity associated with variety, region, farming practice, time of the season or tissue type were observed regardless of the ecological community similarity measurements used. Results indicated that local fungal endophyte communities may be affected by both time of the year and plant tissue, but the specific community composition varies across sites. In addition to providing insights into fungal endophyte community structure, our survey provides candidates for further evaluation as potential management tools against a variety of pests and diseases when present as endophytes in cotton and other plants.


Change in physical activity from adolescence to early adulthood: a systematic review and meta-analysis of longitudinal cohort studies.
To systematically review and meta-analyse how physical activity (PA) changes from adolescence to early adulthood (13-30 years). Seven electronic databases were searched: Medline, Embase, PsycInfo, SCOPUS, ASSIA, SPORTdiscus and Web of Science. English-language, longitudinal studies (from 01/1980 to 01/2017) assessing PA ≥twice, with the mean age of ≥1 measurement in adolescence (13-19 years) and ≥1 in young adulthood (16-30 years) were included. Where possible, data were converted to moderate-to-vigorous physical activity (MVPA) min/day, and meta-analyses were conducted between weighted mean differences (WMDs) in adolescence and adulthood. Heterogeneity was explored using meta-regression. Of 67 included studies, 49 were eligible for meta-analysis. PA was lower during adulthood than adolescence WMD (95% CI) -5.2 (-7.3 to -3.1) min/day MVPA over mean (SD) 3.4 (2.6) years; heterogeneity was high (I2 >99.0%), and no predictors explained this variation (all p>0.05). When we restricted analysis to studies with data for males (n=29) and females (n=30) separately, there were slightly larger declines in WMD (-6.5 (-10.6 to -2.3) and -5.5 (-8.4 to -2.6) min/day MVPA) (both I2 >99.0%). For studies with accelerometer data (n=9), the decline was -7.4 (-11.6 to -3.1) and longer follow-up indicated more of a decline in WMD (95% CI) (-1.9 (-3.6 to -0.2) min/day MVPA), explaining 27.0% of between-study variation. Of 18 studies not eligible for meta-analysis, nine statistically tested change over time: seven showed a decline and two showed no change. PA declines modestly between adolescence and young adulthood. More objective longitudinal PA data (eg, accelerometry) over this transition would be valuable, as would investigating how PA change is associated with contemporaneous social transitions to better inform PA promotion interventions. PROSPERO ref:CRD42015030114.


Short-term and long-term financial toxicity from breast cancer treatment: a qualitative study.
The rising cost of breast cancer treatment has increased patients' financial burden, intensifying an already stressful treatment process. Although researchers increasingly recognize the harmful impact of medical and nonmedical costs associated with cancer treatment, understanding patients' perspectives of financial toxicity is limited. We aimed to explore the topic of financial toxicity through the lived experiences of patients with breast cancer from groups at risk of social and economic marginalization. We conducted semi-structured interviews with 50 women with breast cancer from four specific groups: Black women, Medicaid enrollees, rural residents, and women age ≤ 40. We transcribed, coded, and analyzed the data using deductive and inductive approaches. Two overarching themes captured patients' experiences of financial toxicity: short-term and long-term impacts. Short-term stressors included direct medical (e.g., co-pays, premiums), nonmedical (e.g., transportation, lodging), and indirect (e.g., job loss, reduced work hours) costs. Early in their treatments, patients' focus on survival took precedence over financial concerns. However, as the treatment course progressed, fear of consequences from compounding costs of care and financial distress negatively impacted patients' lifestyles and outlooks for the future. Programs addressing financial toxicity that look beyond early-phase interventions are needed. Specifically, patients struggling with the accumulation of treatment costs and the resultant stress require ongoing support. Long-term support is especially needed for groups vulnerable to financial instability and social marginalization.


Contributions of cell behavior to geometric order in embryonic cartilage.
During early development, cartilage provides shape and stability to the embryo while serving as a precursor for the skeleton. Correct formation of embryonic cartilage is hence essential for healthy development. In vertebrate cranial cartilage, it has been observed that a flat and laterally extended macroscopic geometry is linked to regular microscopic structure consisting of tightly packed, short, transversal clonar columns. However, it remains an ongoing challenge to identify how individual cells coordinate to successfully shape the tissue, and more precisely which mechanical interactions and cell behaviors contribute to the generation and maintenance of this columnar cartilage geometry during embryogenesis. Here, we apply a three-dimensional cell-based computational model to investigate mechanical principles contributing to column formation. The model accounts for clonal expansion, anisotropic proliferation and the geometrical arrangement of progenitor cells in space. We confirm that oriented cell divisions and repulsive mechanical interactions between cells are key drivers of column formation. In addition, the model suggests that column formation benefits from the spatial gaps created by the extracellular matrix in the initial configuration, and that column maintenance is facilitated by sequential proliferative phases. Our model thus correctly predicts the dependence of local order on division orientation and tissue thickness. The present study presents the first cell-based simulations of cell mechanics during cranial cartilage formation and we anticipate that it will be useful in future studies on the formation and growth of other cartilage geometries.


Advice about Work-Related Issues to Peers and Employers from Head and Neck Cancer Survivors.
The purpose of this exploratory and descriptive study is to contribute to the sparse return-to-work literature on head and neck cancer (HNC) survivors. Interview participants were asked to reflect upon their work-related experience with cancer by answering two specific questions: (1) What advice would you give someone who has been newly diagnosed with head and neck cancer? (2) What advice would you give to employers of these people? Data were gathered through 10 individual semi-structured in-depth interviews with HNC clinic patients at a regional cancer center's head and neck clinic in Ontario, Canada. A constant comparative method of theme development was used. Codes identified in and derived from the data were discussed by research team members until consensus was reached. Codes with similar characteristics were grouped together and used to develop overarching themes. Work-related advice for peers focused on personal self-care and interactions within workplaces. Work-related advice to employers focused on demonstrating basic human values as well as the importance of communication. The study results suggest HNC clinic patients should be proactive with employers and help to set reasonable expectations and provide a realistic plan for work to be successfully completed. HNC clinic patients should develop communication skills to effectively disclose their cancer and treatment to employers. In this exploratory study, HNC clinic patients' advice was solution-focused underscoring the importance of self-care and pro-active communication and planning with employers. Employers were advised to demonstrate core human values throughout all phases of the work disability episode beginning at diagnosis.


Tumor necrosis factor-related apoptosis-inducing ligand reduces the expression of the neuroprotective Na+ /Ca2+ exchanger isoform NCX3 in human neuroblastoma SH-SY5Y cells.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cytokine belonging to the TNF superfamily, is regarded as a mediator of neurotoxicity. The constitutively expressed ion exchanger Na+ /Ca2+ exchanger isoform-3 (NCX3) has been shown to protect neurons from injury. Its expression is induced by nerve growth factor (NGF) through activation of its tyrosine kinase receptor trkA. The latter, in turn, activates downstream kinases, such as extracellular signal-regulated kinase (ERK) and the survival-related kinase protein kinase B (AKT). Here, we verified whether TRAIL could influence the expression of NCX3 via modulation of the NGF/trkA system. Differentiated human neuroblastoma SH-SY5Y cells were incubated with TRAIL and, subsequently, the expression of the NCX3 protein was studied at different times by means of western blot analysis. Then, the expression of the phosphorylated forms of either trkA, ERK or AKT was analyzed at identical intervals. Western blot analysis revealed that the expression of NCX3 protein decreased in a time-dependent fashion in SH-SY5Y cells treated with TRAIL, to reach its minimum at 48 h. On the other hand, p-trkA, p-ERK, and p-AKT expression was increased in cells treated with TRAIL after 6 and 16 h; then it declined to nearly undetectable levels after 48 h. Results indicate that the increase in TRAIL expression occurring during neuronal damage may be responsible of NCX3 down-regulation and weakens its neuroprotective effects. The TRAIL system could thus represent a potential target for treatment of neuronal damage characterized by NCX3 function impairment.


Perioperative hemodynamic monitoring in cardiac surgery.
Cardiac surgery has traditionally relied upon invasive hemodynamic monitoring, including regular use of pulmonary artery catheters. More recently, there has been advancement in our understanding as well as broader adoption of less invasive alternatives. This review serves as an outline of the key perioperative hemodynamic monitoring options for cardiac surgery. Recent study has revealed that the use of invasive monitoring such as pulmonary artery catheters or transesophageal echocardiography in low-risk patients undergoing low-risk cardiac surgery is of questionable benefit. Lesser invasive approaches such a pulse contour analysis or ultrasound may provide a useful alternative to assess patient hemodynamics and guide resuscitation therapy. A number of recent studies have been published to support broader indication for these evolving technologies. More selective use of indwelling catheters for cardiac surgery has coincided with greater application of less invasive alternatives. Understanding the advantages and limitations of each tool allows the bedside clinician to identify which hemodynamic monitoring modality is most suitable for which patient.


Sepsis at a neonatal intensive care unit: a four-year retrospective study (1989-1992).
During the 4-year period 1989-1992, 18,227 neonates were born at Kaplan Hospital and 614 (3.4%) were admitted to the neonatal intensive care unit. During this period, 120 episodes (6.6/1000 live births) of neonatal sepsis were recorded in 109 neonates (6/1000 live births). The incidence of early-onset sepsis was 19/109 (17%). The main pathogens of early-onset sepsis were S. agalactiae (42%) and E. coli (32%). Seven of the 8 S. agalactiae cases were recorded during 1989-1990. The main pathogens of late-onset sepsis were Klebsiella spp. (31%), coagulase-negative staphylococci (18%) and Candida spp (16%). There were 11 cases (10%) of meningitis, 5 due to Klebsiella spp. The overall fatality rate due to sepsis was 14% (0.8/1000 live births) with an early-onset sepsis death rate of 37%. The mortality from S. agalactiae sepsis was 63%. The main trends recorded during the period of the study were 1) the emergence of S. agalactiae as the main pathogen of early-onset sepsis, followed by a sharp decrease in its incidence during the last part of the study, 2) the emergence of extremely virulent, multi-antibiotic-resistant Klebsiella organisms, and 3) the persistent high incidence of Candida sepsis.


Hospitalizations for primary care sensitive conditions: association with socioeconomic status and quality of family health teams in Belo Horizonte, Brazil.
Hospitalizations for primary care sensitive conditions (HPCSC) have been used as a measure of the effectiveness of primary care. Few studies, however, have measured the quality of primary health care (PHC) and how it impacts HPCSC trends. We employed previously calculated quality scores of PHC attributes (access, continuous/ongoing care, coordinated care and comprehensive care) assigned to health centres and investigated the correlation between these quality scores and HPCSC time trends in public hospitals in the city of Belo Horizonte, Brazil, adjusted by demographic and socioeconomic factors between 2010 and 2013. Socioeconomic risk was determined using the Health Vulnerability Index, a composite indicator including sanitation, habitation, education, income and health variables. Between 2010 and 2013, 447 500 hospitalizations, excluding births, were recorded in Belo Horizonte. Of these, 85 211 were HPCSC (19% of total admissions). Of 145 health centres, 133 were analysed in this study, with 75 059 HPCSC in the 4-year period. In the initial univariate model, only the PCH attribute 'access' and 'social vulnerability' had an effect on hospitalization rates. In the multilevel analysis, socioeconomic vulnerability became the only predictor of HPCSC rates. A 10% increase in high socioeconomic risk population meant an increase of 5 HPCSC/10 000 in women and 4/10 000 in men for each individual primary care unit, while a 10% increase in low-risk population meant a reduction in HPCSC of 6/10 000 in women and 5/10 000 in men. The results support the importance of using HPCSC as a measure of PHC effectiveness, considering individual, health service-related and socioeconomic characteristics; however, additional measures of effectiveness of care provided by family health teams seem necessary to assess PHC performance.


Measurement Properties of the Craniocervical Flexion Test: A Systematic Review.
Patients with neck pain commonly have altered activity of the neck muscles. The craniocervical flexion test (CCFT) is used to assess the function of the deep neck flexor muscles in patients with musculoskeletal neck disorders. Systematic reviews summarizing the measurement properties of the CCFT are outdated. The objective of this study was to systematically review the measurement properties of the CCFT for assessing the deep neck flexor muscles. The data sources MEDLINE, EMBASE, Physiotherapy Evidence Database, Cochrane Central Register of Controlled Trials, Scopus, and Science Direct were searched in April 2019. Studies of any design that reported at least 1 measurement property of the CCFT for assessing the deep neck flexor muscles were selected. Two reviewers independently extracted data and rated the risk of bias of individual studies using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) risk-of-bias checklist. The overall rating for each measurement property was classified as "positive," "indeterminate," or "negative." The overall rating was accompanied with a level of evidence. Fourteen studies were included in the data synthesis. The ratings were positive, and the level of evidence was moderate for interrater and intrarater reliability and convergent validity. There was conflicting rating and level of evidence for discriminative validity. Measurement error was indeterminate, with an unknown level of evidence. Responsiveness was negative, with a limited level of evidence. A limitation of this study was that only papers published in English were included. The CCFT is a valid and reliable test that can be used in clinical practice as an assessment test. Because of the conflicting and low-quality evidence, caution is advised when using the CCFT as a discriminative test and as an outcome measure. Future better-designed studies are warranted.


A cross-sectional study of dietary patterns with glucose intolerance and other features of the metabolic syndrome.
Previous epidemiological studies have demonstrated relationships between individual nutrients and glucose intolerance and type 2 diabetes, but the association with the overall pattern of dietary intake has not previously been described. In order to characterize this association, 802 subjects aged 40-65 years were randomly selected from a population-based sampling frame and underwent a 75 g oral glucose-tolerance test. Principal component analysis was used to identify four dietary patterns explaining 31.7% of the dietary variation in the study cohort. These dietary patterns were associated with other lifestyle factors including socio-economic group, smoking, alcohol intake and physical activity. Component 1 was characterized by a healthy balanced diet with a frequent intake of raw and salad vegetables, fruits in both summer and winter, fish, pasta and rice and low intake of fried foods, sausages, fried fish, and potatoes. This component was negatively correlated with central obesity, fasting plasma glucose, 120 min non-esterified fatty acid and triacylglycerol, and positively correlated with HDL-cholesterol. It therefore appears to be protective for the metabolic syndrome. Component 1 was negatively associated with the risk of having undiagnosed diabetes, and this association was independent of age, sex, smoking and obesity. The findings support the hypothesis that dietary patterns are associated with other lifestyle factors and with glucose intolerance and other features of the metabolic syndrome. The results provide further evidence for the recommendation of a healthy balanced diet as one of the main components of chronic disease prevention.


Gene expression in primate liver during viral hemorrhagic fever.
Rhesus macaques infected with lymphocytic choriomeningitis virus (LCMV) provide a model for human Lassa fever. Disease begins with flu-like symptoms and progresses rapidly with fatal consequences. Previously, we profiled the blood transcriptome of LCMV-infected monkeys (M. Djavani et al J. Virol. 2007) showing distinct pre-viremic and viremic stages that discriminated virulent from benign infections. In the present study, changes in liver gene expression from macaques infected with virulent LCMV-WE were compared to gene expression in uninfected monkeys as well as to monkeys that were infected but not diseased. Based on a functional pathway analysis of differentially expressed genes, virulent LCMV-WE had a broader effect on liver cell function than did infection with non-virulent LCMV-Armstrong. During the first few days after infection, LCMV altered expression of genes associated with energy production, including fatty acid and glucose metabolism. The transcriptome profile resembled that of an organism in starvation: mRNA for acetyl-CoA carboxylase, a key enzyme of fatty acid synthesis was reduced while genes for enzymes in gluconeogenesis were up-regulated. Expression was also altered for genes associated with complement and coagulation cascades, and with signaling pathways involving STAT1 and TGF-beta. Most of the 4500 differentially expressed transcripts represented a general response to both virulent and mild infections. However, approximately 250 of these transcripts had significantly different expression in virulent infections as compared to mild infections, with approximately 30 of these being differentially regulated during the pre-viremic stage of infection. The genes that are expressed early and differently in mild and virulent disease are potential biomarkers for prognosis and triage of acute viral disease.


Modulation of angiotensin II signaling for GATA4 activation by homocysteine.
Homocysteine (Hcy) is a redox active thiol-containing compound with pro-oxidant and pathogenic properties in the cardiovascular system. Angiotensin II (Ang II) also plays important roles in age-associated cardiovascular disease. Recently, the GATA4 transcription factor was recognized as a mediator of heart failure. We investigated the interrelationship of these elements in NIH/3T3 fibroblasts and found that Ang II induces GATA4 activity and Hcy alters Ang II signaling. Electrophoretic mobility shift assays determined that treatment of cells with Ang II induced DNA binding activity to the GATA consensus sequence. This activation was transient with a peak occurring at 30 min. Supershift analysis revealed the GATA binding protein as GATA4. Ang II also induced NFAT activity with similar kinetics. Pretreatment of cells with Hcy (100 microM) delayed the peak of Ang II-induced NFAT and GATA activation to 60 min. Ang II-mediated activation of c-fos serum response factor (SRF) was similarly delayed by Hcy. These results suggest the pathogenic mechanism of Hcy action may be mediated in part via modulation of Ang II-signaling for gene transcription.


Evaluation of North American isolates of Soybean mosaic virus for gain of virulence on Rsv-genotype soybeans with special emphasis on resistance-breaking determinants on Rsv4.
Resistance to Soybean mosaic virus (SMV) in soybean is conferred by three dominant genes: Rsv1, Rsv3 and Rsv4. Over the years, scientists in the USA have utilized a set of standard pathotypes, SMV-G1 to SMV-G7, to study interaction with Rsv-genotype soybeans. However, these pathotypes were isolated from a collection of imported soybean germplasm over 30 years ago. In this study, 35 SMV field isolates collected in recent years from 11 states were evaluated for gain of virulence on soybean genotypes containing individual Rsv genes. All isolates were avirulent on L78-379 (Rsv1), whereas 19 were virulent on L29 (Rsv3). On PI88788 (Rsv4), 14 of 15 isolates tested were virulent; however, only one was capable of systemically infecting all of the inoculated V94-5152 (Rsv4). Nevertheless, virulent variants from 11 other field isolates were rapidly selected on initial inoculation onto V94-5152 (Rsv4). The P3 cistrons of the original isolates and their variants on Rsv4-genotype soybeans were sequenced. Analysis showed that virulence on PI88788 (Rsv4) was not associated, in general, with selection of any new amino acid, whereas Q1033K and G1054R substitutions were consistently selected on V94-5152 (Rsv4). The role of Q1033K and G1054R substitutions, individually or in combination, in virulence on V94-5152 (Rsv4) was confirmed on reconstruction in the P3 cistron of avirulent SMV-N, followed by biolistic inoculation. Collectively, our data demonstrate that SMV has evolved virulence towards Rsv3 and Rsv4, but not Rsv1, in the USA. Furthermore, they confirm that SMV virulence determinants on V94-5152 (Rsv4) reside on P3.


Invasive fungal infection by saprochaeta capitata in an immunocompromised child- a case report from cancer hospital in Pakistan.
Saprochaeta Capitata is an emerging fungus known to cause life-threatening infections in immunocompromised patients. Here, we describe the case of a 4-year-old male child seen in Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, after obtaining informed consent from the parents. He had Pre-B ALL (acute lymphoblastic leukaemia) and contracted this infection during induction chemotherapy. With the use of dual antifungals, he was able to survive this otherwise fatal fungal infection.


Responsiveness of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing to hypothalamic deep brain stimulation.
Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a severe primary headache disorder that is often refractory to medical therapy. Although the pathogenesis of this and other trigeminal autonomic cephalalgias is not completely understood, ipsilateral activation of the posterior and inferior hypothalamus has been identified on functional imaging studies during attacks. The authors report on a case of SUNCT syndrome successfully treated with hypothalamic deep brain stimulation and discuss the current literature.


Stochastic many-body perturbation theory for anharmonic molecular vibrations.
A new quantum Monte Carlo (QMC) method for anharmonic vibrational zero-point energies and transition frequencies is developed, which combines the diagrammatic vibrational many-body perturbation theory based on the Dyson equation with Monte Carlo integration. The infinite sums of the diagrammatic and thus size-consistent first- and second-order anharmonic corrections to the energy and self-energy are expressed as sums of a few m- or 2m-dimensional integrals of wave functions and a potential energy surface (PES) (m is the vibrational degrees of freedom). Each of these integrals is computed as the integrand (including the value of the PES) divided by the value of a judiciously chosen weight function evaluated on demand at geometries distributed randomly but according to the weight function via the Metropolis algorithm. In this way, the method completely avoids cumbersome evaluation and storage of high-order force constants necessary in the original formulation of the vibrational perturbation theory; it furthermore allows even higher-order force constants essentially up to an infinite order to be taken into account in a scalable, memory-efficient algorithm. The diagrammatic contributions to the frequency-dependent self-energies that are stochastically evaluated at discrete frequencies can be reliably interpolated, allowing the self-consistent solutions to the Dyson equation to be obtained. This method, therefore, can compute directly and stochastically the transition frequencies of fundamentals and overtones as well as their relative intensities as pole strengths, without fixed-node errors that plague some QMC. It is shown that, for an identical PES, the new method reproduces the correct deterministic values of the energies and frequencies within a few cm(-1) and pole strengths within a few thousandths. With the values of a PES evaluated on the fly at random geometries, the new method captures a noticeably greater proportion of anharmonic effects.


[Effect of rabbit thrombomodulin on the inhibition of thrombin by the antithrombin-heparin complex: role of the acid domain of thrombomodulin].
Acidic and non-acidic forms of rabbit thrombomodulin were studied with regard to their effects on the inhibition of thrombin by antithrombin in the presence of exogenous heparin. The non acidic form was obtained by proteolytic cleavage of a polyanionic component (presumably a sulfated polysaccharide) from the parent acidic form of thrombomodulin, and purified by ion-exchange chromatography. It was previously found that the acidic form of thrombomodulin increases the rate of thrombin inactivation by antithrombin. The present study showed that thrombin bound to acidic thrombomodulin was inactivated at a lower rate by antithrombin in the presence of exogenous heparin than was free thrombin or thrombin bound to the non-acidic form of thrombomodulin. The data suggest that the acidic component of thrombomodulin is primarily responsible for the retardation of thrombin-antithrombin complex formation in the presence of exogenous heparin. It is proposed that the polyanionic component of thrombomodulin blocks a site on thrombin required for heparin binding, thus rendering the antithrombin-heparin complex ineffective.


Predicting factors of elderly patients' discharge to home after rehabilitation in rural Japan: a retrospective cohort study.
The aging of society continues to progress in Japan. As aging is more pronounced in rural than in urban societies, rehabilitation can contribute to rural elderly patients' discharge to home after hospitalization for various causes. The relationship between rural elderly patients' improvement of motor and cognitive function in relation to activities of daily life (ADL) through rehabilitation and their discharge to home has not been clarified in rural communities. The purpose of this study was to clarify whether an improvement of ADL can enable elderly hospitalized patients to discharge to their homes in a rural community. This retrospective cohort study included 783 consecutive patients aged over 65 years with frailty and multimorbidity who were admitted with acute diseases and underwent active rehabilitation at a rural community hospital. This study was conducted from April 2016 to March 2020. The following patient data were collected from the electronic medical records: age, sex, body mass index, serum albumin, diagnosis on admission, the Charlson Comorbidity Index, living with family or alone, duration of disease from the onset of symptoms to the start of rehabilitation, duration of rehabilitation, care level based on the Japanese insurance system, cognitive and motor components of the functional independence measure (FIM) as the measurement of the level of ADL at both admission and discharge, change in these components of the FIM, and the place to which patients were discharged (home or facility). Two groups of patients were distinguished based on whether the discharge was to home or a facility. Logistic regression was performed to investigate the relationships between patients' characteristics and the effects of rehabilitation determined as a change in the FIM on one hand and to where patients were discharged on the other. The variables with statistically significant differences in the logistic regression were further analyzed to calculate sensitivity, specificity and likelihood ratio with the area under the curve for predicting discharge to home. Patients' average age was 82.1 years, and 33.5% were male. A high score in the motor component of the FIM after rehabilitation and short duration of rehabilitation were statistically related to discharge to home. The cognitive component of the FIM was not associated with discharge to home. The motor-FIM cutoff after rehabilitation was calculated to be 60, resulting in sensitivity, specificity and positive likelihood ratio to predict discharge to home of 0.86, 0.78, and 4.00, respectively. This study showed that elderly patients' motor aspect of ADL after rehabilitation in rural community hospitals might predict discharge to home in rural settings. Rehabilitation in rural community hospitals can be effective in rural elderly patients with frailty and multimorbidity. The improvement in physical abilities was more important than cognitive functions for the effective discharge of the elderly patients in this study to their rural homes. By respecting patients' and their families' desires, effective rehabilitation may enable elderly patients to live at home.


The signaling peptide PapR is required for the activity of the quorum-sensor PlcRa in Bacillus thuringiensis.
The transcriptional regulator PlcR, its cognate cell-cell signaling heptapeptide PapR7, and the oligopeptide permease OppABCDF, required for PapR7 import, form a quorum-sensing system that controls the expression of virulence factors in Bacillus cereus and Bacillus thuringiensis species. In B. cereus strain ATCC 14579, the transcriptional regulator PlcRa activates the expression of abrB2 gene, which encodes an AbrB-like transcriptional regulator involved in cysteine biosynthesis. PlcRa is a structural homolog of PlcR: in particular, its C-terminal TPR peptide-binding domain could be similarly arranged as in PlcR. The signaling peptide of PlcRa is not known. As PlcRa is a PlcR-like protein, the cognate PapR7 peptide (ADLPFEF) is a relevant candidate to act as a signaling peptide for PlcRa activation. Also, the putative PapRa7 peptide (CSIPYEY), encoded by the papRa gene adjacent to the plcRa gene, is a relevant candidate as addition of synthetic PapRa7 induces a dose-dependent increase of abrB2 expression. To address the issue of peptide selectivity of PlcRa, the role of PapR and PapRa peptides in PlcRa activity was investigated in B. thuringiensis 407 strain, by genetic and functional complementation analyses. A transcriptional fusion between the promoter of abrB2 and lacZ was used to monitor the PlcRa activity in various genetic backgrounds. We demonstrated that PapR was necessary and sufficient for PlcRa activity. We showed that synthetic PapRs from pherogroups II, III and IV and synthetic PapRa7 were able to trigger abrB2 expression, suggesting that PlcRa is less selective than PlcR. Lastly, the mode of binding of PlcRa was addressed using an in silico approach. Overall, we report a new role for PapR as a signaling peptide for PlcRa activity and show a functional link between PlcR and PlcRa regulons in B. thuringiensis.


Locally Ordered Single-Atom Catalysts for Electrocatalysis.
Single-atom catalysts manifest nearly 100 % atom utilization efficiency, well-defined active sites, and high selectivity. However, their practical applications are hindered by a low atom loading density, uncontrollable location, and ambiguous interaction with the support, thereby posing challenges to maximizing their electrocatalytic performance. To address these limitations, the ability to arrange randomly dispersed single atoms into locally ordered single-atom catalysts (LO-SACs) substantially influences the electronic effect between reactive sites and the support, the synergistic interaction among neighboring single atoms, the bonding energy of intermediates with reactive sites and the complexity of the mechanism. As such, it dramatically promotes reaction kinetics, reduces the energy barrier of the reaction, improves the performance of the catalyst and simplifies the reaction mechanism. In this review, firstly, we introduce a variety of compelling characteristics of LO-SACs as electrocatalysts. Subsequently, the synthetic strategies, characterization methods and applications of LO-SACs in electrocatalysis are discussed. Finally, the future opportunities and challenges are elaborated to encourage further exploration in this rapidly evolving field.


Making the heart resistant to infarction: how can we further decrease infarct size?
Acute myocardial infarction (AMI) following coronary artery occlusion is a common cause of mortality and morbidity world-wide. Patients currently receive reperfusion therapy as the only anti-infarct intervention. A number of agents have been evaluated to further improve myocardial salvage, but until recently, none has demonstrated clear efficacy in clinical trials. A new target of cardioprotection, the Reperfusion Injury Salvage Kinase (RISK) pathway, has been proposed. These kinases are involved in mediating the cardioprotection of myocardial preconditioning and postconditioning induced by short non-lethal cycles of ischemia/reperfusion performed before (preconditioning) or just after (postconditioning) a lethal ischemic insult. Many pharmacological interventions are now available that protect the heart by activating the RISK pathway at the time of reperfusion. The present review will examine the efficacy of several strategies that have been proposed to protect the acutely ischemic myocardium including (1) those intended to directly alter adverse reperfusion events (e.g., calcium overload and free radical attack), (2) those based on activation of the RISK pathway including postconditioning, and (3) myocardial cooling.


Experimental West Nile Virus Infection in Rabbits: An Alternative Model for Studying Induction of Disease and Virus Control.
The economic impact of non-lethal human and equine West Nile virus (WNV) disease is substantial, since it is the most common presentation of the infection. Experimental infection with virulent WNV strains in the mouse and hamster models frequently results in severe neural infection and moderate to high mortality, both of which are not representative features of most human and equine infections. We have established a rabbit model for investigating pathogenesis and immune response of non-lethal WNV infection. Two species of rabbits, New Zealand White (Oryctolagus cuniculus) and North American cottontail (Sylvilagus sp.), were experimentally infected with virulent WNV and Murray Valley encephalitis virus strains. Infected rabbits exhibited a consistently resistant phenotype, with evidence of low viremia, minimal-absent neural infection, mild-moderate neuropathology, and the lack of mortality, even though productive virus replication occurred in the draining lymph node. The kinetics of anti-WNV neutralizing antibody response was comparable to that commonly seen in infected horses and humans. This may be explained by the early IFNα/β and/or γ response evident in the draining popliteal lymph node. Given this similarity to the human and equine disease, immunocompetent rabbits are, therefore, a valuable animal model for investigating various aspects of non-lethal WNV infections.


Efficacy of Preventing Relapse Evaluated by a Multicenter Randomized Double-Blind Placebo-Controlled Withdrawal Study of Escitalopram in Japanese Adolescents with Major Depressive Disorder.
Objective: To evaluate the efficacy and safety of escitalopram (ESC) in a 48-week relapse prevention study in Japanese adolescents with major depressive disorder (MDD). Methods: This was a 48-week multicenter randomized double-blind placebo-controlled parallel-group study of patients aged 12-17 years with MDD. Patients received ESC for 12 weeks as an open-label treatment period (open-label period). Patients who achieved criteria for remission or response in the open-label period received either ESC or placebo for 36 weeks as a double-blind treatment period (double-blind period). The primary endpoint was the time to relapse during the double-blind period. Safety was evaluated in terms of type, incidence, and severity of adverse events. Results: Of the 128 patients who entered the open-label period, 80 patients entered the double-blind period, all of whom were in the primary analysis population. The primary endpoint, time to relapse, was marginally less than statistically significant between the ESC and placebo groups (p = 0.051, log-rank test). In the Cox proportional hazards model, the estimated hazard ratio [two-sided 95% confidence interval] for relapse in the placebo group versus the ESC group was 2.96 [0.94, 9.30]. There were statistically significant differences between the ESC and placebo groups in several secondary endpoints (change in Children's Depression Rating Scale-Revised, change in Clinical Global Impressions-Severity Scale, etc.). No notable safety/tolerability issues were observed in this study compared with the results of studies in Japanese adults with MDD. Conclusions: Superiority of ESC over placebo for relapse prevention in Japanese adolescents aged 12-17 years with MDD could not be verified with time to relapse evaluated by log-rank test. However, secondary endpoint results and a post hoc analysis of time to relapse suggest that ESC may be effective in preventing MDD relapse. No notable safety/tolerability issues were observed compared with the results of studies in Japanese adults with MDD. Study Registry Number: jRCT2080224520.


Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone.
The phase 3 Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone study in newly diagnosed multiple myeloma patients ineligible for high-dose therapy demonstrated that bortezomib-melphalan-prednisone (VMP) was superior to melphalan-prednisone across all efficacy end points. We assessed the prognostic impact of response on time-to-event parameters in the intent-to-treat population. Patients received nine 6-week cycles of treatment. Time to progression, time to next therapy, and treatment-free interval were associated with quality of response. When European Group for Blood and Marrow Transplantation criteria were used, complete response (CR) was associated with significantly longer time to progression (hazard ratio [HR] = 0.45, P = .004), time to next therapy (HR = 0.46, P = .0004), and treatment-free interval (HR = 0.38, P < .0001) versus partial response, but there was no significant difference in overall survival (HR = 0.87, P = .54); similar differences were seen with CR versus very good partial response by uniform criteria. Quality of response improved with prolonged VMP treatment, with 28% of CRs achieved during cycles 5-9. CR duration appeared similar among patients with "early" (cycles 1-4) and "late" CRs (cycles 5-9) and among patients receiving 9 versus < 9 cycles of bortezomib within VMP. These results highlight that CR is an important treatment goal and support prolonged VMP therapy to achieve maximal response. This study is registered at http://www.clinicaltrials.gov as NCT00111319.


Phase 1 study of combination treatment with PTK 787/ZK 222584 and cetuximab for patients with advanced solid tumors: safety, pharmacokinetics, pharmacodynamics analysis.
PTK/ZK is a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor, colony-stimulating factor 1 receptor, and cytokine stem cell factor receptor. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combining inhibition of VEGF and EGF signaling might act additive or synergistically. In phase 1 design, patients with advanced solid tumors were treated with PTK/ZK daily (cohort 1, 750 mg once daily; cohort 2, 1250 mg once daily; cohort 3, 250 mg [morning] and 500 mg [evening]; and cohort 4, 500 mg [morning] and 750 mg [evening]) in combination with cetuximab 250 mg/m(2) weekly in cycles of 28 days in cohorts of three patients. Toxicity was evaluated conform the Common Terminology Criteria for Adverse Events classification 3.0. Pharmacokinetics and pharmacodynamics consisting of circulating endothelial (progenitor) cell (CE[P]C) analysis by flow cytometry were performed. Safety and tolerability was evaluated in 16 patients. The most frequently reported adverse events were acne, dry skin, fatigue, nausea, dizziness, vomiting, headache, and diarrhea. One dose-limiting toxicity occurred in cohort 3 consisting of a grade 3 transaminitis. Pharmacokinetic analysis revealed no significant changes in PTK/ZK exposure on coadministration with cetuximab and in bioavailability at equivalent total daily doses. Biomarker analysis showed no significant change in the number of CE(P)Cs during treatment. One of 14 evaluable patients showed a partial response for at least 11.5 months, and 7 patients (50%) stable disease for at least 2 months. This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has antitumor activity.


Posttranscriptional regulation of thyrotropin beta-subunit messenger ribonucleic acid by thyroid hormone in murine thyrotrope tumor cells: a conserved mechanism across species.
Thyroid hormone (T3) negatively regulates TSH beta-subunit (TSHbeta) messenger RNA (mRNA) gene expression in whole rat pituitary, in part at the level of mRNA stability. However, the regulation of TSHbeta mRNA turnover by T3 in pure populations of thyrotropes and in other species is unknown. To further investigate this, we used murine thyrotropic TtT97 tumor cells. Using primary cultures of TtT97 cells, T3 down-regulated TSHbeta mRNA to approximately 35% of the control level by 8 h. Actinomycin D chase revealed that T3 destabilized TSHbeta mRNA, reducing the half-life from approximately 24 to 7 h, and was accompanied by a decrease in TSHbeta mRNA size. Ribonuclease H analysis revealed that this T3-induced decrease in size was due to a shortening of poly(A) tail from approximately 160 to approximately 30 nucleotides and was specific for TSHbeta mRNA. Cycloheximide mimicked the poly(A) tail effect observed with T3. In the absence of T3, actinomycin D deadenylated TSHbeta mRNA without inducing rapid decay. We conclude that T3 reduces the steady state half-life of TSHbeta mRNA in murine TtT97 thyrotropic tumor cells accompanied by a reduction in poly(A) tail length. However, in the absence of T3, deadenylation alone is not sufficient to induce TSHbeta mRNA decay. Together with the high degree of sequence conservation in the 3'-untranslated region of murine and rat TSHbeta mRNA sequences and the similarities of the T3 effect, these data provide the first evidence for a highly conserved posttranscriptional mechanism operative across species. We propose a model in which T3 coordinately regulates shortening of the poly(A) tail and the activity of a transacting RNA-binding protein and/or an exonuclease to accelerate TSHbeta mRNA turnover.


4-bp insertion/deletion (rs3783553) polymorphism within the 3'UTR of IL1A contributes to the risk of prostate cancer in a sample of Iranian population.
Growing evidence demonstrated the presence of an association between IL1A rs3783553 polymorphism and the risk of various cancers. We aimed to evaluate whether the 4-bp insertion/deletion polymorphism (rs3783553) within the 3' untranslated region (3'UTRs) of IL1A was associated to the risk of prostate cancer (PCa) in a sample of Iranian population. A case-control study, including 150 prostate cancer patients and 155 healthy men, was done to examine the possible association between IL1A 4-bp ins/del polymorphism and PCa risk in a sample of southeast Iranian population. Mismatched polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was designed for genotyping the studied variant. Our findings showed that 4-bp ins/del polymorphism significantly increased the risk of PCa in codominant, recessive and allelic inheritance model. We also evaluated the association between the IL1A 4-bp ins/del polymorphism and clinicopathological characteristics of the patients, and found a significant association between 4-bp ins/del variant and stage, perineural invasion and surgical margin of tumor samples. Bioinformatics analysis revealed that the ins/del variant affected the IL1A mRNA stability leading to a structural shift in IL1A mRNA and has-miR-125a-3p hybrid. In conclusion, our findings proposed an association between IL1A 4-bp ins/del polymorphism and PCa risk. Additional studies with enlarged sample size and diverse ethnicities are required to validate our finding.


[Evaluation of the surveillance of invasive meningococcal disease in Tunisia: capture-recapture method].
The objective of this study was to assess the completeness of the epidemiological surveillance system for invasive meningococcal diseases in greater Tunis. A six-year retrospective study (2003-2008) identified all cases of invasive meningococcal disease reported on Mandatory Notification records of the Tunis Regional Department of Health and those reported by the Tunis Children's hospital microbiology laboratory, considered to be the main source of diagnoses of invasive meningococcal disease in Greater Tunis. The "capture-recapture" method was applied. Thirty-eight cases of invasive meningococcal disease reported to the Regional Department of Health and 47 cases provided by the children's hospital were analysed during the study period and 25 cases common to both sources were identified. The total number of cases of invasive meningococcal disease was estimated to be 71 (95% CI = [60-82]), using the capture-recapture method. Completeness rates were 53.5% (95% CI = [46.6 to 62.9]) for Mandatory Notification to the Regional Department of Health and 66.2% (95% CI = [57.6 to 77.8]) for children's hospital. Stratified analyses suggest that the two data sources were probably independent. The capture-recapture method applied to the invasive meningococcal disease surveillance system in Greater Tunis showed a poor sensitivity of the Mandatory Notification. Factors influencing under-reporting of cases should be identified to improve this surveillance.


Development of a Limb-Preservation Program.
In the global scenario, as the prevalence of renal failure and diabetes increases, healing and limb preservation assume increasing clinical importance for patients and healthcare systems. Unfortunately, there continues to be variation in the care delivered to patients at risk of losing a limb based on geography, race, socioeconomic status, and insurance status. There are also a variety of therapeutic approaches to patients with limb-threatening ischemia; 25% undergo primary amputation, 25% undergo medical therapy, and only 50% undergo any attempt at revascularization. Nearly 50% of patients undergoing major amputation have not had a simple diagnostic arteriogram to assess the possibility of limb preservation. The Society of Vascular Surgery and the American Podiatric Medical Association have recognized the benefits of a multidisciplinary approach to limb preservation. Benefits to the patient include rapid assessment, improved healing, and enhanced revascularization. Advantages for the providers include the ability to efficiently manage complex patients with help from the appropriate specialties, an increase in referrals, enhanced identity of the institution, and clinical research and trials. Such a program requires the coordinated effort of physicians, nurses, allied health professionals, and administrators dedicated to the preservation of functional limbs. Beneficial components include identifiable space, a vascular laboratory, hyperbaric oxygen therapy, and protocol-driven care involving diagnostic and therapeutic modalities such as endovascular revascularization, open bypass, and soft tissue reconstruction. Prosthetic expertise is also important to maintain function in those patients for whom amputation is appropriate. But, the key to a program is cooperation and communication among the participants who have a passion for limb preservation. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=452746.


Choice architecture in physician-patient communication: a mixed-methods assessments of physicians' competency.
Clinicians' use of choice architecture, or how they present options, systematically influences the choices made by patients and their surrogate decision makers. However, clinicians may incompletely understand this influence. To assess physicians' abilities to predict how common choice frames influence people's choices. We conducted a prospective mixed-methods study using a scenario-based competency questionnaire and semistructured interviews. Participants were senior resident physicians from a large health system. Of 160 eligible participants, 93 (58.1%) completed the scenario-based questionnaire and 15 completed the semistructured interview. The primary outcome was choice architecture competency, defined as the number of correct answers on the eight-item scenario-based choice architecture competency questionnaire. We generated the scenarios based on existing decision science literature and validated them using an online sample of lay participants. We then assessed senior resident physicians' choice architecture competency using the questionnaire. We interviewed a subset of participating physicians to explore how they approached the scenario-based questions and their views on choice architecture in clinical medicine and medical education. Physicians' mean correct score was 4.85 (95% CI 4.59 to 5.11) out of 8 scenario-based questions. Regression models identified no associations between choice architecture competency and measured physician characteristics. Physicians found choice architecture highly relevant to clinical practice. They viewed the intentional use of choice architecture as acceptable and ethical, but felt they lacked sufficient training in the principles to do so. Clinicians assume the role of choice architect whether they realise it or not. Our results suggest that the majority of physicians have inadequate choice architecture competency. The uninformed use of choice architecture by clinicians may influence patients and family members in ways clinicians may not anticipate nor intend.


Complex dislocations of the metacarpophalangeal joints.
Complex dislocations of the metacarpophalangeal joints, those blocked by soft tissue interposition, occur infrequently and are often misdiagnosed and mishandled. While these injuries can be treated in a closed fashion, they may actually be induced by incorrect technique in reducing simple MP dislocations. Open surgical reduction is the treatment of necessity, although there is currently no consensus on approach. This article presents an overview of the history, pathoanatomy, and clinical and radiographic findings of this fairly uncommon hand injury. The literature on the various treatment modalities is reviewed, and therapeutic guidelines are offered.


A methylation-switchable conformational probe for the sensitive and selective detection of RNA demethylase activity.
We describe a novel methylation-sensitive nucleic acid (RNA) probe which switches conformation according to its methylation status. When combined with a differential scanning fluorimetry technique, it enables highly sensitive and selective detection of demethylase activity at a single methylated-base level. The approach is highly versatile and may be adapted to a broad range of RNA demethylases.


Undiagnosed genetic muscle disease in the north of England: an in depth phenotype analysis.
Advances in the molecular characterisation of genetic muscle disease has been rapid, as demonstrated by a recent analysis of these conditions in the north of England by Norwood et al (2009), in which a genetic diagnosis was achieved for 75.7% of patients. However, there remain many patients with suspected genetic muscle disease in who a diagnosis is not obtained, often despite considerable diagnostic effort, and these patients are now being considered for the application of new technologies such as next generation sequencing. This study aimed to provide an in-depth phenotype analysis of undiagnosed patients referred to the Northern region muscle clinic with suspected genetic muscle disease, with the intention of gaining insight into these conditions, identifing cases with a shared phenotype who may be amenable to collective diagnostic testing or research, and evaluating the strengths and limitations of our current diagnostic strategy. We used two approaches: a review of clinical findings in patients with undiagnosed muscle disease, and a hierarchical cluster analysis to provide an unbiased interpretation of the phenotype data. These joint approaches identified a correlation of phenotypic features according to the age of disease onset and also delineated several interesting groups of patients, as well as highlighting areas of frequent diagnostic difficulty that could benefit from the use of new high-throughput diagnostic techniques. Correspondence to: email@example.com.


[Recurrent upper respiratory tract infections during and after rituximab therapy].
Rituximab maintenance therapy is indicated for the treatment of patients with non-Hodgkin's lymphoma (NHL) who responded to induction therapy. More than 10% of patients will develop rituximab-induced upper respiratory tract infections (URTIs). These infections are usually mild in patients receiving first-line or second-line treatment. Heavily pretreated patients sometimes undergo additional rituximab maintenance therapy. We describe three female patients aged 53, 43 and 42 years who were successfully treated with rituximab maintenance therapy after chemotherapy for three or more recurrences of NHL. These patients developed more serious recurrent URTIs due to rituximab-induced long-term hypogammaglobulinaemia. In one patient, serum IgG levels continued to decline for four years after rituximab therapy. Long-term immunoglobulin substitution was needed to treat these patients. Physicians should be aware that URTIs may develop in heavily pretreated patients even years after rituximab maintenance therapy and substitution with immunoglobulin may be warranted.


Treatment of high-risk Hodgkin lymphoma with a modified Stanford V regimen in the AHOPCA: Substituting chemotherapy agents and hampered outcomes.
High-risk Hodgkin lymphoma (HRHL) in children is curable with combined modality therapy. The Association of Pediatric Hematology-Oncology of Central America (AHOPCA) is a consortium of cancer centers from Central America. In 2004, AHOPCA implemented a guideline with a short course of chemotherapy (mStanfordV), strict diagnostics, and radiation guidelines, aimed at reducing abandonment and improving outcomes. Newly diagnosed children less than 18 years of age with high-risk HL (Ann Arbor stages: IIB, IIIB, IV) from AHOPCA centers were staged with chest radiography and ultrasound or computed tomography. Therapy was a modified Stanford V (mStanfordV), substituting cyclophosphamide for mechlorethamine and involved field radiation. Of 219 patients with HRHL, 181 patients were eligible and evaluable; 146 (81%) were boys, 22% being less than 6 years; 43 were stage IIB, 84 IIIB, and 54 IV. Thirty-one (17%) abandoned therapy, 28 (15%) progressed, 30 (17%) relapsed, and eight (4%) died of toxicity. Radiation guidelines were not followed. Five-year abandonment-sensitive event-free survival and overall survival (AS-EFS, AS-OS ± SE) for the cohort were 46% ± 4% and 56% ± 4%; 5-year AS-OS for stages IIB, IIIB, and IV was 76% ± 7%, 59% ± 7%, and 35% ± 7% (p = .0006). Despite instituting a short treatment guideline, it did not improve the abandonment rate (17%) and did not achieve the reported outcomes of Stanford V. The cyclophosphamide dose used to replace merchlorethamine was inadequate. Despite strict guidelines, the radiation therapy application was inaccurate. Weekly chemotherapy may have adversely affected abandonment of therapy by increasing the burden of travel time. Based on these results, AHOPCA established a new abandonment strategy and a new guideline.


Enhanced Signal Detection by Adaptive Decorrelation of Interspike Intervals.
Spike trains with negative interspike interval (ISI) correlations, in which long/short ISIs are more likely followed by short/long ISIs, are common in many neurons. They can be described by stochastic models with a spike-triggered adaptation variable. We analyze a phenomenon in these models where such statistically dependent ISI sequences arise in tandem with quasi-statistically independent and identically distributed (quasi-IID) adaptation variable sequences. The sequences of adaptation states and resulting ISIs are linked by a nonlinear decorrelating transformation. We establish general conditions on a family of stochastic spiking models that guarantee this quasi-IID property and establish bounds on the resulting baseline ISI correlations. Inputs that elicit weak firing rate changes in samples with many spikes are known to be more detectible when negative ISI correlations are present because they reduce spike count variance; this defines a variance-reduced firing rate coding benchmark. We performed a Fisher information analysis on these adapting models exhibiting ISI correlations to show that a spike pattern code based on the quasi-IID property achieves the upper bound of detection performance, surpassing rate codes with the same mean rate-including the variance-reduced rate code benchmark-by 20% to 30%. The information loss in rate codes arises because the benefits of reduced spike count variance cannot compensate for the lower firing rate gain due to adaptation. Since adaptation states have similar dynamics to synaptic responses, the quasi-IID decorrelation transformation of the spike train is plausibly implemented by downstream neurons through matched postsynaptic kinetics. This provides an explanation for observed coding performance in sensory systems that cannot be accounted for by rate coding, for example, at the detection threshold where rate changes can be insignificant.


Overexpression of ThMYB8 mediates salt stress tolerance by directly activating stress-responsive gene expression.
MYB transcription factors are important in abiotic stress responses; however, the detailed mechanisms are unclear. Tamarix hispida contains multiple MYB genes. The present study characterized T. hispida MYB8 (ThMYB8) during salt stress using transgenic T. hispida and Arabidopsis assays. ThMYB8 overexpression and ThMYB8 RNAi analysis demonstrated that ThMYB8 enhanced the salt stress tolerance. Transgenic Arabidopsis ectopic expression of ThMYB8 significantly increased root growth, fresh weight, and seed germination rate compared with that of the wild-type under salt stress. Physiological parameters analysis in T. hispida and Arabidopsis showed that ThMYB8 overexpressing plants had the lowest levels of O2, H2O2, cell death, malondialdehyde, and electrolyte leakage. Overexpression of ThMYB8 regulated Na+ and K+ concentrations in plant tissues while maintaining K+/Na+ homeostasis. Analysis using qRT-PCR and ChIP-PCR identified possible downstream ThMYB8-regulated genes. ThMYB8 regulated the expression of ThCYP450-2 (cytochrome p450-2), Thltk (leucine-rich repeat transmembrane protein kinase), and ThTIP (aquaporin TIP) by binding to the MBSI motif ('CAACTG') in their promoters. The results indicated that ThMYB8 enhanced salt stress tolerance in T. hispida by regulating gene expression related to the activation of stress-associated physiological changes, such as enhanced reactive oxygen species scavenging capability, maintaining K+/Na+ homeostasis, and decreasing the malondialdehyde content and lipid peroxidation cell membranes.


Volatilomes of human infection.
The human volatilome comprises a vast mixture of volatile emissions produced by the human body and its microbiomes. Following infection, the human volatilome undergoes significant shifts, and presents a unique medium for non-invasive biomarker discovery. In this review, we examine how the onset of infection impacts the production of volatile metabolites that reflects dysbiosis by pathogenic microbes. We describe key analytical workflows applied across both microbial and clinical volatilomics and emphasize the value in linking microbial studies to clinical investigations to robustly elucidate the metabolic species and pathways leading to the observed volatile signatures. We review the current state of the art across microbial and clinical volatilomics, outlining common objectives and successes of microbial-clinical volatilomic workflows. Finally, we propose key challenges, as well as our perspectives on emerging opportunities for developing clinically useful and targeted workflows that could significantly enhance and expedite current practices in infection diagnosis and monitoring.


[Effects of hypoxic and cold stimuli on heat production and catecholamine content in mice].
Hypoxic and low-temperature effects on the thermal regulation and the content of catecholamines (epinephrine--E and norepinephrine--NE) in mice have been compared. Continuous and repeated hypoxia brought about a significant drop of the rodent body temperature and heat content. Found was a significant elevation of catecholamines in the pituitary and adrenal tissues, and blood plasma with E prevalence after the continuous exposure. Repeated stimulus resulted in a more pronounced effect. Exception was the adrenal tissue where enhanced E and NE secretion into blood was noted. The uninterrupted and repeated cold conditions were also responsible for heat release. Continuous exposure to low temperature increased NE and decreased insignificantly E in blood and adrenal. Multiple stimulation increased sharply catecholamines concentration in blood plasma with the dominance of epinephrine in the pituitary gland, and norepinephrine in the adrenal.


Health, wellbeing and nutritional status of older people living in UK care homes: an exploratory evaluation of changes in food and drink provision.
Food and drink are important determinants of physical and social health in care home residents. This study explored whether a pragmatic methodology including routinely collected data was feasible in UK care homes, to describe the health, wellbeing and nutritional status of care home residents and assess effects of changed provision of food and drink at three care homes on residents' falls (primary outcome), anaemia, weight, dehydration, cognitive status, depression, lipids and satisfaction with food and drink provision. We measured health, wellbeing and nutritional status of 120 of 213 residents of six care homes in Norfolk, UK. An intervention comprising improved dining atmosphere, greater food choice, extended restaurant hours, and readily available snacks and drinks machines was implemented in three care homes. Three control homes maintained their previous system. Outcomes were assessed in the year before and the year after the changes. Use of routinely collected data was partially successful, but loss to follow up and levels of missing data were high, limiting power to identify trends in the data. This was a frail older population (mean age 87, 71% female) with multiple varied health problems. During the first year 60% of residents had one or more falls, 40% a wound care visit, and 40% a urinary tract infection. 45% were on diuretics, 24% antidepressants, and 43% on psychotropic medication. There was a slight increase in falls from year 1 to year 2 in the intervention homes, and a much bigger increase in control homes, leading to a statistically non-significant 24% relative reduction in residents' rate of falls in intervention homes compared with control homes (adjusted rate ratio 0.76, 95% CI 0.57 to 1.02, p = 0.06). Care home residents are frail and experience multiple health risks. This intervention to improve food and drink provision was well received by residents, but effects on health indicators (despite the relative reduction in falls rate) were inconclusive, partly due to problems with routine data collection and loss to follow up. Further research with more homes is needed to understand which, if any, components of the intervention may be successful.


Nonlinear Optical Spectroscopy of Molecular Assemblies: What Is Gained and Lost in Action Detection?
This study elucidates the information content that is extracted from action-2D electronic spectroscopy (A-2DES) when the output intensity is not proportional to the number of excitations generated. Such a scenario can be realized in both fluorescence and photocurrent detection because of direct interaction like exciton-exciton annihilation or indirect effects in the signal generation or detection. By means of an intuitive probabilistic model supported by nonlinear response theory, the study concludes that in molecular assemblies the ground-state bleaching contribution can dominate the nonlinear signal and partially or completely hide the stimulated emission. In this case, the spectral effect resembles incoherent mixing, even in the absence of exciton-exciton annihilation, implying reduced information about the excited-state dynamics with an increasing number of chromophores. This finding has important implications for the selection of samples for A-2DES as well as for its interpretation.


Identification of discrete chromosomal deletion by binary recursive partitioning of microarray differential expression data.
DNA copy number abnormalities (CNA) are characteristic of tumours, and are also found in association with congenital anomalies and mental retardation. The ultimate impact of copy number abnormalities is manifested by the altered expression of the encoded genes. We previously developed a statistical method for the detection of simple chromosomal amplification using microarray expression data. In this study, we significantly advanced those analytical techniques to allow detection of localised chromosomal deletions based on differential gene expression data. Using three cell lines with known chromosomal deletions as model system, mRNA expression in those cells was compared with that observed in diploid cell lines of matched tissue origin. Results show that genes from deleted chromosomal regions are substantially over-represented (p<0.000001 by chi2) among genes identified as underexpressed in deletion cell lines relative to normal matching cells. Using a likelihood based statistical model, we were able to identify the breakpoint of the chromosomal deletion and match with the karyotype data in each cell line. In one such cell line, our analyses refined a previously identified 10p chromosomal deletion region. The deletion region was mapped to between 10p14 and 10p12, which was further confirmed by subtelomeric fluorescence in situ hybridisation. These data show that microarray differential expression data can be used to detect and map the boundaries of submicroscopic chromosomal deletions.


Comments on "Constraining the optimization of a fuzzy logic controller".
Genetic algorithms (GAs) are a highly effective and efficient means of solving optimization problems. Gene encoding, fitness landscape and genetic operations are vital to successfully developing a GA. F. Cheong and R. Lai (see ibid., vol. 30, p. 31-46 (2000)) described a novel method, which employed an enhanced genetic algorithm with multiple populations, to optimize a fuzzy controller, and the experimental results revealed that their method was effective in producing a well-formed fuzzy rule-base. However, their encoding method and fitness function appear unnatural and inefficient. This study proposes an alternative method of concise genetic encoding and fitness design.