Human papillomavirus types distribution in organised cervical cancer screening in France.
Knowledge of prevalence rates and distribution of human papillomavirus (HPV) genotypes prior high HPV vaccine coverage is necessary to assess its expected impact on HPV ecology and on cervical lesions and cancers. Residual specimens of cervical cytology (N = 6,538) were obtained from 16 sites participating in organised cervical cancer screening pilot programs throughout France, anonymised and tested for HPV DNA using the PapilloCheck® genotyping test. Samples were stratified according to age of women and cytological grades. The age-standardised prevalence rates of HPV 16 and/or 18 (with or without other high-risk types) was 47.2% (95% Confidence Interval, CI: 42.4-52.1) in high-grade squamous intraepithelial lesions (HSILs), 20.2% in low-grade SIL (95% CI: 16.7-23.7) and 3.9% (95% CI: 2.8-5.1) in normal cytology. Overall HR HPV were detected in 13.7% (95%I CI: 11.7-15.6) of normal cytology. In women below 30 years of age, 64% of HSILs were associated with HPV16 and/or 18. In our study population, HPV16 was the most commonly detected type in all cervical grades with prevalence rates ranking from 3.0% in normal cytology to 50.9% in HSILs. HPV16 was also detected in 54% (27/50) of invasive cervical cancers including 5 adenocarcinomas. HPV16 was strongly associated with cervical precancer and cancer. The high prevalence rates of HPV16/18 infection among women below 30 years of age with HSILs suggests that the impact of vaccination would be primarily observed among young women.


Pathological Result of Basilar Artery Stenosis Rapidly Progressed and Ruptured with Stent-assisted Angioplasty.
Intracranial artery angioplasty utilizing coronary stent is now widely tried as an effective alternative for treating intracranial artery stenosis, and several successful result of stent-assisted angioplasty for intracranial artery were reported. Authors experienced a case of the basilar artery stenosis, in which re-stenosis progressed rapidly after simple balloon angioplasty and resulted in vessel rupture during stent-assisted angioplasty. Pathological result achieved by autopsy showed vessel wall disruption at the stent and multiple interruptions and defect of elastic laminar.


Exploring the feasibility of the use of biopolymers as a carrier in the formulation of amorphous solid dispersions - Part I: Gelatin.
Biopolymers have rarely been used so far as carriers in the formulation of amorphous solid dispersions (ASD) to overcome poor solubility of active pharmaceutical ingredients (APIs). In an attempt to enlarge our knowledge on this topic, gelatin, type 50PS was selected. A screening study was initiated in which twelve structurally different poorly soluble biopharmaceutical classification system (BCS) Class II drugs (carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen) were selected for evaluation. Solid dispersions of five different drug loadings of these twelve compounds were prepared by lyophilization and evaluated for their solid state properties by mDSC and XR(P)D, and in vitro dissolution performance. Even without any process optimization it was possible to form either fully amorphous or partially amorphous systems, depending on the API and API to carrier ratio. Hence in this respect, gelatin 50PS behaves as any other carrier. Dissolution of the API from the solid dispersions significantly exceeded that of their crystalline counterparts. This study shows the potential of gelatin as a carrier to formulate amorphous solid dispersions.


Partners in Public Health: Public Health Collaborations With Schools of Pharmacy, 2015.
To collect data on public health collaborations with schools of pharmacy, we sent a short electronic survey to accredited and preaccredited pharmacy programs in 2015. We categorized public health collaborations as working or partnering with local and/or state public health departments, local and/or state public health organizations, academic schools or programs of public health, and other public health collaborations. Of 134 schools, 65 responded (49% response rate). Forty-six (71%) responding institutions indicated collaborations with local and/or state public health departments, 34 (52%) with schools or programs of public health, and 24 (37%) with local and/or state public health organizations. Common themes of collaborations included educational programs, community outreach, research, and teaching in areas such as tobacco control, emergency preparedness, chronic disease, drug abuse, immunizations, and medication therapy management. Interdisciplinary public health collaborations with schools of pharmacy provide additional resources for ensuring the health of communities and expose student pharmacists to opportunities to use their training and abilities to affect public health. Examples of these partnerships may stimulate additional ideas for possible collaborations between public health organizations and schools of pharmacy.


Soil bacterial and fungal communities respond differently to various isothiocyanates added for biofumigation.
The meals from many oilseed crops have potential for biofumigation due to their release of biocidal compounds such as isothiocyanates (ITCs). Various ITCs are known to inhibit numerous pathogens; however, much less is known about how the soil microbial community responds to the different types of ITCs released from oilseed meals (SMs). To simulate applying ITC-releasing SMs to soil, we amended soil with 1% flax SM (contains no biocidal chemicals) along with four types of ITCs (allyl, butyl, phenyl, and benzyl ITC) in order to determine their effects on soil fungal and bacterial communities in a replicated microcosm study. Microbial communities were analyzed based on the ITS region for fungi and 16S rRNA gene for bacteria using qPCR and tag-pyrosequencing with 454 GS FLX titanium technology. A dramatic decrease in fungal populations (~85% reduction) was observed after allyl ITC addition. Fungal community compositions also shifted following ITC amendments (e.g., Humicola increased in allyl and Mortierella in butyl ITC amendments). Bacterial populations were less impacted by ITCs, although there was a transient increase in the proportion of Firmicutes, related to bacteria know to be antagonistic to plant pathogens, following amendment with allyl ITC. Our results indicate that the type of ITC released from SMs can result in differential impacts on soil microorganisms. This information will aid selection and breeding of plants for biofumigation-based control of soil-borne pathogens while minimizing the impacts on non-target microorganisms.


Lactobacillus nagelii sp. nov., an organism isolated from a partially fermented wine.
A Gram-positive rod was isolated from a commercial grape wine undergoing a sluggish/stuck alcoholic fermentation. The organism produced DL-lactic acid from glucose without gas formation, produced dextran from sucrose, hydrolysed aesculin and fermented galactose, D-glucose, D-fructose, D-mannose, L-sorbose, rhamnose, mannitol, sorbitol, methyl alpha-D-glucoside, N-acetylglucosamine, amygdalin, salicin, cellobiose, maltose, sucrose, trehalose and beta-gentiobiose. 16S rRNA gene sequence analysis revealed that the isolate was phylogenetically a member of the genus Lactobacillus and formed a distinct subline within the Lactobacillus casei cluster of species. On the basis of phenotypic and phylogenetic evidence, Lactobacillus nagelii sp. nov. ATCC 700692T is proposed as a new species.


Care of persons with AIDS in the nursing home.
AIDS is becoming a chronic illness for some patients whose significant accumulated functional impairments may limit community-based care. Nursing homes can provide an appropriate level of care, although reported experience caring for persons with AIDS in this setting is limited. A retrospective case-series review was conducted in a 242-bed community teaching nursing home to describe the initial 26-month experience in providing care for patients with AIDS requiring nursing home admission. A total of 42 admissions by 32 patients with AIDS (mean age = 33.5 years, 81% male) involved a shorter length of stay (mean 63.1 days) and higher numbers of medications (mean = 11.2), facility charges (mean $11,971/admission, $189/day), and greater clinical management complexity than usual nursing home patients. Thirteen patients were discharged, seven for rehospitalization and six into community settings, although ultimately 29 of the 32 patients died in the facility. AIDS care in the nursing home presents significant, distinct challenges in complex management and terminal care prioritization.


Current trends in treatment of osteoid osteoma with an emphasis on radiofrequency ablation.
This article reviews current trends in the treatment of osteoid osteoma with an emphasis on the evolving use of radiofrequency thermoablation as a primary definitive treatment and for recurrent and residual lesions. In so doing, the article reviews merits and relative disadvantages of both surgical and non-surgical imaging-guided techniques in treatment. Radiofrequency ablation of osteoid osteoma is a highly effective, efficient, minimally invasive and safe method of treating osteoid osteoma. Clinical success range from 76 to 100%. Surgery remains the standard treatment in cases where histology of the lesion is in doubt, neurovascular structures are within 1.5 cm or in repeated failure of any other minimally invasive ablative technique or percutaneous resection. Clinical success of surgery ranges from 88 to 100%. Laser interstitial thermal therapy shares many of the advantages and much of the success of radiofrequency thermoablation but has not been as available. Clinical success ranges from 87 to 100%. Cryotherapy, ethanol therapy and imaging-guided excision remain second-line therapies. Clinical success ranges from 77 to 100% for imaging-guided resection and 100% for ethanol therapy.


Drop-out from parenting training programmes: a retrospective study.
Parent training programmes are a well-established treatment approach for children and adolescents with disruptive behaviour disorders. However, dropout from treatment is a common problem that confounds research on the efficacy of this approach, and wastes important mental health resources. This study sought to further our understanding of the reasons why parents drop out of parent training programmes. Nine parents of children with disruptive behaviour disorders who had dropped out of a parent training programme were interviewed to investigate why they discontinued the programme. Parents who dropped out of treatment believed that their children were more difficult than other children with the same disorder and may have been better suited to a child-focused intervention. The parents themselves had very stressful lives, with the majority being single mothers with little support. Dropout parents also had difficulty with the group context and putting strategies into place. Practical concerns included parking, timing of session and the length and number of sessions. The findings are discussed in terms of what modifications can be made to these programmes to increase retention.


Results of a consensus meeting on the use of argatroban in patients with heparin-induced thrombocytopenia requiring antithrombotic therapy - a European Perspective.
Argatroban has been introduced as an alternative parenteral anticoagulant for HIT-patients in several European countries in 2005. In 2009 a panel of experts discussed their clinical experience with argatroban balancing risks and benefits of argatroban treatment in managing the highly procoagulant status of HIT-patients. This article summarizes the main conclusions of this round table discussion. An ongoing issue is the appropriate dosing of argatroban in special patient groups. Therefore, dosing recommendations for different HIT-patient groups (ICU patients; non-ICU patients, paediatric patients, and for patients undergoing renal replacement therapies) are summarized in this consensus statement. Because of the strong correlation between argatroban dosing requirements and scores used to characterize the severity of illness (APACHE; SAPS, SOFA) suitable dosing nomograms are given. This consensus statement contributes to clinically relevant information on the appropriate use and monitoring of argatroban based on the current literature, and provides additional information from clinical experience. As the two other approved drugs for HIT, danaparoid and lepirudin are either currently not available due to manufacturing problems (danaparoid) or will be withdrawn from the market in 2012 (lepirudin), this report should guide physicians who have limited experience with argatroban how to use this drug safely in patients with HIT.


Autonomic regulation in fragile X syndrome.
Autonomic reactivity was studied in individuals with fragile X syndrome (FXS), a genetic disorder partially characterized by abnormal social behavior. Relative to age-matched controls, the FXS group had faster baseline heart rate and lower amplitude respiratory sinus arrhythmia (RSA). In contrast to the typically developing controls, there was a decrease in RSA with age within the FXS group. Moreover, within the FXS group heart rate did not slow with age. The FXS group also responded with an atypical increase in RSA to the social challenge, while the control group reduced RSA. In a subset of the FXS group, the autonomic profile did not change following 2 months and 1 year of lithium treatment. The observed indices of atypical autonomic regulation, consistent with the Polyvagal Theory, may contribute to the deficits in social behavior and social communication observed in FXS.


A polymorphic, prespore-specific cell surface glycoprotein is present in the extracellular matrix of Dictyostelium discoideum.
Polymorphisms of a major developmentally regulated prespore-specific protein (PsA) in Dictyostelium discoideum slugs are described. These polymorphisms allowed discrimination between PsA (found on the cell surface and in the extracellular matrix) and a similar extracellular but nonpolymorphic protein, ShA. The two proteins were also distinguished by their differing reactivities with a range of monoclonal antibodies and by their sensitivity to release from the sheath with cellulase. The results are discussed in terms of the molecular and genetic relationships between the cell surface and the extracellular matrix during development.


Traditional Chinese medicine for neck pain and low back pain: a systematic review and meta-analysis.
Neck pain (NP) and low back pain (LBP) are common symptoms bothering people in daily life. Traditional Chinese medicine (TCM) has been used to treat various symptoms and diseases in China and has been demonstrated to be effective. The objective of the present study was to review and analyze the existing data about pain and disability in TCM treatments for NP and LBP. Studies were identified by a comprehensive search of databases, such as MEDLINE, EMBASE, and Cochrane Library, up to September 1, 2013. A meta-analysis was performed to evaluate the efficacy and safety of TCM in managing NP and LBP. Seventy five randomized controlled trials (n = 11077) were included. Almost all of the studies investigated individuals experiencing chronic NP (CNP) or chronic LBP (CLBP). We found moderate evidence that acupuncture was more effective than sham-acupuncture in reducing pain immediately post-treatment for CNP (visual analogue scale (VAS) 10 cm, mean difference (MD) = -0.58 (-0.94, -0.22), 95% confidence interval, p = 0.01), CLBP (standardized mean difference = -0.47 (-0.77, -0.17), p = 0.003), and acute LBP (VAS 10 cm, MD = -0.99 (-1.24, -0.73), p< 0.001). Cupping could be more effective than waitlist in VAS (100 mm) (MD = -19.10 (-27.61, -10.58), p < 0. 001) for CNP or medications (e.g. NSAID) for CLBP (MD = -5.4 (-8.9, -0.19), p = 0.003). No serious or life-threatening adverse effects were found. Acupuncture, acupressure, and cupping could be efficacious in treating the pain and disability associated with CNP or CLBP in the immediate term. Gua sha, tai chi, qigong, and Chinese manipulation showed fair effects, but we were unable to draw any definite conclusions, and further research is still needed. The efficacy of tuina and moxibustion is unknown because no direct evidence was obtained. These TCM modalities are relatively safe.


LoCKAmp: lab-on-PCB technology for <3 minute virus genetic detection.
The recent COVID-19 outbreak highlighted the need for lab-on-chip diagnostic technology fit for real-life deployment in the field. Existing bottlenecks in multistep analytical microsystem integration and upscalable, standardized fabrication techniques delayed the large-scale deployment of lab-on-chip solutions during the outbreak, throughout a global diagnostic test shortage. This study presents a technology that has the potential to address these issues by redeploying and repurposing the ubiquitous printed circuit board (PCB) technology and manufacturing infrastructure. We demonstrate the first commercially manufactured, miniaturised lab-on-PCB device for loop-mediated isothermal amplification (LAMP) genetic detection of SARS-CoV-2. The system incorporates a mass-manufactured, continuous-flow PCB chip with ultra-low cost fluorescent detection circuitry, rendering it the only continuous-flow μLAMP platform with off-the-shelf optical detection components. Ultrafast, SARS-CoV-2 RNA amplification in wastewater samples was demonstrated within 2 min analysis, at concentrations as low as 17 gc μL-1. We further demonstrate our device operation by detecting SARS-CoV-2 in 20 human nasopharyngeal swab samples, without the need for any RNA extraction or purification. This renders the presented miniaturised nucleic-acid amplification-based diagnostic test the fastest reported SARS-CoV-2 genetic detection platform, in a practical implementation suitable for deployment in the field. This technology can be readily extended to the detection of alternative pathogens or genetic targets for a very broad range of applications and matrices. LoCKAmp lab-on-PCB chips are currently mass-manufactured in a commercial, ISO-compliant PCB factory, at a small-scale production cost of £2.50 per chip. Thus, with this work, we demonstrate a high technology-readiness-level lab-on-chip-based genetic detection system, successfully benchmarked against standard analytical techniques both for wastewater and nasopharyngeal swab SARS-CoV-2 detection.


Associations between social capital and HIV stigma in Chennai, India: considerations for prevention intervention design.
Stigma against persons living with HIV/AIDS (PLHA) is a barrier to seeking prevention education, HIV testing, and care. Social capital has been reported as an important factor influencing HIV prevention and social support upon infection. In the study, we explored the associations between social capital and stigma among men and women who are patrons of wine shops or community-based alcohol outlets in Chennai. We found that reports of social capital indicators were associated with reduced fear of transmission of HIV/AIDS, lower levels of feelings of shame, blame and judgment, lower levels of personal support and perceived community support for discriminatory actions against PLHA. Specifically, when participants reported membership in formal groups, perception of high levels of collective action toward community goals, high norms of reciprocity between neighbors and residents in daily life, and presence of trusted sexually transmitted disease care providers, all levels of measures of stigma were lower. Although we defined social capital rather narrowly in this study, our findings suggest that seeking partnerships with existing organizations and involving health care providers in future interventions may be explored as a strategy in community-based prevention interventions.


The impact of chronic inflammation on the growing skeleton: lessons from interleukin-6 transgenic mice.
Chronic inflammatory diseases in children are associated with impairment of linear growth and bone mineral accrual. In addition to poor nutrition, reduced mobility and glucocorticoid treatment, several observations in patients suggest that inflammation itself may have a direct detrimental effect on the growing skeletal system. Among the various inflammatory cytokines produced during the inflammatory response, data in animals suggest that interleukin-6 (IL-6) may mediate the effects of inflammation on the developing skeleton. Mice overexpressing IL-6 during the prepubertal stage show stunted growth, abnormalities of the insulin-like growth factor I system, defective growth plates, delayed development of ossification centres, uncoupling of osteoblast and osteoclast activity and defective ossification. These changes appear to mirror the features observed in children with chronic inflammatory diseases. The tissue, cellular and molecular abnormalities reviewed provide a rationale for therapeutic approaches aimed at correcting the detrimental effects of inflammation on the developing skeletal system.


Arthrogryposis multiplex congenita, AD 1156.
A case of arthrogryposis multiplex congenita in an eight-year-old girl was recounted by Thomas of Monmouth in a mid twelfth-century English hagiographic narrative, The Life and Miracles of St William of Norwich. The child had deformities of both hands and both feet at birth, and she developed torticollis and probably had some degree of hypotonia. She needed total care, her family took her to the tomb of St William in the cathedral at Norwich. This visit produced some sort of improvement in her health. Her parents, seeking a miracle, were satisfied that one had occurred.


Speculation on quantum mechanics and the operation of life giving catalysts.
The origin of life necessitated the formation of catalytic functionalities in order to realize a number of those capable of supporting reactions that led to the proliferation of biologically accessible molecules and the formation of a proto-metabolic network. Here, the discussion of the significance of quantum behavior on biological systems is extended from recent hypotheses exploring brain function and DNA mutation to include origins of life considerations in light of the concept of quantum decoherence and the transition from the quantum to the classical. Current understandings of quantum systems indicate that in the context of catalysis, substrate-catalyst interaction may be considered as a quantum measurement problem. Exploration of catalytic functionality necessary for life's emergence may have been accommodated by quantum searches within metal sulfide compartments, where catalyst and substrate wave function interaction may allow for quantum based searches of catalytic phase space. Considering the degree of entanglement experienced by catalytic and non catalytic outcomes of superimposed states, quantum contributions are postulated to have played an important role in the operation of efficient catalysts that would provide for the kinetic basis for the emergence of life.


Increased Usage of Antiseptics Is Associated with Reduced Susceptibility in Clinical Isolates of Staphylococcus aureus.
Hospital-acquired infection is a major cause of morbidity and mortality, and regimes to prevent infection are crucial in infection control. These include the decolonization of vulnerable patients with methicillin-resistant Staphylococcus aureus (MRSA) carriage using antiseptics, including chlorhexidine and octenidine. Concern has been raised, however, regarding the possible development of biocide resistance. In this study, we assembled a panel of S. aureus isolates, including isolates collected before the development of chlorhexidine and octenidine and isolates, from a major hospital trust in the United Kingdom during a period when the decolonization regimes were altered. We observed significant increases in the MIC and minimum bactericidal concentration (MBC) of chlorhexidine in isolates from periods of high usage of chlorhexidine. Isolates with increased MICs and MBCs of octenidine rapidly emerged after octenidine was introduced in the trust. There was no apparent cross-resistance between the two biocidal agents. A combination of variable-number tandem repeat (VNTR) analysis, PCR for qac genes, and whole-genome sequencing was used to type isolates and examine possible mechanisms of resistance. There was no expansion of a single strain associated with decreased biocide tolerance, and biocide susceptibility did not correlate with carriage of qac efflux pump genes. Mutations within the NorA or NorB efflux pumps, previously associated with chlorhexidine export, were identified, however, suggesting that this may be an important mechanism of biocide tolerance. We present evidence that isolates are evolving in the face of biocide challenge in patients and that changes in decolonization regimes are reflected in changes in susceptibility of isolates.IMPORTANCE Infection in hospitals remains a major cause of death and disease. One way in which we combat this is by decolonizing at-risk patients from carriage of bacteria which can cause disease such as MRSA. This is done with antiseptics, including chlorhexidine and octenidine. There is concern, however, that bacteria may be able to become resistant to these antiseptics. In this study, we looked at isolates of MRSA and found that there was a correlation between the use of antiseptics and increased resistance in the isolates. We also suggest that the mechanism by which these more tolerant isolates may become resistant to antiseptics is that of changing a transport pump that exports these agents. This information suggests that we need to study the impact of antiseptics on clinically important bacteria more closely.


Empirical study on mutual fund objective classification.
Mutual funds are usually classified on the basis of their objectives. If the activities of mutual funds are consistent with their stated objectives, investors may look at the latter as signals of their risks and incomes. This work analyzes mutual fund objective classification in China by statistical methods of distance analysis and discriminant analysis; and examines whether the stated investment objectives of mutual funds adequately represent their attributes to investors. That is, if mutual funds adhere to their stated objectives, attributes must be heterogeneous between investment objective groups and homogeneous within them. Our conclusion is to some degree, the group of optimized exponential funds is heterogeneous to other groups. As a whole, there exist no significant differences between different objective groups; and 50% of mutual funds are not consistent with their objective groups.


Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-gamma receptor-deficient hosts.
The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type I T-cell process. However, a prototypical type I cytokine, interferon-gamma (IFN-gamma), can protect against several manifestations of GVHD in recipients of major histocompatibility complex (MHC)-mismatched hematopoietic cells. We transplanted hematopoietic cells from C3H.SW donors in wild-type (wt) and IFN-gamma-receptor-deficient (IFN-gammaRKO) MHC-matched C57BL/6 recipients. In IFN-gammaRKO recipients, host cells were unresponsive to IFN-gamma, whereas wt donor cells were exposed to exceptionally high levels of IFN-gamma. From an IFN-gamma perspective, we could therefore evaluate the impact of a loss-of-function on host cells and gain-of-function on donor cells. We found that lack of IFN-gammaR prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-gammaRKO recipients involved donor cells: lymphoid hypoplasia and hematopoietic failure. Lymphopenia was due to FasL-induced apoptosis and decreased cell proliferation. Bone marrow aplasia resulted from a decreased proliferation of hematopoietic stem/progenitor cells that was associated with down-regulation of 2 genes negatively regulated by IFN-gamma: Ccnd1 and Myc. We conclude that IFN-gamma produced by alloreactive T cells may entail a severe graft-versus-graft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD.


Radioimmunoscintigraphy of tumors autocrine for human met and hepatocyte growth factor/scatter factor.
Inappropriate expression of the c-met-protooncogene product (Met) and/or of its ligand, hepatocyte growth factor/scatter factor (HGF/SF), has been correlated with poor prognosis in a variety of human solid tumors. We are developing animal models for nuclear imaging of Met and HGF/SF expression in tumors in vivo. We radioiodinated a mixture of monoclonal antibodies (MAbs) that bind to human HGF/SF and to the external ligand-binding domain of human Met, and then injected the I-125-MAb mixture intravenously into mice bearing tumors either autocrine for human HGF/SF and human Met or autocrine-paracrine for murine HGF/SF and murine Met. Serial total body gamma camera images were obtained, and regional activity was determined by quantitative region-of-interest (ROI) analysis. Tumors autocrine for human HGF/SF and Met demonstrated significantly more rapid uptake and more rapid clearance of the I-125-MAb mixture than tumors expressing one or both murine homologues, reaching a mean tumor to total body activity ratio of > 0.3 by 1 day postinjection. We conclude that radioimmunodetection of tumors autocrine for human HGF/SF and Met is feasible with an I-125-MAb mixture reactive against the ligand-receptor pair.


Sample size and power determination in joint modeling of longitudinal and survival data.
Owing to the rapid development of biomarkers in clinical trials, joint modeling of longitudinal and survival data has gained its popularity in the recent years because it reduces bias and provides improvements of efficiency in the assessment of treatment effects and other prognostic factors. Although much effort has been put into inferential methods in joint modeling, such as estimation and hypothesis testing, design aspects have not been formally considered. Statistical design, such as sample size and power calculations, is a crucial first step in clinical trials. In this paper, we derive a closed-form sample size formula for estimating the effect of the longitudinal process in joint modeling, and extend Schoenfeld's sample size formula to the joint modeling setting for estimating the overall treatment effect. The sample size formula we develop is quite general, allowing for p-degree polynomial trajectories. The robustness of our model is demonstrated in simulation studies with linear and quadratic trajectories. We discuss the impact of the within-subject variability on power and data collection strategies, such as spacing and frequency of repeated measurements, in order to maximize the power. When the within-subject variability is large, different data collection strategies can influence the power of the study in a significant way. Optimal frequency of repeated measurements also depends on the nature of the trajectory with higher polynomial trajectories and larger measurement error requiring more frequent measurements.


Comorbid mental disorders among adults in the mental health surveillance survey.
To examine the prevalence and correlates of mental disorder comorbidity in the adult U.S. household population. Data are from a nationally representative sample of noninstitutionalized, civilian adults aged 18 years or older (n = 5653) who participated in the 2008-2012 Mental Health Surveillance Study. Mental disorders, including substance use disorders, were assessed by clinical interviewers using a semistructured diagnostic instrument. Analyses examined co-occurrence of mental disorders and associations with sociodemographic, functional impairment, and treatment correlates. Approximately one-third of adults (31.1%, or more than 15 million) with a past-year mental disorder had a co-occurring mental disorder. Correlates of comorbidity in adjusted models included being of young age, being of non-Hispanic white race/ethnicity, having low family income, and living in a large metropolitan area. Adults with comorbid mental disorders had lower mean levels of functioning and were more likely to report past-year treatment than adults with a single disorder; they also had higher estimates of past-year perceived unmet need for care (21.7% vs. 11.6%, P < .01). About one in three adults with a mental disorder have a co-occurring mental disorder. Elucidating factors associated with co-occurrence may lend clues to shared etiologies, help improve prevention efforts, facilitate early identification, and improve treatment regimens.


Transient Kluver-Bucy Syndrome as a Manifestation of Post-temporal Lobe Seizure: A Rare Case Entity.
Following epileptic seizures, patients can subsequently experience a post-ictal state characterized by disorienting symptoms, such as confusion, drowsiness, hypertension, headache, and nausea, rather than neurobehavioral sequelae. We report the case of a 64-year-old male with unilateral left temporal lobe injury, who presented with post-ictal transient Kluver-Bucy Syndrome symptomatology following a complex partial seizure. Brain magnetic resonance imaging revealed encephalomalacia of the left temporo-parieto-occipital region from a previous infarct, and his symptoms resolved following the administration of antiepileptic medications. Therefore, transient Kluver-Bucy Syndrome can follow unilateral temporal lobe injury and should be suspected in patients who fit the clinical criteria, even in the absence of classic bilateral temporal lobe damage on imaging.


Multicenter registry of Impella-assisted high-risk percutaneous coronary interventions and cardiogenic shock in Poland (IMPELLA-PL).
Impella is a percutaneous mechanical circulatory support device for treatment of cardiogenic shock (CS) and high-risk percutaneous coronary interventions (HR-PCIs). IMPELLA-PL is a national retrospective registry of Impella-treated CS and HR-PCI patients in 20 Polish interventional cardiological centers, conducted from January 2014 until December 2021. We aimed to determine the efficacy and safety of Impella using real-world data from IMPELLA-PL and compare these with other registries. IMPELLA-PL data were analyzed to determine primary endpoints: in-hospital mortality and rates of mortality and major adverse cardiovascular and cerebrovascular events (MACCE) at 12 months post-discharge. Of 308 patients, 18% had CS and 82% underwent HR-PCI. In-hospital mortality rates were 76.4% and 8.3% in the CS and HR-PCI groups, respectively. The 12-month mortality rates were 80.0% and 18.2%, and post-discharge MACCE rates were 9.1% and 22.5%, respectively. Any access site bleeding occurred in 30.9% of CS patients and 14.6% of HR-PCI patients, limb ischemia in 12.7% and 2.4%, and hemolysis in 10.9% and 1.6%, respectively. Impella is safe and effective during HR-PCIs, in accordance with previous registry analyses. The risk profile and mortality in CS patients were higher than in other registries, and the potential benefits of Impella in CS require investigation.


Junior doctors' working hours: perspectives on the reforms.
The European Working Time Directive for junior doctors came into force in Britain in August 2004. The reforms themselves have been a long time in development and implementation since the inception and debates regarding the New Deal, to the current formations under health and safety legislation. This study, undertaken within a hospital trust setting in England, provides an insight into the perspectives of doctors, nurses and human resources managers in relation to the European Working Time Directive. Critical consideration is given to the impact of the reforms upon the National Health Service and more specifically to daily working relationships at the point of implementation. The results demonstrate some ambivalence towards the reforms because of the major shift in culture for the professions per se, but also for the future of health-care delivery where there are considerable tensions.


C3H/HeN mouse model for the evaluation of antiviral agents for the treatment of Venezuelan equine encephalitis virus infection.
The TC-83 vaccine strain of Venezuelan equine encephalitis virus (VEEV) causes encephalitis and death in C3H/HeN mice infected by intranasal (i.n.) instillation. Since TC-83 is exempt as a select agent, this mouse model was used in the evaluation of antiviral therapies. Virus titers in the brains of infected mice peaked on 4 dpi and persisted at high levels until death at 9.4+/-0.5 dpi. Mouse brains appeared histologically normal on 2 dpi, but developed meningoencephalitis, neuropil vacuolation, and gliosis by 8 dpi. Results from a protein cytokine array showed significant elevations over time in interleukin (IL)-1alpha, IL-1beta, IL-6, IL-12, MCP-1, IFNgamma, TNFalpha, MIP-1alpha, and RANTES in homogenized brain samples of infected mice. Immunohistochemical staining showed a colocalization of viral antigen with neuron markers. Treatment with interferon-alpha B/D or ampligen significantly improved survival, brain virus titer and cytokine levels, mean day-to-death, and weight change in infected mice. The time-course of infection and disease parameters of mice infected with TC-83 VEEV were similar in many ways to disease parameters in mice infected with other VEEV strains. Thus, infection of C3H/HeN mice with TC-83 VEEV may serve as a suitable model for the evaluation of antiviral compounds for the treatment of this viral disease.


Allosteric ribozymes sensitive to the second messengers cAMP and cGMP.
We have engineered allosteric ribozymes by combining modular rational design with combinatorial strategies. This new procedure was used to create allosteric ribozymes that are activated by specific nucleoside 3',5'-cyclic monophosphates (cNMPs). A random-sequence domain was attached to stem II of hammerhead ribozymes via a communication module that serves as an interface between ribozyme and the effector binding site. Subjecting this initial random pool to in vitro selection methods produced populations that respond, or cleave, only in the presence of specific effector molecules. From generation 18, 20 and 23, cGMP, cCMP and cAMP-specific responsive ribozymes, respectively, were isolated and characterized. These methods show great promise for engineering allosteric ribozymes and for creating new ligand-specific aptamers.


Current Status of Measurement Accuracy for Total Hemoglobin Concentration in the Clinical Context.
The main objective of this investigation is to provide data about the accuracy of total hemoglobin concentration measurements with respect to clinical settings, and to devices within the categories of point-of-care and reference systems. In particular, tolerance of hemoglobin concentrations below 9 g/dL that have become common in clinical practice today determines the need to demonstrate the limits of measurement accuracy in patient care. Samples extracted from six units of heparinized human blood with total hemoglobin concentrations ranging from 3 to 18 g/dL were assigned to the test devices in a random order. The pool of test devices comprised blood gas analyzers, an automatic hematology analyzer, a laboratory reference method, and the point-of-care system HemoCue. To reduce the pre-analytic error, each sample was measured three times. Due to the characteristics of the tested devices and methods, we selected the mean values of the data from all these devices, measured at the corresponding total hemoglobin concentrations, as the reference. The measurement results of the test devices overlap within strict limits (R2 = 0.999). Only the detailed analysis provides information about minor but systematic deviations. In the group of clinically relevant devices, which are involved in patient blood management decisions, the relative differences were within the limit of +/- 5 % for values down to 3 g/dL. A clinically relevant change of +/- 0.5 g/dL of total hemoglobin concentration can be detected with all selected devices and methods. Compliance with more stringent definitions-these are the relative differences of 5 % in relation to the corresponding reference values and the clinically adapted thresholds in the format of a tolerance level analysis-was achieved by the clinical devices assessed here.


A reconfigurable and programmable FPGA-based system for nonstandard ultrasound methods.
The availability of programmable and reconfigurable ultrasound (US) research platforms may have a considerable impact on the advancement of ultrasound systems technology; indeed, they allow novel transmission strategies or challenging processing methods to be tested and experimentally refined. In this paper, the ULtrasound Advanced Open Platform (ULA-OP), recently developed in our University laboratory, is shown to be a flexible tool that can be easily adapted to a wide range of applications. Five nonstandard working modalities are illustrated. Vector Doppler and quasi-static elastography applications emphasize the real-time potential and versatility of the system. Flow-mediated dilation, pulse compression, and high-frame-rate imaging highlight the flexibility of data access at different points in the reception chain. For each modality, the role played by the onboard programmable devices is discussed. Experimental results are reported, indicating the relative performance of the system for each application.


Characterization of xenotropic and dual-tropic type C retroviruses isolated from Abelson tumour.
Tumours induced in Balb/c mice by Abelson virus complex were found to contain a xenotropic virus (A-X-MuLV) and an NB-tropic, dual-tropic virus (NBX), in addition to the Moloney leukaemia virus (M-MuLV) and the defective, transforming Abelson virus genome. Both A-X-MuLV and NBX virus were presumably present in a genomically masked form and could be recovered only by co-cultivation of tumour cells with permissive cells. Only about 0.87% and 0.13% of the viruses in the co-culture supernatant represented A-X-MuLV and NBX virus respectively; the majority were M-MuLV. The NBX virus acted more efficiently than the HIX virus (Fischinger et al., 1975) as helper to rescue murine sarcoma virus (MSV) from S+L-cells of hamster, rat and mouse origin, whereas the converse was true for those of cat and human origin. The interference and nuetralization patterns suggested that the NBX virus was an env gene recombinant between A-X-MuLV and M-MuLV. The fact that NBX virus cross-reacted in radioimmunoassays with gp70s of both M-MuLV and Balb: virus-2 provides evidence for the recombinant nature of the NBX gp 70-coding gene which was probably derived from both M-MuLV and a virus similar to Balb: virus-2 or A-X-MuLV. The presence of a unique antigenic determinant on the gp70 of NBX virus is also suggested. Both A-X-MuLV and NBX virus cross-reacted with type-specific p12s of M-MuLV and Balb: virus 2- suggesting that the gag gene coding for p12 of NBX virus was derived from the A-X-MuLV, which was itself a recombinant, its p12-coding gene being derived from both Balb: virus-2-like virus and M-MuLV. The NBX virus was not oncogenic when tested in newborn Balb/c mice.


Impacts of Himalayas on black carbon over the Tibetan Plateau during summer monsoon.
The Tibetan Plateau (TP) plays important roles in global climate and environment. This study combines in-situ BC measurements in the Himalayas and the Indo-Gangetic Plain (IGP) with a regional dynamical and chemical model (WRF-Chem model) to investigate the effect of the trans-Himalayas on black carbon (BC) from the IGP to the TP during Indian summer monsoon. To determine topographic effects of the trans-Himalayas on BC concentrations over the TP, sensitive experiments were conducted by applying the WRF-Chem model. The results showed that the reduction of the altitude of the Himalayas had an important effect on the trans-Himalayas transport of BC. There was an obvious increase in BC concentration over the trans-Himalayas region, but no significant increase over the TP because the TP (a.m.s.l ~4km) always acted as a wall to prevent BC transport from the IGP to the TP. The trans-Himalayas transport of BC was strongly dependent upon meteorological conditions over the IGP. During summer monsoon, there were three types of cyclones at different locations and one kind of convergent circulation in the IGP. Under the condition of convergent airflows, a strong northeastward wind produced the trans-Himalayas transport of BC. As a result, BC concentrations in the southeastern TP significantly increased to 0.6-0.8μgm-3. When the cyclone located in the eastern IGP, high BC concentrations over the IGP were transported along the foothill of the Himalayas, resulting in a significant reduction of the trans-Himalayas transport. When the cyclone moved to the west, the dynamical perturbations for the trans-Himalayas transport were weaker than the eastern cyclone, and the trans-Himalayas transport were enhanced in the middle and eastern Himalayas. This study will be helpful to assess the impacts of BC particles emitted from South Asia on regional climate change and ecological environment over the TP in the future.


Seasonal fluctuations in the concentration of UV-absorbing compounds in the leaves of some Mediterranean plants under field conditions.
Leaves of 14 representative Mediterranean plant species were collected on a monthly basis and assayed for UV-absorbing compounds concentration, either on an area or a dry mass basis, from 1995 to 1997. Strong seasonal fluctuations were observed in eight species (all evergreens, two phrygana, one deciduous, one summer perennial and one winter perennial). Two different patterns of changing concentrations of UV-absorbing compounds were observed. In the first, concentration of these compounds was higher in young developing leaves and concentration declined during maturation, whereas in other plants, the opposite trend was observed. These differences could be attributed to the particular leaf surface morphology of each plant. The observed seasonal fluctuations of UV-absorbing compounds seem to be more correlated to developmental processes, than to seasonal fluctuations of the naturally occurring UV-B radiation. Most of the winter perennials did not show strong fluctuations during the period of development. The concentration of these compounds varied not only on a seasonal basis among the examined plants, but between different life forms as well: during winter, examination of the leaves of 13 species showed that evergreen sclerophylls and phrygana had at least two-fold higher concentration of UV-B-absorbing compounds on a leaf area basis than winter perennials. In addition, during the same season and irrespective of life form and species, the absorbance at 300 nm per unit of mature leaf area followed an asymptotic exponential decrease when specific leaf area increased. The UV-B radiation screening capacity of the leaves of these plants is discussed in relation to each adaptive strategy.


Mobile Communication Log Time Series to Detect Depressive Symptoms.
Major Depressive Disorder (MDD) is highly prevalent and characterized by often debilitating behavioral and cognitive symptoms. MDD is poorly understood, likely due to considerable heterogeneity and self-report-driven symptomatology. While researchers have been exploring the ability of machine learning to screen for MDD, much less attention has been paid to individual symptoms. We posit that understanding the relationship between objective data streams and individual depression symptoms is important for understanding the considerable heterogeneity in MDD. Thus, we conduct a comprehensive comparative study to explore the ability of machine learning to predict nine self-reported depressive symptoms with call and text logs. We created time series from the logs of over 300 participants by aggregating communication attributes- average length, count, or contacts- every 4, 6, 12, or 24 hours. We were most successful predicting movement irregularities with a balanced accuracy of 0.70. Further, we predicted suicidal ideation with a balanced accuracy of 0.67. Outgoing texts proved to be the most useful log type. This study provides valuable insights for future mobile health research aimed at personalizing assessment and intervention for MDD.


[Structure and variability of hereditary disease in the Kirov Province].
The main purpose of this report is to present the nosological spectrum of hereditary diseases in 9 Districts of Kirov Province and to compare it with that studies earlier in other Russian populations. This comparison is undertaken in an attempt to define a "nucleus" of hereditary diseases in the Russian population studied. During this study 343 families with 546 affected were registered. The spectrum covered 55 different autosomal dominant, 14 autosomal recessive and 11 X-linked recessive hereditary disorders in the population under study. Some of these forms could be considered as common forms for the whole Russian population, because they were met in all Russian populations which were analysed. This conclusion is proved by the cluster analysis of genetic distances calculated on the basis of gene frequencies for autosomal recessive hereditary disorders.


Enhanced Contactless Heart Rate Monitoring Using Camera with Motion Artifact Removal During Physical Activities.
Contactless monitoring of heart rate (HR) can improve passive and continuous tracking of cardiovascular activities and overall people's health. Remote photoplethysmography (rPPG) using a camera eliminates the need for a wearable device. rPPG-based HR has shown promising results to be accurate and comparable to conventional methods such as contact PPG. Most experiments use stationary subjects while motion is known to affect the accuracy of remote PPG. In this paper, a novel methodology is introduced to enhance the accuracy and reliability of HR monitoring based on rPPG in the presence of physical activities like Yoga. This method quickly and accurately tracks HR and analyzes head motion to exclude unreliable data within short windows of rPPG signals. The method was tested with smartphone video data collected from 60 subjects when they are doing activities with varying levels of movement. Results show that our method without motion removal improves the accuracy of the HR readings by 0.7 bpm, reaching 3.57 bpm on average for a 30-sec-window. The accuracy is further improved by another 1.3 bpm after removing the motion artifacts, and reaches 2.29 bpm.Clinical relevance- The enhancement of HR readings from shorter rPPG signal with motion tolerance during physical activities can ultimately help with a more reliable HR tracking of people in uncontrolled settings like home which is a critical step towards remote health-care or wellness tracking.


Efficient suspension bioreactor expansion of murine embryonic stem cells on microcarriers in serum-free medium.
Large numbers of cells will be required for successful embryonic stem cell (ESC)-based cellular therapies or drug discovery, thus raising the need to develop scaled-up bioprocesses for production of ESCs and their derived progeny. Traditionally, ESCs have been propagated in adherent cultures in static flasks on fibroblasts layers in serum-containing medium. Direct translation of two-dimensional flatbed cultures to large-scale production of the quantities of cells required for therapy simply by increasing the number of dishes or flasks is not practical or economical. Here, we describe successful scaled-up production of ESCs on microcarriers in a stirred culture system in a serum-free medium. Cells expanded on CultiSpher S, Cytodex 3, and Collagen microcarriers showed superior cell-fold expansions of 439, 193, and 68, respectively, without excessive agglomeration, compared with 27 in static culture. In addition, the ESCs maintained their pluripotency after long-term culture (28 days) in serum-free medium. This is the first time mESCs have been cultured on microcarriers without prior exposure to serum and/or fibroblasts, while also eliminating the excessive agglomeration plaguing earlier studies. These protocols provide an economical, practical, serum-free means for expanding ESCs in a stirred suspension bioprocess.


Evaluation of left ventricular mechanical dyssynchrony with phase analysis in end-stage renal disease patients with normal gated SPECT-MPI.
Phase analysis using gated single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) is a relatively new tool for the assessment of ventricular synchrony. Hypertension, diabetes, renal diseases, and dyslipidemia may affect the phase parameters though their impact is not well understood. The present study aimed to evaluate the incidence of the left ventricular mechanical dyssynchrony (LVMD) in end-stage renal disease (ESRD) patients with normal gated SPECT-MPI and QRS duration (<120 ms) on electrocardiogram. Data of 129 patients (86 males) referred for gated SPECT-MPI for their pretransplant evaluation with normal gated stress SPECT-MPI (SSS <3 and ejection fraction ≥50%) were included in the study analysis. Documented clinical history along with confounding factors such as hypertension, dyslipidemia, smoking, and alcoholism were evaluated. Left ventricle functional (end-diastolic, end-systolic, and LV myocardial volume) and phase parameters (phase standard deviation [PSD], phase bandwidth [PBW] and entropy) were calculated using the QPS-QGS program. LVMD was noted in 36 (28%) of ESRD patients with normal QRS duration and gated SPECT-MPI. The mean attenuated corrected LV myocardial volume, ejection fraction, mean PSD, and PBW values were 84.3 ± 38.1 ml, 65.3 ± 13.5%, 9.8° ± 3.9°, and 61.4° ± 24.7°, respectively. The LV myocardial volume shows statistically significant correlation with the phase parameters (r = 0.31-0.47; P < 0.001). LVMD is present in a significant number of ESRD patients, and its extent is more with increase in LV myocardial volume. It may have an additional role in risk-stratification for cardiovascular disease in ESRD patients.


The scaffold role of the fibrous sheath.
The fibrous sheath (FS) is a novel structural feature in the principal piece region of the sperm flagellum in marsupial and eutherian mammals. It begins anteriorly at the annulus, is composed of two longitudinal columns connected by circumferential ribs, and surrounds the outer dense fibers in the principal piece. The formation of the FS was described eloquently nearly twenty-five years ago, but the identification of its components has occurred only during the last few years. Most of the genes encoding the known FS components are expressed during the postmeiotic period of spermatogenesis, are expressed only in spermatogenic cells, and are either novel genes or paralogues of genes expressed in somatic cells. The proteins of the FS can be classified in nine categories based on their functional or structural roles. Most of these are resistant to solubilization and remain in the FS during rigorous isolation procedures. Mouse sperm with a knock out of the gene encoding GAPDHS are immotile, which demonstrates that most of the ATP needed for sperm motility is generated by glycolysis. Most of the glycolytic enzymes have been localised to the principal piece and some are tightly associated with the FS. However, the nature of the protein-protein interactions involved in assembly and maintenance of FS are known for only a few of the component proteins.


Cartier loop biopsy of the cervix: a retrospective study of 6 months' experience with a one-year follow-up.
Ninety-six women with cervical pathology underwent Cartier loop biopsy at Christchurch Women's Hospital, during the first 6 months of 1987. Eighty-four (88%) patients had full follow-up past 11 months, of whom 10 (12%) had dysplasia/CIN. Initial follow-up (3-8 months) was achieved in 91 (95%) patients, of whom 11 (12%) had dysplasia/CIN. Follow-up was predominantly by cytology. These rates were not significantly influenced by any single preoperative or operative factor. The implications of these results are discussed.


[Structural organization of choroid plexus primordium in human telencephalon].
Using the methods of light and electron microscopy and immunocytochemistry, the structure of choroid plexus primordium of telencephalon (epithelial plate) was studied in human embryos at weeks 5-6 of development. It was established that at this stage human choroid plexus primordium is an area of active morphogenesis. Rapid changes in its configuration in the course of choroid plexus formation are preceded by a suppression of proliferation and an activation of degenerative processes. Ultrastructural organization of choroid plexus primordium and specific structural features of its cells indicate that the tissue, forming the epithelial plate, substantially differs from the neuroepithelium that forms the primordia of hippocampus and neocortex, already at this very early stage of prenatal ontogenesis. Accumulation of p53 and bcl-2, proteins participating in apoptosis control, is the evidence of a special functional state of this morphogenetic zone, the detailed characteristic of which requires further research applying a wider spectrum of functional markers.


SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling.
Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of 'imprinting' by cytokines of the TGF-β family. We studied mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-β family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection. Mechanistically, SMAD4 restrained non-canonical TGF-β signaling mediated by the cytokine receptor TGFβR1 in NK cells. NK cells from a SMAD4-deficient person affected by polyposis were also hyper-responsive to TGF-β. These results identify SMAD4 as a previously unknown regulator that restricts non-canonical TGF-β signaling in NK cells.


Alternative reactions at the interface of glycolysis and citric acid cycle in Saccharomyces cerevisiae.
Pyruvate and acetyl-coenzyme A, located at the interface between glycolysis and TCA cycle, are important intermediates in yeast metabolism and key precursors for industrially relevant products. Rational engineering of their supply requires knowledge of compensatory reactions that replace predominant pathways when these are inactivated. This study investigates effects of individual and combined mutations that inactivate the mitochondrial pyruvate-dehydrogenase (PDH) complex, extramitochondrial citrate synthase (Cit2) and mitochondrial CoA-transferase (Ach1) in Saccharomyces cerevisiae. Additionally, strains with a constitutively expressed carnitine shuttle were constructed and analyzed. A predominant role of the PDH complex in linking glycolysis and TCA cycle in glucose-grown batch cultures could be functionally replaced by the combined activity of the cytosolic PDH bypass and Cit2. Strongly impaired growth and a high incidence of respiratory deficiency in pda1Δ ach1Δ strains showed that synthesis of intramitochondrial acetyl-CoA as a metabolic precursor requires activity of either the PDH complex or Ach1. Constitutive overexpression of AGP2, HNM1, YAT2, YAT1, CRC1 and CAT2 enabled the carnitine shuttle to efficiently link glycolysis and TCA cycle in l-carnitine-supplemented, glucose-grown batch cultures. Strains in which all known reactions at the glycolysis-TCA cycle interface were inactivated still grew slowly on glucose, indicating additional flexibility at this key metabolic junction.


Investigation of mouth washing by patients after inhaling corticosteroids.
We report an effective method for mouth washing after inhalation of corticosteroids for the prevention of local adverse effects such as hoarseness and oropharyngeal candidiasis. This method involves gargling and rinsing immediately after inhalation, repeated at least twice. We performed a questionnaire survey on mouth washing after inhalation of corticosteroids of 19 inpatients who used inhaled corticosteroids at the University of Tokyo Hospital. The questions concerned: 1) awareness of local adverse effects of inhaled corticosteroids; 2) gargling and rinsing habits; 3) repeating mouth washing at least twice; and 4) mouth washing immediately after inhalation. The percentage of patients correctly performing the individual maneuvers were: 1) 63.2%; 2) 36.8%; 3) 36.8%; and 4) 63.2%. The percentage of patients performing our recommended method of mouth washing (all four elements) was 11%. These results suggest that patients receiving inhaled corticosteroids poorly comprehend mouth washing procedures after inhalation of corticosteroids. It is important that pharmacists advise patients on the correct method of mouth washing.


Organochlorines and breast cancer: the uses of scientific evidence in claimsmaking.
This paper explores the role and utilization of scientific evidence concerning one of the potential adverse health impacts (breast cancer) of the use of chlorine through examining the aims of an environmental group, Greenpeace, and its opponents. Specifically, the paper identifies the claims of Greenpeace and the scientific evidence used to justify those claims in its (Thornton, 1993) report Chlorine, Human Health and the Environment: The Breast Cancer Warning. A media analysis was conducted over a ten year period to assess what counter-claims were generated. The claimsmaking activities of breast cancer advocacy groups, scientists, pro-chlorine groups, and environmentalists were monitored. To counter the Greenpeace claims, pro-chlorine supporters argued for the responsible use of science, and redefined the chlorine issue as one of public health and economic security. The counter-claims between the supporters and the opponents of the chlorine issue stemmed from differences in their agendas, values, and solutions proffered in the environmental health policy domain.


Carbapenem Antibiotics for the Empiric Treatment of Nosocomial Pneumonia: A Systematic Review and Meta-analysis.
Previous meta-analyses suggested that treating hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), with empiric carbapenems was associated with lower mortality rates but higher rates of clinical failure for pseudomonal pneumonia. This study was an updated meta-analysis with sensitivity analyses and meta-regression to better understand the impact of carbapenem use in HAP/VAP. What is the efficacy of carbapenems for empiric treatment of nosocomial pneumonia? Databases were searched for randomized controlled studies evaluating empiric treatment for HAP and/or VAP, and studies were included comparing carbapenem- vs non-carbapenem-containing regimens. The primary outcome was all-cause mortality. Secondary outcomes included subgroup stratification and resistance development. Of 9,140 references, 20 trials enrolling 5,489 patients met inclusion criteria. For mortality, carbapenem use had a risk ratio (RR) of 0.84 (95% CI, 0.74-0.96; P = .01). Stratified according to VAP proportion (< 33%, 33%-66%, and > 66%), RRs were 0.95 (95% CI, 0.77-1.17; P = .66), 0.78 (95% CI, 0.57-1.07; P = .13), and 0.81 (95% CI, 0.65-0.99; P = .04), respectively. Stratified according to severity, only groups with Acute Physiology and Chronic Health Evaluation II scores < 14 and between 14 and 17 showed mortality benefit (RRs of 0.64 [95% CI, 0.45-0.92; P = .01] and 0.77 [95% CI, 0.61-0.97; P = .03]). Meta-regression did not show an association between Pseudomonas prevalence and mortality (P = .44). Carbapenem use showed a trend toward developing resistance (RR, 1.40; 95% CI, 0.95-2.06; P = .09) and a 96% probability of resistance emergence. Carbapenem-based empiric regimens were associated with lower mortality rates compared with non-carbapenems, largely driven by trials of VAP. The mortality effect was not observed in trials with high disease severity and was not associated with Pseudomonas. The mortality difference was observed mainly in studies that used ceftazidime as control. There was a trend toward increasing resistance associated with carbapenems. International Prospective Register of Systematic Reviews; No. CRD42018093602; URL: https://www.crd.york.ac.uk/prospero/.


Postresectional anemia. A preventable complication of total gastrectomy.
The incidence of anemia after total gastrectomy has not received sufficient clinical emphasis. During a follow-up period averaging 32 months, postresectional anemia developed in seven of ten patients without evidence of malignant neoplasm; all but one of these patients had received parenterally administered cyanocobalamin. Despite low levels of circulating erythrocytes and proportionately increased erythropoietin levels, reticulocytosis was not evident. This observation suggests an uncharacterized failure of marrow erythyroid precursors. Multiple deficits in intake of constituents necessary for the production of erythrocytes were demonstrated. With the possible exception of iron, malabsorption of these constituents is not an important factor in the production of anemia. Postresectional anemia is multicausal, but is primarily nutritional. As total gastrectomy becomes more commonly employed in the treatment of nonmalignant conditions, recognition of the frequency and causes of postresectional anemia should assist both diagnostic anticipation and therapy.


Visual capture of action, experience of ownership, and the illusion of self-touch: a new rubber hand paradigm.
A new rubber hand paradigm evokes an illusion with three conceptually distinct components: (i) the participant experiences her/his hidden right hand as administering touch at the location of the examiner's viewed administering hand (visual capture of action); (ii) the participant experiences the examiner's administering hand as being the participant's own hand (experience of ownership); and (iii) the participant experiences her/his two hands as being in contact, as if she/he were touching her/his own hand (illusion of self-touch). The presence of these illusory experiences was confirmed by questionnaire responses and proprioceptive drift data.


The use of sliding time windows for the exploratory analysis of temporal effects of smoking histories on lung cancer risk.
To examine the time-dependent effects of exposure histories on disease we use sliding time windows as an exploratory alternative to the analysis of variables like time since last exposure and duration of exposure. The method fits a series of risk models which contain total cumulative exposure and an additional covariate for exposures received during fixed time intervals. Characteristics of the fitted models provide insight into the influence of exposure increments at different times on disease risk. A simulation study is performed to check the validity of the approach. We apply the method to data from a recent German case-control study on smoking and lung cancer risk with about 4300 lung cancer cases and a similiar number of controls. The sliding time window approach indicates that the amount of cigarettes smoked from two to 11 years before disease incidence is most predicitive of lung cancer incidence. Among different smoking profiles that result in the same lifelong cumulative number of cigarettes smoked, those with a concentration of smoked cigarettes within 20 years before interview bear substantially larger risk than others.


Visual Distraction's "Silver Lining": Distractor Suppression Boosts Attention to Competing Stimuli.
Efficient search of the environment requires that people attend to the desired elements in a scene and ignore the undesired ones. Recent research has shown that this endeavor can benefit from the ability to proactively suppress distractors with known features, but little is known about the mechanisms that produce the suppression. We show here in five experiments (N = 120 college students) that, surprisingly, identification of a sought-for target is enhanced when it is grouped with a suppressed distractor compared with when it is in a different perceptual group. The results show that the suppressive mechanism not only downweights undesired elements but also enhances responses to task-relevant elements in competition for attention with the distractor, fine tuning the suppression. The findings extend the understanding of how people efficiently process their visual world.


Training in using earplugs or using earplugs with a higher than necessary noise reduction rating? A randomized clinical trial.
Noise-induced hearing loss (NIHL) is one of the most common occupational diseases and the second most common cause of workers' claims for occupational injuries. Due to high prevalence of NIHL and several reports of improper use of hearing protective devices (HPDs), we conducted this study to compare the effect of face-to-face training in effective use of earplugs with appropriate NRR to overprotection of workers by using earplugs with higher than necessary noise reduction rating (NRR). In a randomized clinical trial, 150 workers referred to occupational medicine clinic were randomly allocated to three arms---a group wearing earplugs with an NRR of 25 with no training in appropriate use of the device; a group wearing earplugs with an NRR of 25 with training; another group wearing earplugs with an NRR of 30, with no training. Hearing threshold was measured in the study groups by real ear attenuation at threshold (REAT) method. This trial is registered with Australian New Zealand clinical trials Registry, number ACTRN00363175. The mean ± SD age of the participants was 28 ± 5 (range: 19-39) years. 42% of participants were female. The mean noise attenuation in the group with training was 13.88 dB, significantly higher than those observed in other groups. The highest attenuation was observed in high frequencies (4, 6, and 8 kHz) in the group with training. Training in appropriate use of earplugs significantly affects the efficacy of earplugs---even more than using an earplug with higher NRR.


Changes of HCO3-/Cl- exchanger activity during meiotic maturation in Balb/c strain mouse oocytes and zygotes.
Intracellular pH-regulatory mechanisms are acquired by growing mouse oocytes with meiotic competence, and these mechanisms become fully active when the oocytes develop to the germinal vesicle (GV) stage as shown in CF1 and Balb/c strains mice. On the other hand, there is some evidence showing that intracellular pH-regulatory mechanisms are inhibited at the stages of Metaphase I (MI) and II (MII) oocytes in the CF1 strain mouse and hamster. Since it has been shown that the intracellular pH regulatory mechanism can be functionally different among mouse strains (e.g., CF1, Balb/c), the aim of this study was to investigate the activity of HCO3-/Cl- exchanger (anion exchanger, AE), which protects cells against alkalosis during the meiotic maturation process, in the GV oocyte up to the pronuclear (PN) zygote derived from the Balb/c strain mouse. Intracellular pH (pHi) was recorded using a microspectrofluorometric technique during meiotic maturation stages. KSOM-based solutions were used as culture and recording solutions. AE activity was determined using a Cl- removal assay and was reported as the change in pHi per minute. AE activity was high in GV stage oocytes but was significantly inhibited at the MI and MII stages. AE activity was higher in the PN zygote stage. This activity was significantly inhibited in all oocyte and zygote stages by 4,4'-Diisocyanatostilbene-2,2'-disulfonic acid disodium salt. After alkalosis induction, the pHi of MI and MII stage oocytes did not completely recover; however, almost complete recovery occurred in the GV stage oocytes and PN zygotes. These results suggest that AE is inhibited during the meiotic maturation process in the Balb/c strain mouse.


Plasma sex steroid hormones and breast cancer risk in Chinese women.
Estrogens regulate the growth and differentiation of mammary cells and play an important role in the development of breast cancer. High circulating levels of estrogens are associated with increased risk of breast cancer in Caucasian women. Because Asian women have low estrogens in the circulation compared with their Caucasian counterparts, the effect of estrogens on breast cancer risk in populations with low circulating estrogens remains to be elucidated. We conducted a population-based case-control study in China to evaluate the association of sex steroid hormones with breast cancer risk in Chinese women. Our study included 300 incident cases with primary breast cancer and 300 age- and menopausal status-matched healthy controls randomly selected from the general population in Shanghai. Fasting blood samples were collected from cases prior to any treatment and from their matched controls. Commercial immunoassays were used to measure plasma concentrations of estradiol, estrone, estrone sulfate, testosterone, progesterone, dehydroepiandrosteindian sulfate (DHEA-S) and steroid hormone-binding globulin (SHBG). Conditional logistic regression analysis was performed to examine the association between steroid hormones and breast cancer risk. The results showed that breast cancer risk was elevated with increasing levels of estrone and testosterone (p for trend < 0.05) but not with DHEA-S, estradiol, estrone sulfate, progesterone or SHBG. The estimated relative risks between upper and lower tertiles were 2.07 (95% confidence interval [CI] 0.97-4.41) for estrone in postmenopausal women, 2.01 (95% CI 0.96-4.21) for testosterone in premenopausal women, and 2.40 (95% CI 1.11-5.21) for testosterone in postmenopausal women, after adjusting for age at first live birth, waist-to-hip ratio, total calorie intake, a history of fibroadenoma, a family history of breast cancer and SHBG. These results, in general, are consistent with the findings in Caucasian women and indicate that high sex steroid hormones in the circulation, both androgen and estrogen, are associated with increased risk of breast cancer even in populations with relatively low sex hormones.


The herpes simplex virus type 1 alpha protein ICP27 can act as a trans-repressor or a trans-activator in combination with ICP4 and ICP0.
The herpes simplex virus type 1 (HSV-1) alpha proteins ICP4, ICP0, and ICP27 are trans-acting proteins which affect HSV-1 gene expression. To investigate potential interactions between these alpha products and to determine the specificity of action of the alpha proteins in combination with each other compared with their activities individually, we performed a series of transient-expression assays. In these assays we used plasmids containing the alpha genes encoding ICP4, ICP0, and ICP27 either singly or in combination as effectors and HSV-1 genes of different kinetic classes and heterologous genes as targets. The HSV-1 targets consisted of promoter-regulatory domains from alpha (ICP0 and ICP27), beta (thymidine kinase and alkaline exonuclease), beta-gamma (glycoprotein D, glycoprotein B, and VP5), and gamma (glycoprotein C) genes, each fused to the chloramphenicol acetyltransferase (CAT) gene. The heterologous target genes consisted of the simian virus 40 early promoter with enhancer and the Rous sarcoma virus long terminal repeat promoter and enhancer each fused to the CAT gene. Target promoter activity was measured by the assay of CAT activity in extracts of transfected cells and by Northern (RNA) blot hybridization of CAT mRNA. The results of these experiments showed that ICP4 activated only HSV-1 target genes, whereas ICP0 activated all of the targets and ICP27 had little effect on any of the targets. ICP4 and ICP0 had a synergistic effect when inducing HSV-1 targets, but they did not have this effect on the heterologous targets pSV2-CAT or pRSV-CAT. In fact, lower levels of CAT activity and CAT mRNA were found in the presence of both effectors than with ICP0 alone. Most interestingly, although the effector plasmid containing the ICP27 gene had little effect on its own, two different and marked effects depending on the target were observed when ICP27 was combined with ICP4 or ICP0 or both. A trans-repression of the induction seen with ICP4 and ICP0 was found when ICP27 was present in the transfections with pSV2-CAT, pRSV-CAT, pICP0-CAT, pICP27-CAT, pTK-CAT, pgD-CAT, pgB-CAT, and pgC-CAT. This resulted in CAT activity levels which were similar to or lower than the basal level of expression of the target genes in the absence of effector plasmids. This trans-repression occurred over a wide range of concentrations of input ICP27 plasmid. In contrast to this repressive effect of ICP27, a trans-activation was seen when ICP4, ICP0, and ICP27 plasmids were combined in transfections with pAE-CAT and pVP5-CAT as targets. This trans-activation also occurred over a 10-fold range of input ICP27 plasmid. These results suggest that ICP27 can facilitate both down


Multidirectional Pathways between Attachment, Mentalizing, and Posttraumatic Stress Symptomatology in the Context of Childhood Trauma.
Exposure to traumatic stressful events in childhood is an important risk factor for the development of posttraumatic symptomatology. From a mentalization-based developmental perspective, childhood adversity can affect attachment in children and may result in insecure attachment and impaired mentalizing abilities, which increase the lifetime risk for psychopathology. The present cross-sectional study examined the potential mediating role of attachment insecurity and impaired mentalizing on the relationship between childhood trauma and posttraumatic symptomatology. Adults who had experienced childhood neglect and abuse (n = 295, 184 patients with personality disorder and 111 community controls) completed self-report measures of posttraumatic stress disorder (PTSD) symptoms, dissociative experiences, adult attachment insecurity, and mentalizing. Structural equation modelling results revealed that attachment insecurity together with lower mentalizing mediated the link between childhood trauma and PTSD symptoms, and lower mentalizing mediated the link between childhood trauma and dissociative experiences. The findings show that attachment insecurity and lower mentalizing play significant mediating roles in the reporting of posttraumatic symptomatology among survivors of childhood abuse and neglect, with treatment implications for mentalization-based therapy as beneficial for individuals with a history of childhood trauma.


Wireless, Battery-Free Implants for Electrochemical Catecholamine Sensing and Optogenetic Stimulation.
Neurotransmitters and neuromodulators mediate communication between neurons and other cell types; knowledge of release dynamics is critical to understanding their physiological role in normal and pathological brain function. Investigation into transient neurotransmitter dynamics has largely been hindered due to electrical and material requirements for electrochemical stimulation and recording. Current systems require complex electronics for biasing and amplification and rely on materials that offer limited sensor selectivity and sensitivity. These restrictions result in bulky, tethered, or battery-powered systems impacting behavior and that require constant care of subjects. To overcome these challenges, we demonstrate a fully implantable, wireless, and battery-free platform that enables optogenetic stimulation and electrochemical recording of catecholamine dynamics in real time. The device is nearly 1/10th the size of previously reported examples and includes a probe that relies on a multilayer electrode architecture featuring a microscale light emitting diode (μ-LED) and a carbon nanotube (CNT)-based sensor with sensitivities among the highest recorded in the literature (1264.1 nA μM-1 cm-2). High sensitivity of the probe combined with a center tapped antenna design enables the realization of miniaturized, low power circuits suitable for subdermal implantation even in small animal models such as mice. A series of in vitro and in vivo experiments highlight the sensitivity and selectivity of the platform and demonstrate its capabilities in freely moving, untethered subjects. Specifically, a demonstration of changes in dopamine concentration after optogenetic stimulation of the nucleus accumbens and real-time readout of dopamine levels after opioid and naloxone exposure in freely behaving subjects highlight the experimental paradigms enabled by the platform.


Bifunctional nanoparticles for SERS monitoring and magnetic intervention of assembly and enzyme cutting of DNAs.
The ability to harness the nanoscale structural properties is essential for the exploration of functional properties of nanomaterials. This report demonstrates a novel strategy exploring bifunctional nanoparticles for spectroscopic detection and magnetic intervention of DNA assembly, disassembly, and enzyme cutting processes in a solution phase. In contrast to existing single-function based approaches, this strategy exploits magnetic MnZn ferrite nanoparticles decorated with gold or silver on the surface to retain adequate magnetization while producing sufficient plasmonic resonance features to impart surface-enhanced Raman scattering (SERS) functions. The decoration of MnZn ferrite nanoparticles with Au or Ag (MZF/Au or MZF/Ag) was achieved by thermally activated deposition of Au or Ag atoms/nanoparticles on MZF nanoparticles. Upon interparticle double-stranded DNA linkage of the MZF/Au (or MZF/Ag) nanoparticles with gold nanoparticles labeled with a Raman reporter, the resulting interparticle "hot spots" are shown to enable real time SERS monitoring of the DNA assembly, disassembly, or enzyme cutting processes, where the magnetic component provides an effective means for intervention of the biomolecular processes in the solution. The unique bifunctional combination of the SERS "hot spots" and the magnetic separation capability serves as the first example of bifunctional nanoprobes for biomolecular recognition and intervention.


Genomic landscape of paediatric adrenocortical tumours.
Paediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyse 37 adrenocortical tumours (ACTs) by whole-genome, whole-exome and/or transcriptome sequencing. Most cases (91%) show loss of heterozygosity (LOH) of chromosome 11p, with uniform selection against the maternal chromosome. IGF2 on chromosome 11p is overexpressed in 100% of the tumours. TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 are observed in 28 ACTs (76%). Chromosomes 11p and 17 undergo copy-neutral LOH early during tumorigenesis, suggesting tumour-driver events. Additional genetic alterations include recurrent somatic mutations in ATRX and CTNNB1 and integration of human herpesvirus-6 in chromosome 11p. A dismal outcome is predicted by concomitant TP53 and ATRX mutations and associated genomic abnormalities, including massive structural variations and frequent background mutations. Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in paediatric ACT and outline a hypothetical model of paediatric adrenocortical tumorigenesis.


The evolutionary role of gravity.
Analysis of the part played by gravity in development in the organic world shows that this factor has had an impact on evolution. All terrestrial organisms, including man, have adapted themselves to gravity by developing a number of important features of their composition and functions. Variations of gravitational field in any direction bring about numerous changes in organisms, ranging from metabolism to changes in more conservative systems which also include hereditary structures. Gravitational forces determine the form and the size of organisms, the development of skeletal supporting organs, and energetics. The study of the role of gravity in the variability of the organic world will be of great importance for long-term systems of life support and for work on space orbital stations or at bases on the moon and planets where gravitational forces may differ greatly those from on the earth.


From elementary flux modes to elementary flux vectors: Metabolic pathway analysis with arbitrary linear flux constraints.
Elementary flux modes (EFMs) emerged as a formal concept to describe metabolic pathways and have become an established tool for constraint-based modeling and metabolic network analysis. EFMs are characteristic (support-minimal) vectors of the flux cone that contains all feasible steady-state flux vectors of a given metabolic network. EFMs account for (homogeneous) linear constraints arising from reaction irreversibilities and the assumption of steady state; however, other (inhomogeneous) linear constraints, such as minimal and maximal reaction rates frequently used by other constraint-based techniques (such as flux balance analysis [FBA]), cannot be directly integrated. These additional constraints further restrict the space of feasible flux vectors and turn the flux cone into a general flux polyhedron in which the concept of EFMs is not directly applicable anymore. For this reason, there has been a conceptual gap between EFM-based (pathway) analysis methods and linear optimization (FBA) techniques, as they operate on different geometric objects. One approach to overcome these limitations was proposed ten years ago and is based on the concept of elementary flux vectors (EFVs). Only recently has the community started to recognize the potential of EFVs for metabolic network analysis. In fact, EFVs exactly represent the conceptual development required to generalize the idea of EFMs from flux cones to flux polyhedra. This work aims to present a concise theoretical and practical introduction to EFVs that is accessible to a broad audience. We highlight the close relationship between EFMs and EFVs and demonstrate that almost all applications of EFMs (in flux cones) are possible for EFVs (in flux polyhedra) as well. In fact, certain properties can only be studied with EFVs. Thus, we conclude that EFVs provide a powerful and unifying framework for constraint-based modeling of metabolic networks.


Phytochemical and Biological Profile of Moricandia arvensis (L.) DC.: An Inhibitor of Pancreatic Lipase.
Pancreatic lipase, a key enzyme for lipid absorption, is one of the most important targets for the treatment of obesity, while natural compounds have recently attracted much interest as potential inhibitors of this enzyme. Here, in an attempt to find new effective agents, the methanolic extract from Moricandia arvensis (L.) DC. and its sub-extracts were investigated for their potential inhibitory activity. The ability to inhibit pancreatic lipase was verified through the in vitro evaluation of the prevention of p-nitrophenyl caprylate hydrolysis. The antioxidant activity was also verified by means of DPPH and β-carotene bleaching tests. Compositional profiling revealed that flavonoid glycosides were the main specialized metabolites present in the methanolic extract from the aerial parts of the plant with kaempferol and quercetin representing the two O-glycosylated aglycones. Kaempferol-3-O-β-(2″-O-glucosyl)-rutinoside and kaempferol-3-O-a-arabinosyl-7-O-rhamnoside were the most abundant flavonols. The crude methanolic extract and the dichloromethane and ethyl acetate sub-extracts showed a strong lipase inhibitory activity, with IC50 values of 2.06 ± 0.02, 1.52 ± 0.02 and 1.31 ± 0.02 mg/mL, respectively. The best capacity to scavenge DPPH radical was detected for the ethyl acetate sub-extract (IC50 = 171.9 ± 1.0 µg/mL), which was also effective in protecting linoleic acid from peroxidation (IC50 = 35.69 ± 2.30 µg/mL). Obtained results support the hypothesis that M. arvensis can be a source of bioactive phytochemicals for the pharmacological inhibition of dietary lipids absorption.


A phase II study for metabolic in vivo response monitoring with sequential 18FDG-PET-CT during treatment with the EGFR-monoclonal-antibody cetuximab in metastatic colorectal cancer: the Heidelberg REMOTUX trial.
The epidermal growth factor receptor monoclonal antibody cetuximab has proven activity in metastatic colorectal cancer. To date, the mechanisms of action are not completely understood. Especially the impact on tumor glucose metabolism, or tumor vascularization remains largely unclear. The understanding of mechanisms such as early changes in tumor metabolism is of clinical importance since there may be a substantial influence on choice and sequence of drug combinations. Early signals of response to cetuximab may prove useful to identify patients having a relevant clinical treatment benefit. The objective of this trial is to evaluate the predictive relevance of the relative change in (18)F-Fluorodeoxyglucose tumor uptake for early clinical response during short-term single agent treatment with cetuximab. Early clinical response will be routinely measured according to the response evaluation criteria in solid tumors. Accompanying research includes cytokine immune monitoring and analysis of tumor proteins and tumor genes. The REMOTUX trial is an investigator-initiated, prospective, open-label, single-arm, single-center early exploratory predictive study. The first (18)F-FDG PET-CT is conducted at baseline followed by the run-in phase with cetuximab at days 1 and 8. At day 14, the second (18)F-FDG PET-CT is performed. Subsequently, patients are treated according to the Folfiri-cetuximab regimen as an active and approved first-line regimen for metastatic colorectal carcinoma. At day 56, clinical response is evaluated with a CT-scan compared to the baseline analysis. Tracer uptake is assessed using standardized uptake values (SUVs). The main hypothesis to be tested in the primary analysis is whether or not the relative change in the SUV from baseline to day 14 has any predictive relevance for early clinical response determined at day 56. Patients are followed until death from any cause or until 24 months after the last patient has ended trial treatment. The aim of this trial is to evaluate metabolic changes in metastatic colorectal cancer during short-term single agent treatment with cetuximab and to analyse their potential of predicting early clinical response. This could be helpful to answer the question if early identification of patients not responding to cetuximab is possible. ClinicalTrials.gov NCT200811021020; EudraCT 200901327923.


Prenatal and lactational exposure to methylmercury affects select parameters of mouse cerebellar development.
Animal studies of the neuropathological effects of prenatal methylmercury (MeHg) seldom use regimens that represent environmental exposures. While acute administration of high doses of MeHg to developing rodents can model some of the outcomes MeHg produces in the human cerebellum, their long-term relevance to cerebellar development is unknown. The present study was undertaken to determine the effect of chronic dietary exposure to MeHg. Pregnant mice were exposed throughout gestation to 0.0 or 4.0 ppm methylmercury in their drinking water. Postpartum exposure of pups and lactating dams continued to postnatal day (PND) 30. On PND7, 14, 21, and 30, several morphometric indices of cerebellar cortex development, as well as blood and brain levels of total Hg, were measured in pairs of male and female littermates. No signs of overt toxicity were observed in the dams or offspring. Blood and brain levels of total Hg were highest in the exposed PND7 offspring and fell throughout the sampling period despite continued exposure. In a region of molecular layer in the anterodorsal lobe, MeHg exposure reduced the density of migrating cells in PND7 offspring. Molecular layer widths were reduced in PND30 offspring. In a region of the inferior lobe of PND7 offspring, MeHg exposure reduced external granular layer widths and decreased the density of migrating cells in the molecular layer. However, MeHg did not affect cerebellar cortex development in the central lobe, suggesting a regional sensitivity to chronic, low-level MeHg exposure during development.


Analysis of Gender Perceptions in Health Technology: A Call to Action.
Gender diversity has been linked to positive business results. Yet limited data exist to characterize the gender landscape in health technology, a field that draws employees from both biomedical engineering and medicine. To better understand the state of gender diversity in this industry, we developed a survey to explore leadership representation and perceptions of workplace equality, job satisfaction, and work-life balance. Data from 400 + health technology professionals revealed that women are significantly underrepresented in senior leadership and that men and women experience the workplace differently. Men believe in greater numbers than females that senior leaders are focused on recruiting and promoting women, promotion criteria are equitable, and the major barrier to leadership roles for women is work/family balance. In contrast, women perceive a less meritocratic and inclusive workplace in which their ability to rise is hampered by exclusion from influential communication networks and stereotyping/bias. Perhaps as a result, more than one-third of female respondents are considering leaving their current jobs, citing dissatisfaction with management and a desire for greater advancement opportunities. This study highlights significant gender perception differences in health technology that require further study and proactive remediation for the field to fully realize the benefits of gender diversity.


Nonenzymatic lipid mediators, neuroprostanes, exert the antiarrhythmic properties of docosahexaenoic acid.
Neuroprostanes are lipid mediators produced by nonenzymatic free radical peroxidation of docosahexaenoic acid (DHA). DHA is associated with a lower atherosclerosis risk, suggesting a beneficial role in cardiovascular diseases. The aim of this study was to investigate the influence of DHA peroxidation on its potentially antiarrhythmic properties (AAP) in isolated ventricular cardiomyocytes and in vivo in post-myocardial infarcted mice. Calcium imaging and biochemical experiments indicate that cardiac arrhythmias induced by isoproterenol are associated with Ca(2+) leak from the sarcoplasmic reticulum after oxidation and phosphorylation of the type 2 ryanodine receptor (RyR2) leading to dissociation of the FKBP12.6/RyR2 complex. Both oxidized DHA and 4(RS)-4-F4t-NeuroP prevented cellular arrhythmias and posttranslational modifications of the RyR2 leading to a stabilized FKBP12.6/RyR2 complex. DHA per se did not have AAP. The AAP of 4(RS)-4-F4t-NeuroP was also observed in vivo. In this study, we challenged the paradigm that spontaneously formed oxygenated metabolites of lipids are undesirable as they are unconditionally toxic. This study reveals that the lipid mediator 4(RS)-4-F4t-neuroprostane derived from nonenzymatic peroxidation of docosahexaenoic acid can counteract such deleterious effects through cardiac antiarrhythmic properties. Our findings demonstrate 4(RS)-4-F4t-NeuroP as a mediator of the cardioprotective AAP of DHA. This discovery opens new perspectives for products of nonenzymatic oxidized ω3 polyunsaturated fatty acids as potent mediators in diseases that involve ryanodine complex destabilization such as ischemic events.


Interactions between local medical systems and the biomedical system: a conceptual and methodological review in light of hybridization subprocesses.
Local medical systems (LMSs) are complex and dynamic, encompassing local perceptions of diseases, prevention and treatment strategies, and evaluations of therapeutic responses. These systems are not isolated and interact with other medical systems, such as the biomedical system. The interaction between these systems creates a "contact zone", which some authors refer to as intermedicality, involving both competitive and complementary interactions. However, there is limited discussion in the literature regarding the complexity of these interactions. Some studies seek to understand this interaction through the lens of hybridization, a concept introduced to ethnobiology by Ana Ladio and Ulysses Albuquerque. The authors conceptualize hybridization as "discrete structures and practices coming together to form a new practice not necessarily implying homogenization." They discuss hybridization in the context of medicinal plants used in urban settings and propose seven hybridization subprocesses to gain a deeper understanding of this phenomenon. In this study, we update these hybridization subprocesses, expanding the concepts to comprehend the specific interaction of resources from LMS and biomedical systems known and used by different human groups. In this context, we propose a new subprocess and have made adjustments to the existing subprocesses to encompass the diversity of possible interactions between medicinal plants and pharmaceuticals, providing evidence from the literature demonstrating interactions that can be classified within the proposed subprocesses. Furthermore, we discuss, from a theoretical standpoint, how these subprocesses may have implications for the resilience of medical systems. Moreover, we propose a flowchart that can be utilized to identify these hybridization subprocesses in intermedicality contexts in future studies. These classifications are crucial because they enable us to comprehend the complexity of interactions between medicinal plants and pharmaceuticals, as well as the impacts that these different interactions can have on the resilience of LMSs.