Determining the time to maximal bronchodilator response in asthmatic children.
The interval between bronchodilator administration and post-bronchodilator lung function testing is critical for accurate interpretation of the bronchodilator response. The time course of this response in children is not well documented. We aimed to document the time taken to achieve maximal lung function following salbutamol inhalation. Eighteen asthmatic children between 7 and 18 years of age with a history of bronchodilator responsiveness were recruited. Spirometry was performed before and at 0, 10, 15, 20, 40, 60, and 90 minutes after salbutamol inhalation 600 microg (Ventolin; GlaxoSmithKline) via a spacer (Volumatic; GlaxoSmithKline). Spirometric indices significantly increased after salbutamol inhalation (p < 0.001). The group median time to maximal response in forced expiratory volume in 1 second (FEV(1)) was 17.5 (10-60: 10th-90th centiles) minutes after salbutamol. The magnitude of group response in FEV(1) was significantly higher at 15 and 20 minutes than at 0 and 10 minutes post-salbutamol inhalation (repeat measures analysis of variance [ANOVA] on ranks; p < 0.05). We conclude that a minimal interval of 20 minutes, before re-testing spirometry, is required to document the maximal response to bronchodilators in the majority of asthmatic children.


Anaplasmosis: experimental immunodeficient state model.
Introduction: The recently described anaplasmosis infection is widespread but concerns to the insufficiently known group of diseases. The aim of our research is the development of uniform biological model for reproducing of artificial immunodeficient state by experimental anaplasmosis. Materials and methods: Algorithm of experimental anaplasmosis reproducing, consisted of such consecutive stages: 1) artificial forming of the immunodeficient state at nonlinear white mise (Mus musculus L.); 2) preparation of the tested biological material samples; 3) inoculation by prepared samples of the laboratory animals with the artificially formed immunodeficient state; 4) sampling from the dead or slaughtered (by the method of chloroformed anesthesia) experimental animals of sectional material (organs and targets tissues); 5) verification of aetiology by express detection of causative agents by the method of PCR in the selected samples of sectional material. Results: Biological model of experimental anaplasmosis have been created suitable for realization of both diagnostic and epidemiological, epizootic, ecobiological and other researches of different origin biological material samples, including samples of solid and liquid consistency material. Formed model realised in premature death of experimental animals in 17.4 % cases; resulted in an onset of disease clinical signs without death during the term of supervision in 43.8 % cases; coursed in the absence of the expressed symptoms of infection in 31.3 % cases. Conclusions: Developed biological model of experimental anaplasmosis consists in that as laboratory animals with the increased sensitiveness to the infection and accumulation of causative agent are used white nonlinear mice with the artificially formed immunodeficient state.


Innate immunity in Crohn's disease: the reverse side of the medal.
The etiology of Crohn's disease (CD) remains poorly understood. Both mice and human studies suspected a perverse link between the microbiota and the lining of the gut mucosa. There is now emerging evidence that suggests that such a pathologic condition might result from an overly aggressive immune response to microbial antigens in genetically predisposed individuals. However, the multiple pathophysiologic processing steps linking environmental exposure to the clinical expression of CD are, for the most part, unknown. Herein, we review evidences reflecting a general causing defect of the innate immune function of the intestinal mucosa of CD patients, which might lead to a sustained microbial-induced inflammatory response. Changing the paradigms of CD pathophysiology might lead to entirely new therapeutic approaches aiming to boost the innate immune response.


Rethinking the basis of medical knowledge.
Twentieth-century medical education constructed medicine as biomedical science. Although bioscientific knowledge has brought large benefits to clinical practice, many have questioned the appropriateness of its domination of the medical curriculum. As the content of that curriculum is itself a historically mediated social construct, it can be changed to fit current descriptions of the competent doctors medical schools are expected to produce. Such doctors are expected not only to have biomedical expertise, but also to carry out multiple other roles as described in competency frameworks such as that of CanMEDS. Many of these other roles are socio-culturally based and thus not supported by bioscientific knowledge. We designed a thought experiment to delineate the need to identify and integrate the range of foundational knowledges required to support the development of doctors capable of performing all the roles described in the competency frameworks. We specified assumptions and demarcated our scope. To illustrate our ideas, we selected examples from the medical curriculum that linked to non-Medical Expert roles and outlined the disciplines that supported them. Students educated in the foundational knowledge necessary for competence in all doctor roles would need to be exposed to ideas and ways of thinking from a wide array of disciplines outside the traditional biomedical sciences. These would need to be introduced in context and in ways that would support future medical practice. They would also broaden students' understanding of the nature of legitimate medical knowledge. There are currently major gaps between the goals and objectives of competency frameworks such as CanMEDS and the actual contents of medical curricula. Addressing these will require curricular transformation to add knowledges, in context and in ways that positively affect practice, from disciplines not currently present within the medical school. In order to accomplish this, we will need to engage with colleagues throughout the university.


The location of the t(4;14) translocation breakpoint within the NSD2 gene identifies a subset of patients with high-risk NDMM.
Although translocation events between chromosome 4 (NSD2 gene) and chromosome 14 (immunoglobulin heavy chain [IgH] locus) (t(4;14)) is considered high risk in newly diagnosed multiple myeloma (NDMM), only ∼30% to 40% of t(4;14) patients are clinically high risk. We generated and compared a large whole genome sequencing (WGS) and transcriptome (RNA sequencing) from 258 t(4;14) (n = 153 discovery, n = 105 replication) and 183 non-t(4;14) NDMM patients with associated clinical data. A landmark survival analysis indicated only ∼25% of t(4;14) patients had an overall survival (OS) <24 months, and a comparative analysis of the patient subgroups identified biomarkers associated with this poor outcome, including translocation breakpoints located in the NSD2 gene and expression of IgH-NSD2 fusion transcripts. Three breakpoints were identified and are designated as: "no-disruption" (upstream of NSD2), "early-disruption" (in the 5' UTR), and "late-disruption" (within the NSD2 gene). Our results show a significant difference in OS based on the location of DNA breakpoints (median OS 28.6 "late-disruption" vs 59.2 "early disruption" vs 75.1 months "no disruption"). These findings have been replicated in an independent replication dataset. Also, univariate and multivariate analysis suggest high-risk markers such as del17p, 1p independently contribute to poor outcome in t(4;14) MM patients.


Comparison of 16S Ribosomal RNA Targeted Sequencing and Culture for Bacterial Identification in Normally Sterile Body Fluid Samples: Report of a 10-Year Clinical Laboratory Review.
As 16S ribosomal RNA (rRNA)-targeted sequencing can detect DNA from non-viable bacteria, it can be used to identify pathogens from clinical samples even in patients pretreated with antibiotics. We compared the results of 16S rRNA-targeted sequencing and culture for identifying bacterial species in normally sterile body fluid (NSBF): cerebrospinal, pericardial, peritoneal and pleural fluids. Over a 10-year period, a total of 312 NSBF samples were evaluated simultaneously using 16S rRNA-targeted sequencing and culture. Results were concordant in 287/312 (92.0%) samples, including 277 (88.8%) negative and 10 (3.2%) positive samples. Of the 16 sequencing-positive, culture-negative samples, eight showed clinically relevant isolates that included Fusobacterium nucleatum subsp. nucleatum, Streptococcus pneumoniae, and Staphylococcus spp. All these samples were obtained from the patients pretreated with antibiotics. The diagnostic yield of 16S rRNA-targeted sequencing combined with culture was 11.2%, while that of culture alone was 6.1%. 16S rRNA-targeted sequencing in conjunction with culture could be useful for identifying bacteria in NSBF samples, especially when patients have been pretreated with antibiotics and when anaerobic infection is suspected.


Transforming growth factor-beta1 signaling contributes to development of smooth muscle cells from embryonic stem cells.
Knockout of transforming growth factor (TGF)-beta1 or components of its signaling pathway leads to embryonic death in mice due to impaired yolk sac vascular development before significant smooth muscle cell (SMC) maturation occurs. Thus the role of TGF-beta1 in SMC development remains unclear. Embryonic stem cell (ESC)-derived embryoid bodies (EBs) recapitulate many of the events of early embryonic development and represent a more physiological context in which to study SMC development than most other in vitro systems. The present studies showed induction of the SMC-selective genes smooth muscle alpha-actin (SMalphaA), SM22alpha, myocardin, smoothelin-B, and smooth muscle myosin heavy chain (SMMHC) within a mouse ESC-EB model system. Significantly, SM2, the SMMHC isoform associated with fully differentiated SMCs, was expressed. Importantly, the results showed that aggregates of SMMHC-expressing cells exhibited visible contractile activity, suggesting that all regulatory pathways essential for development of contractile SMCs were functional in this in vitro model system. Inhibition of endogenous TGF-beta with an adenovirus expressing a soluble truncated TGF-beta type II receptor attenuated the increase in SMC-selective gene expression in the ESC-EBs, as did an antibody specific for TGF-beta1. Of interest, the results of small interfering (si)RNA experiments provided evidence for differential TGF-beta-Smad signaling for an early vs. late SMC marker gene in that SMalphaA promoter activity was dependent on both Smad2 and Smad3 whereas SMMHC activity was Smad2 dependent. These results are the first to provide direct evidence that TGF-beta1 signaling through Smad2 and Smad3 plays an important role in the development of SMCs from totipotential ESCs.


PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism.
To test the safety and recanalization efficacy of intra-arterial local delivery of plasminogen activators in acute ischemic stroke, a randomized trial of recombinant pro-urokinase (rpro-UK) versus placebo was undertaken in patients with angiographically documented proximal middle cerebral artery occlusion. After exclusion of intracranial hemorrhage by CT scan, patients with abrupt onset of symptoms of focal ischemia likely to receive treatment within 6 hours who satisfied all clinical eligibility criteria underwent carotid angiography. Patients displaying Thrombolysis in Acute Myocardial Infarction grade 0 or 1 occlusion of the M1 or M2 middle cerebral artery were randomized 2:1 to receive rpro-UK (6 mg) or placebo over 120 minutes into the proximal thrombus face. All patients received intravenous heparin. Recanalization efficacy was assessed at the end of the 2-hour infusion, and intracerebral hemorrhage causing neurological deterioration was assessed at 24 hours. Of 105 patients who underwent angiography, 59 were excluded from randomization. Among the 46 patients randomized, 40 were treated with rpro-UK (n=26) or placebo (n=14) a median of 5.5 hours from symptom onset. Recanalization was significantly associated with rpro-UK (2P=.017). Hemorrhagic transformation causing neurological deterioration within 24 hours of treatment occurred in 15.4% of the rpro-UK-treated patients and 7.1% of the placebo-treated patients (2P=.64). Both recanalization and hemorrhage frequencies were influenced by heparin dose. Intra-arterial local rpro-UK infusion was associated with superior recanalization in acute thrombotic/ thromboembolic stroke compared with placebo. In this regimen, heparin dose influenced hemorrhage frequency and recanalization. Although symptomatic hemorrhage remains a concern, this study suggests that recanalization is enhanced with rpro-UK and heparin.


Failure to Report Effect Sizes: The Handling of Quantitative Results in Published Health Education and Behavior Research.
Given the American Psychological Association's strong recommendation to always report effect sizes in research, scholars have a responsibility to provide complete information regarding their findings. The purposes of this study were to (a) determine the frequencies with which different effect sizes were reported in published, peer-reviewed articles in health education, promotion, and behavior journals and (b) discuss implications for reporting effect size in social science research. Across a 4-year time period (2010-2013), 1,950 peer-reviewed published articles were examined from the following six health education and behavior journals: American Journal of Health Behavior, American Journal of Health Promotion, Health Education & Behavior, Health Education Research, Journal of American College Health, and Journal of School Health Quantitative features from eligible manuscripts were documented using Qualtrics online survey software. Of the 1,245 articles in the final sample that reported quantitative data analyses, approximately 47.9% (n = 597) of the articles reported an effect size. While 16 unique types of effect size were reported across all included journals, many of the effect sizes were reported with little frequency across most journals. Overall, odds ratio/adjusted odds ratio (n = 340, 50.1%), Pearson r/r(2) (n = 162, 23.8%), and eta squared/partial eta squared (n = 46, 7.2%) accounted for the most frequently used effect size. Quality research practice requires both testing statistical significance and reporting effect size. However, our study shows that a substantial portion of published literature in health education and behavior lacks consistent reporting of effect size.


Impact of SARS-CoV-2 infection on patients with hematological malignancies: a retrospective study.
This study aimed to evaluate the characteristics of patients with hematological malignancies (HM) and SARS-CoV-2 infection and analyze the risk factors of their severity and mortality. A retrospective study including inpatients diagnosed HM and SARS-CoV-2 infection between December 2022 and February 2023 were conducted. Demographic information, medical history, comorbidities, diagnosis, treatment related information and outcomes were extracted from electronic medical database. The primary outcome of this study were the severity of SARS-CoV-2 infection and case-fatality rate. The clinical characteristic and outcomes of the patients were summarized and analyzed. A total of 74 patients with HM and SARS-CoV-2 infection were included. Out of the total cases, 85.1% (63) had a mild /moderate SARS-CoV-2 infection, and 14.9% (11) were severe/ critical infection cases. A total of 8 deaths occurred in all cases for a case-fatality rate of 10.8%. Multivariate analysis identified patients with acute myeloid leukemia (AML) (P = 0.043, OR:5.274, 95%CI:1.053-26.407), primary hematological disease in active state (P = 0.005, OR:13.905, 95%CI:2.180-88.704) were independent risk factors for the severity of SARS-CoV-2 infection and patients with AML had 11.145-fold higher risk of non-survival (P = 0.020, OR:11.145, 95%CI:1.460-85.103) in comparison to the patients with other types of HM. There were no significant differences in the severity and case-fatality rate (P > 0.05) between the patients receiving chemotherapy drugs administration waiting <14 days and ≥14 days after negative SARS-CoV-2 testing. The primary hematological disease in active state may be the main risk factor for negative outcome of the patents. Waiting 14 days for chemotherapy initiation after negative SARS-CoV-2 testing is unnecessary.


Bronchial hygiene technique with manual hyperinflation and thoracic compression: effectiveness and safety.
To evaluate the effects of the manual hyperinflation with thoracic compression (MHTC) maneuver on the clearance of secretions, pulmonary mechanics, hemodynamics and oxygenation in mechanically ventilated patients. This was a controlled, crossover study that included twenty patients who were under invasive ventilation for more than 48 hours. Four hours after the last airway suctioning procedure, the patients underwent the study interventions, Suction alone or MHTC plus Suction, in sequence at four hour intervals. The sequence order for the procedures was established by randomization. Data were collected before, during and 5, 15, 30 and 60 minutes after each intervention. The suctioned secretions were collected and weighed. No significant differences between the procedures were found regarding tidal volume, plateau pressure and pulmonary compliance (p>0.05). The hemodynamic variables showed increased pressures and heart rate during the procedures and returned to baseline values five minutes after the end of the procedure (p≤0.001). No significant hemodynamic differences were seen between the interventions (p>0.05). For the duration of the study, oxygen saturation was 99% with only two exceptions during the MHTC + Suction procedure, where saturation was 98% (p<0.05). No significant differences were observed between the techniques regarding the weight of the suctioned secretion. The results suggest that MHTC, as performed in this study, adds no benefit with respect to oxygenation optimization, pulmonary mechanics and clearance of secretions. However, the MHTC maneuver did not result in hemodynamic changes when compared to the suctioning procedure alone.


Novel inhibitors with sulfamethazine backbone: synthesis and biological study of multi-target cholinesterases and α-glucosidase inhibitors.
The underlying cause of many metabolic diseases is abnormal changes in enzyme activity in metabolism. Inhibition of metabolic enzymes such as cholinesterases (ChEs; acetylcholinesterase, AChE and butyrylcholinesterase, BChE) and α-glucosidase (α-GLY) is one of the accepted approaches in the treatment of Alzheimer's disease (AD) and diabetes mellitus (DM). Here we reported an investigation of a new series of novel ureido-substituted derivatives with sulfamethazine backbone (2a-f) for the inhibition of AChE, BChE, and α-GLY. All the derivatives demonstrated activity in nanomolar levels as AChE, BChE, and α-GLY inhibitors with KI values in the range of 56.07-204.95 nM, 38.05-147.04 nM, and 12.80-79.22 nM, respectively. Among the many strong N-(4,6-dimethylpyrimidin-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamide derivatives (2a-f) detected against ChEs, compound 2c, the 4-fluorophenylureido derivative, demonstrated the most potent inhibition profile towards AChE and BChE. A comprehensive ligand/receptor interaction prediction was performed in silico for the three metabolic enzymes providing molecular docking investigation using Glide XP, MM-GBSA, and ADME-Tox modules. The present research reinforces the rationale behind utilizing inhibitors with sulfamethazine backbone as innovative anticholinergic and antidiabetic agents with a new mechanism of action, submitting propositions for the rational design and synthesis of novel strong inhibitors targeting ChEs and α-GLY.Communicated by Ramaswamy H. Sarma.


Location on RP4 of a tellurite resistance determinant not normally expressed in IncP alpha plasmids.
The tellurite resistance (Ter) determinant of RP4 is not normally expressed unless variants are selected on medium containing tellurite. The determinant was mapped in the variant plasmid RP4Ter by Tn7 insertion mutagenesis. Based on a 56.4-kilobase (kb) replicon, it covered the region from 56 kb, across the EcoRI site at 0 kb, to 1.5 kb.


The apparent temperature response of leaf respiration depends on the timescale of measurements: a study of two cold climate species.
Productivity and climate models often use a constant Q10 for plant respiration, assuming tight control of respiration by temperature. We studied the temperature response of leaf respiration of two cold climate species (the Australian tree Eucalyptus pauciflora and the subantarctic megaherb Pringlea antiscorbutica, both measured in a field setting) on a short timescale (minutes) during different times within a diel course, and on a longer timescale, using diel variations in ambient temperature. There were great variations in Q10 depending on measuring day, measuring time and measuring method. When Q10 was calculated from short-term (15 min) manipulations of leaf temperature, the resulting values were usually markedly smaller than when Q10 was calculated from measurements at ambient leaf temperatures spread over a day. While for E. pauciflora, Q10 estimates decreased with rising temperature (corroborating the concept of a temperature-dependent Q10), the opposite was the case for P. antiscorbutica. Clearly, factors other than temperature co-regulate both leaf respiration rates and temperature sensitivity and contribute to diel and seasonal variation of respiration.


Preprint articles as a tool for teaching data analysis and scientific communication.
The skill of analyzing and interpreting research data is central to the scientific process, yet it is one of the hardest skills for students to master. While instructors can coach students through the analysis of data that they have either generated themselves or obtained from published articles, the burgeoning availability of preprint articles provides a new potential pedagogical tool. We developed a new method in which students use a cognitive apprenticeship model to uncover how experts analyzed a paper and compare the professional's cognitive approach to their own. Specifically, students first critique research data themselves and then identify changes between the preprint and final versions of the paper that were likely the results of peer review. From this activity, students reported diverse insights into the processes of data presentation, peer review, and scientific publishing. Analysis of preprint articles is therefore a valuable new tool to strengthen students' information literacy and understanding of the process of science.


Structural and community changes during COVID-19 and their effects on overdose precursors among rural people who use drugs: a mixed-methods analysis.
Drug overdose rates in the United States have been steadily increasing, particularly in rural areas. The COVID-19 pandemic and associated mitigation strategies may have increased overdose risk for people who use drugs by impacting social, community, and structural factors. The study included a quantitative survey focused on COVID-19 administered to 50 people who use drugs and semi-structured qualitative interviews with 17 people who use drugs, 12 of whom also participated in the quantitative survey. Descriptive statistics were run for the quantitative data. Qualitative coding was line-by-line then grouped thematically. Quantitative and qualitative data were integrated during analysis. Findings demonstrate how COVID-19 disruptions at the structural and community level affected outcomes related to mental health and drug use at the individual level. Themes that emerged from the qualitative interviews were (1) lack of employment opportunities, (2) food and housing insecurity, (3) community stigma impacting health service use, (4) mental health strains, and (5) drug market disruptions. Structural and community changes increased anxiety, depression, and loneliness on the individual level, as well as changes in drug use patterns, all of which are likely to increase overdose risk. The COVID-19 pandemic, and mitigation strategies aimed at curbing infection, disrupted communities and lives of people who use drugs. These disruptions altered individual drug use and mental health outcomes, which could increase risk for overdose. We recommend addressing structural and community factors, including developing multi-level interventions, to combat overdose. Trial registration Clinicaltrails.gov: NCT04427202. Registered June 11, 2020: https://clinicaltrials.gov/ct2/show/NCT04427202?term=pho+mai&draw=2&rank=3.


Brain White Matter Abnormalities in Female Interstitial Cystitis/Bladder Pain Syndrome: A MAPP Network Neuroimaging Study.
Several chronic pain conditions may be distinguished by condition specific brain anatomical and functional abnormalities on imaging, which are suggestive of underlying disease processes. We present what is to our knowledge the first characterization of interstitial cystitis/bladder pain syndrome associated white matter (axonal) abnormalities based on multicenter neuroimaging from the MAPP Research Network. We assessed 34 women with interstitial cystitis/bladder pain syndrome and 32 healthy controls using questionnaires on pain, mood and daily function. White matter microstructure was evaluated by diffusion tensor imaging to model directional water flow along axons or fractional anisotropy. Regions correlating with clinical parameters were further examined for gender and syndrome dependence. Women with interstitial cystitis/bladder pain syndrome showed numerous white matter abnormalities that correlated with pain severity, urinary symptoms and impaired quality of life. Interstitial cystitis/bladder pain syndrome was characterized by decreased fractional anisotropy in aspects of the right anterior thalamic radiation, the left forceps major and the right longitudinal fasciculus. Increased fractional anisotropy was detected in the right superior and bilateral inferior longitudinal fasciculi. To our knowledge we report the first characterization of brain white matter abnormalities in women with interstitial cystitis/bladder pain syndrome. Regional decreases and increases in white matter integrity across multiple axonal tracts were associated with symptom severity. Given that white matter abnormalities closely correlated with hallmark symptoms of interstitial cystitis/bladder pain syndrome, including bladder pain and urinary symptoms, brain anatomical alterations suggest that there are neuropathological contributions to chronic urological pelvic pain.


Cross-sectional study of female sex workers in Soweto, South Africa: Factors associated with HIV infection.
In South Africa, the rate of HIV in the sex worker (SW) population is exceedingly high, but critical gaps exist in our understanding of SWs and the factors that make them vulnerable to HIV. This study aimed to estimate HIV prevalence among female sex workers (FSWs) in Soweto, South Africa, and to describe their sexual behavior and other factors associated with HIV infection. A cross-sectional, respondent-driven sampling (RDS) recruitment methodology was used to enroll 508 FSWs based in Soweto. Data were collected using a survey instrument, followed by two HIV rapid tests. Raw and RDS adjusted data were analyzed using a chi-squared test of association and multivariate logistic regression to show factors associated with HIV infection. HIV prevalence among FSWs was 53.6% (95% CI 47.5-59.9). FSWs were almost exclusively based in taverns (85.6%) and hostels (52.0%). Less than a quarter (24.4%) were under 25 years of age. Non-partner violence was reported by 55.5%, 59.6% of whom were HIV-infected. Advancing age, incomplete secondary schooling, migrancy and multiple clients increased the likelihood of HIV acquisition: >30 years of age was associated with a 4.9 times (95% CI 2.6-9.3) increased likelihood of HIV; incomplete secondary schooling almost tripled the likelihood (AOR 2.8, 95% CI 1.6-5.0); being born outside of the Gauteng province increased the likelihood of HIV 2.3 times (95% CI 1.3-4.0); and having more than five clients per day almost doubled the likelihood (AOR 1.9, 95% CI 1.1-3.2). Our findings highlight the extreme vulnerability of FSWs to HIV. Advancing age, limited education and multiple clients were risk factors associated with HIV, strongly driven by a combination of structural, biological and behavioral determinants. Evidence suggests that interventions need to be carefully tailored to the varying profiles of SW populations across South Africa. Soweto could be considered a microcosm of South Africa in terms of the epidemic of violence and HIV experienced by the SW population, which is influenced by factors often beyond an individual level of control. While describing a hitherto largely undocumented population of FSWs, our findings confirm the urgent need to scale up innovative HIV prevention and treatment programs for this population.


Longitudinal associations between marine omega-3 supplement users and coronary heart disease in a UK population-based cohort.
Assess the association between marine omega-3 polyunsaturated fatty acid (n-3 PUFA) intake from supplements, mainly cod liver oil, and coronary heart disease (CHD) mortality. Prospective cohort study, with three exposure measurements over 22 years. Norfolk-based European Prospective Investigation into Cancer (EPIC-Norfolk, UK). 22 035 men and women from the general population, 39-79 years at recruitment. Supplement use was assessed in three questionnaires (1993-1998; 2002-2004; 2004-2011). Participants were grouped into non-supplement users (NSU), n-3 PUFA supplement users (SU+n3) and non-n-3 PUFA supplement users (SU-n3). Cox regression adjusted for time-point specific variables: age, smoking, prevalent illnesses, body mass index, alcohol consumption, physical activity and season and baseline assessments of sex, social class, education and dietary intake (7-day diet diary). During a median of 19-year follow-up, 1562 CHD deaths were registered for 22 035 included participants. Baseline supplement use was not associated with CHD mortality, but baseline food and supplement intake of n-3 PUFA was inversely associated with CHD mortality after adjustment for fish consumption. Using time-varying covariate analysis, significant associations were observed for SU+n3 (HR: 0.74, 95% CI 0.66 to 0.84), but not for SU-n3 versus NSU. In further analyses, the association for SU+n3 persisted in those who did not take other supplements (HR: 0.83, 95% CI 0.71 to 0.97). Those who became SU+n3 over time or were consistent SU+n3 versus consistent NSU had a lower hazard of CHD mortality; no association with CHD was observed in those who stopped using n-3 PUFA-containing supplements. Recent use of n-3 PUFA supplements was associated with a lower hazard of CHD mortality in this general population with low fish consumption. Residual confounding cannot be excluded, but the findings observed may be explained by postulated biological mechanisms and the results were specific to SU+n3.


The dilemma of a practice: experiences of abortion in a public maternity hospital in the city of Salvador, Bahia.
The article discusses abortion and miscarriage from the perspective of women admitted to a public maternity hospital in Salvador (BA), Brazil. Based on qualitative and quantitative research, it draws on participant observation of everyday hospital life. Taking an ethnographic approach, it addresses the hospital experiences of women who had miscarriages or induced abortions, also presenting the views of health professionals. It argues that the way the institution structures care for abortion and miscarriage involves symbolic processes that profoundly affect women's experiences. The discrimination against women who have had abortions/miscarriages is an integral part of the structure, organization and culture of these institutions, and does not derive solely from the individual actions of healthcare personnel.


Uses of Youth Risk Behavior Survey and School Health Profiles data: applications for improving adolescent and school health.
To monitor priority health risk behaviors and school health policies and practices, respectively, the Centers for Disease Control and Prevention (CDC) developed the Youth Risk Behavior Surveillance System (YRBSS) and the School Health Profiles (Profiles). CDC is often asked about the use and application of these survey data to improve adolescent and school health. The purpose of this article is to describe the importance and potential impact of Youth Risk Behavior Survey (YRBS) and Profiles data based on examples from participating sites. The authors spoke with representatives from 25 state and 8 local agencies funded by CDC to learn how data from the YRBS, Profiles, and other data sources are used. The authors identified common themes in the responses and categorized the responses accordingly. Representatives indicated survey data are used to describe risk behaviors and school health policies and practices, inform professional development, plan and monitor programs, support health-related policies and legislation, seek funding, and garner support for future surveys. Examples presented highlight the range of possible uses of survey data. State and local agencies use YRBS and Profiles data in many ways to monitor and address issues related to adolescent and school health. Innovative uses of survey data are encouraged, although it is also crucial to continue the more fundamental uses of survey data. If the data are not disseminated, the current health needs of students may not be adequately addressed.


Identification of a prepore large-complex stage in the mechanism of action of Clostridium perfringens enterotoxin.
Clostridium perfringens enterotoxin (CPE) is the etiological agent of the third most common food-borne illness in the United States. The enteropathogenic effects of CPE result from formation of large CPE-containing complexes in eukaryotic cell membranes. Formation of these approximately 155- and approximately 200-kDa complexes coincides with plasma membrane permeability changes in eukaryotic cells, causing a Ca2+ influx that drives cell death pathways. CPE contains a stretch of amino acids (residues 81 to 106) that alternates markedly in side chain polarity (a pattern shared by the transmembrane domains of the beta-barrel pore-forming toxin family). The goal of this study, therefore, was to investigate whether this CPE region is involved in pore formation. Complete deletion of the CPE region from 81 to 106 produced a CPE variant that was noncytotoxic for Caco-2 cells and was unable to form CPE pores. However, this variant maintained the ability to form the approximately 155-kDa large complex. This large complex appears to be a prepore present on the plasma membrane surface since it showed greater susceptibility to proteases, increased complex instability, and a higher degree of dissociation from membranes compared to the large complex formed by recombinant CPE. When a D48A mutation was engineered into this prepore-forming CPE variant, the resultant variant was unable to form any prepore approximately 155-kDa large complex. Collectively these findings reveal a new step in CPE action, whereby receptor binding is followed by formation of a prepore large complex, which then inserts into membranes to form a pore.


A preclinical evaluation of neural stem cell-based cell carrier for targeted antiglioma oncolytic virotherapy.
Oncolytic adenoviral virotherapy (OV) is a highly promising approach for the treatment of glioblastoma multiforme (GBM). In practice, however, the approach is limited by poor viral distribution and spread throughout the tumor mass. To enhance viral delivery, replication, and spread, we used a US Food and Drug Administration-approved neural stem cell line (NSC), HB1.F3.CD, which is currently employed in human clinical trials. HB1.F3.CD cells were loaded with an oncolytic adenovirus, CRAd-Survivin-pk7, and mice bearing various human-derived GBMs were assessed with regard to NSC migration, viral replication, and therapeutic efficacy. Survival curves were evaluated with Kaplan-Meier methods. All statistical tests were two-sided. Antiglioma activity of OV-loaded HB1.F3.CD cells was effective against clinically relevant human-derived glioma models as well as a glioma stem cell-enriched xenograft model. Median survival was prolonged by 34% to 50% compared with mice treated with OV alone (GBM43FL model median survival = 19.5 days, OV alone vs NSC + OV, hazard ratio of survival = 2.26, 95% confidence interval [CI] = 1.21 to 12.23, P = .02; GBM12 model median survival = 43.5 days, OV alone vs NSC + OV, hazard ratio of survival = 2.53, 95% CI = 1.21 to 10.38, P = .02). OV-loaded HB1.F3.CD cells were shown to effectively migrate to the contralateral hemisphere and hand off the therapeutic payload of OV to targeted glioma cells. In vivo distribution and migratory kinetics of the OV-loaded HB1.F3.CD cells were successfully monitored in real time by magnetic resonance imaging. OV-loaded NSCs retained their differentiation fate and were nontumorigenic in vivo. HB1.F3.CD NSCs loaded with CRAd-Survivin-pk7 overcome major limitations of OV in vivo and warrant translation in a phase I human clinical trial for patients with GBM.


Phenotypic Analysis of Early Neurogenesis in a Mouse Chimeric Embryo and Stem Cell-Based Neuruloid Model.
Analyzing the impact of genetic mutations on early neurogenesis of mammalian embryos in conventional mouse mutant models is laborious and time-consuming. To overcome these constraints and to fast-track the phenotypic analysis, we developed a protocol that harnesses the amenability of engineering genetic modifications in embryonic stem cells from which mid-gestation mouse chimeras and in vitro neuruloids are generated. These stem cell-based chimera and neuruloid experimental models allow phenotyping at early developmental time points of neurogenesis.


Genetic organization and regulation of the xylose degradation genes in Streptomyces rubiginosus.
The xylose isomerase (xylA) and the xylulose kinase (xylB) genes from Streptomyces rubiginosus were isolated, and their nucleotide sequences were determined. The xylA and xylB genes encode proteins of 388 and 481 amino acids, respectively. These two genes are transcribed divergently from within a 114-nucleotide sequence separating the coding regions. Regulation of the xyl genes in S. rubiginosus was examined by fusing their promoters to the Pseudomonas putida catechol dioxygenase gene and integrating the fusions into the minicircle integration site on the S. rubiginosus chromosome. The expression of catechol dioxygenase was then measured under a variety of conditions. The results indicated that transcription of the xyl genes was induced by D-xylose and repressed by glucose. Data from quantitative S1 mapping were consistent with this conclusion and suggested that xylA had one and xylB had two transcription initiation sites. The transcription initiation site of xylA was 40 bp upstream of the coding region. The two transcription initiation sites of xylB were 20 and 41 bp 5' of its translation initiation codon. Under control of appropriate regulatory elements, the cloned xyl genes are capable of complementing either Escherichia coli xylose isomerase- or xylulose kinase-deficient strains. The deduced amino acid sequence of the S. rubiginosus xylA protein is highly homologous to sequences of other microbial xylose isomerases.


Principle of maximum caliber and quantum physics.
MaxCal is a variational principle that can be used to infer distributions of paths in the phase space of dynamical systems. It has been successfully applied to different areas of classical physics, in particular statistical mechanics in and out of equilibrium. In this work, guided by the analogy of the formalism of MaxCal with that of the path integral formulation of quantum mechanics, we explore the extension of its applications to the realm of quantum physics, and show how the Lagrangians of both relativistic and nonrelativistic quantum fields can be built from MaxCal, with a suitable set of constraints. Related, the details of the constraints allow us to reinterpret the concept of inertia.


Volatile flavor constituents of fruits from Southern Africa: Mobola plum (Parinari curatellifolia).
The volatile flavor components of Mobola plum (Parinari curatellifolia), a native fruit of Southern Africa, have been isolated by a vacuum headspace concentration method. The concentrate was analyzed by hyphenated gas chromatographic techniques, including gas chromatography (GC)/mass spectrometry (MS) and GC/Fourier transform infrared (FTIR), together with other GC-coupled detection devices for the specific and selective detection of nitrogen- and sulfur-containing compounds. A total of 88 components were identified. Of these compounds, 12 contain nitrogen, including 2-aminobenzaldehyde and phenylacetaldoxime, which are detected for the first time in an edible fruit. In addition, two unusual nitrated compounds have been identified, including optically active (2-nitrobutyl)benzene, which is a new natural product. Quantitative and sensory data of the new compounds are provided.


Structural alterations of the cysteine desulfurase IscS of Salmonella enterica serovar Typhimurium reveal substrate specificity of IscS in tRNA thiolation.
The cysteine desulfurase IscS in Salmonella enterica serovar Typhimurium is required for the formation of all four thiolated nucleosides in tRNA, which is thought to occur via two principally different biosynthetic pathways. The synthesis of 4-thiouridine (s(4)U) and 5-methylaminomethyl-2-thiouridine (mnm(5)s(2)U) occurs by a transfer of sulfur from IscS via various proteins to the target nucleoside in the tRNA, and no iron-sulfur cluster protein participates, whereas the synthesis of 2-thiocytidine (s(2)C) and N(6)-(4-hydroxyisopentenyl)-2-methylthioadenosine (ms(2)io(6)A) is dependent on iron-sulfur cluster proteins, whose formation and maintenance depend on IscS. Accordingly, inactivation of IscS should result in decreased synthesis of all thiolated nucleosides. We selected mutants defective either in the synthesis of a thiolated nucleoside (mnm(5)s(2)U) specific for the iron-sulfur protein-independent pathway or in the synthesis of a thiolated nucleoside (ms(2)io(6)A) specific for the iron-sulfur protein-dependent pathway. Although we found altered forms of IscS that influenced the synthesis of all thiolated nucleosides, consistent with the model, we also found mutants defective in subsets of thiolated nucleosides. Alterations in the C-terminal region of IscS reduced the level of only ms(2)io(6)A, suggesting that the synthesis of this nucleoside is especially sensitive to minor aberrations in iron-sulfur cluster transfer activity. Our results suggest that IscS has an intrinsic substrate specificity in how it mediates sulfur mobilization and/or iron-sulfur cluster formation and maintenance required for thiolation of tRNA.


Long-term prognosis of typical childhood absence epilepsy: remission or progression to juvenile myoclonic epilepsy.
To determine the proportion and characteristics of children presenting with childhood absence epilepsy (CAE) who were not taking anti-epileptic drugs (AEDs) and were seizure-free over the last year of long-term follow-up. For case finding, centralized EEG records for the province of Nova Scotia allowed identification of all children with typical CAE diagnosed between 1977 and 1985. Follow-up was done in 1994 to 1995. Of 81 children with CAE, 72 (89%) were contacted for follow-up. Mean age at seizure onset was 5.7 years (range, 1 to 14 years) and at follow-up was 20.4 years (range, 12 to 31 years). Forty-seven (65%) were in remission. Twelve others (17%) were not taking AEDs but continued to have seizures. Thirteen (18%) were taking AEDs; five were seizure-free over the last year (in four of these a trial without AEDs had previously failed). Fifteen percent of the total cohort had progressed to juvenile myoclonic epilepsy (JME). Multiple clinical and EEG factors were examined as predictors of outcome. Factors predicting no remission (p < 0.05) included cognitive difficulties at diagnosis, absence status prior to or during AED treatment, development of generalized tonic clonic or myoclonic seizures after onset of AEDs, abnormal background on initial EEG, and family history of generalized seizures in first-degree relatives. Only 65% of children presenting with CAE had remission of their epilepsy. Forty-four percent of those without remission had developed JME. At the time of diagnosis, remission is difficult to predict accurately in most patients. However, development of generalized tonic-clonic seizures or myoclonic seizures during AED treatment is ominous, predicting both lack of remission of CAE and progression to JME.


Increase of glycocalyx and altered lectin agglutination profiles of Pasteurella haemolytica A1 after incubation in bovine subcutaneous tissue chambers in vivo or in ruminant serum in vitro.
Pasteurella haemolytica serotype A1 (bovine strain OK) was incubated for 2 and 6 h in bovine subcutaneous tissue chambers in vivo, and ovine strain 82-25 and bovine strain L011 were incubated in vitro for 2 h in heat-inactivated ovine or bovine serum from which gamma globulin had been depleted by protein G affinity chromatography to assess changes in morphology and lectin agglutination profiles (strains 82-25 and L101 only). Cells, removed from chambers after 2 h, were covered with an extensive, dense glycocalyx extending approximately 0.5 microm from the cell surface. In many cells, the glycocalyx was separated from the cell surface by a clear, electron-transparent area. Cells, removed at 6 h, were covered with a sparse glycocalyx of fine fibers 0.2 to 0.3 microm from the cell surface. Strains 82-25 and L101, incubated for 2 h in heat-inactivated ovine or bovine serum or in heat-inactivated ovine or bovine serum depleted of gamma globulin by protein G affinity chromatography, were also covered with a glycocalyx. The glycocalyx did not bind protein A-colloidal gold and therefore did not contain aggregates of accumulated antibody. Strains 82-25 and L101 were incubated individually for 2 h in 10 mM sodium phosphate buffer (pH 7.2) containing 0.14 M NaCl, 0.5 mM CaCl2, and 0.15 mM MgCl2 or with this buffer and either 25% heat-inactivated, gamma globulin-depleted ovine serum or 25% heat-inactivated, gamma globulin-depleted bovine serum. Agglutination profiles were then determined with 17 lectins in 10 mM HEPES-buffered saline (pH 8.4) with 0.1 mM CaCl2 and 0.08% sodium azide. Profiles did not vary with 10 of 17 lectins. However, profiles did vary with peanut agglutinin, Phaseolus vulgaris leucoagglutinin, Sophora japonica agglutinin, Maackia amurensis lectin II, Narcissus pseudonarcissus (daffodil) lectin, Griffonia simplicifolia lectin I, and Pisum sativum agglutinin. Altered profiles indicate a change in the bacterial cell surface, possibly by adsorption or alteration of surface carbohydrate moieties by serum constituents.


Sugar utilisation and conservation of the gal-lac gene cluster in Streptococcus thermophilus.
The adaptation to utilise lactose as primary carbon and energy source is a characteristic for Streptococcus thermophilus. These organisms, however only utilise the glucose moiety of lactose while the galactose moiety is excreted into the growth medium. In this study we evaluated the diversity of sugar utilisation and the conservation of the gal-lac gene cluster in a collection of 18 S. thermophilus strains isolated from a variety of sources. For this purpose analysis was performed on DNA from these isolates and the results were compared with those obtained with a strain from which the complete genome sequence has been determined. The sequence, organisation and flanking regions of the S. thermophilus gal-lac gene cluster were found to be highly conserved among all strains. The vast majority of the S. thermophilus strains were able to utilize only glucose, lactose, and sucrose as carbon sources, some strains could also utilize fructose and two of these were able to grow on galactose. Molecular characterisation of these naturally occurring Gal+ strains revealed up-mutations in the galKTE promoter that were absent in all other strains. These data support the hypothesis that the loss of the ability to ferment galactose can be attributed to the low activity of the galKTE promoter, probably as a consequence of the adaptation to milk in which the lactose levels are in excess.


Chronic Symptoms After Vestibular Neuritis and the High-Velocity Vestibulo-Ocular Reflex.
As the anterior and posterior semicircular canals are vital to the regulation of gaze stability, particularly during locomotion or vehicular travel, we tested whether the high-velocity vestibulo-ocular reflex (VOR) of the three ipsilesional semicircular canals elicited by the modified Head Impulse Test would correlate with subjective dizziness or vertigo scores after vestibular neuritis (VN). Recovery after acute VN varies with around half reporting persistent symptoms long after the acute episode. However, an unanswered question is whether chronic symptoms are associated with impairment of the high-velocity VOR of the anterior or posterior canals. Twenty patients who had experienced an acute episode of VN at least 3 months earlier were included in this study. Participants were assessed with the video head impulse test (vHIT) of all six canals, bithermal caloric irrigation, the Dizziness Handicap Inventory (DHI), and the Vertigo Symptoms Scale short-form (VSS). Of these 20 patients, 12 thought that they had recovered from the initial episode whereas 8 did not and reported elevated DHI and VSS scores. However, we found no correlation between DHI or VSS scores and the ipsilesional single or combined vHIT gain, vHIT gain asymmetry orcaloric paresis. The high-velocity VOR was not different between patients who thought they had recovered and patients who thought they had not. Our findings suggest that chronic symptoms of dizziness after VN are not associated with the high-velocity VOR of the single or combined ipsilesional horizontal, anterior, or posterior semicircular canals.


Pharmacodynamic and pharmacokinetic profile of RBx 343E48F0: a novel, long acting muscarinic receptor antagonist.
RBx 343E48F0 is a novel, potent, selective and long acting muscarinic receptor antagonist with a potential for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD). The aim of the present study was to describe the in vitro and in vivo profile of RBx 343E48F0 and to compare the results with the present day benchmark therapy, tiotropium. Radioligand binding and isolated tissue based functional assays were used to evaluate the affinity, potency and receptor subtype selectivity of RBx 343E48F0. Inhibition of carbachol-induced bronchoconstriction in the anaesthetized rat and acetylcholine-induced bronchoconstriction in the conscious rat were used to assess the extent and duration of the bronchospasmolytic activity of RBx 343E48F0. In vitro and in vivo pharmacokinetic studies were conducted to evaluate the pharmacokinetic and lung retention properties of the compound. In vitro radioligand binding studies using human recombinant muscarinic receptors showed that RBx 343E48F0 had a pKi of 9.6 at the M(3) receptor and a 60-fold selectivity for the M(3) receptor over the M(2) receptor. In isolated tissue bioassays, it exhibited surmountable antagonism at the guinea pig trachea with a pK(B) of 9.5. Intratracheal administration to anaesthetized rats demonstrated a dose-dependent inhibition of carbachol-induced bronchoconstriction with an ED(50) value of 110 ng/kg. RBx 343E48F0 also exhibited a fast onset of action and long duration of action of greater 24h.


ADHD symptoms and their neurodevelopmental correlates in children born very preterm.
This study investigated the association between attention-deficit/hyperactivity disorder (ADHD) symptomatology in preschool-aged children who were born very preterm (<33 weeks) and cognitive outcomes, clinical risk and socio-demographic characteristics. 119 very preterm children who participated in the Evaluation of Preterm Imaging Study at term-equivalent age were assessed at a mean age of 4.5 years. Parents completed the ADHD Rating Scale IV, a norm-referenced checklist that evaluates ADHD symptomatology according to diagnostic criteria, and the Behavior Rating Inventory of Executive Function-Preschool version. Children completed the Wechsler Preschool and Primary Scales of Intelligence and the Forward Digit Span task. Longitudinal data including perinatal clinical, qualitative MRI classification, socio-demographic variables and neurodevelopmental disabilities were investigated in relation to ADHD symptomatology. All results were corrected for multiple comparisons using false discovery rate. Results showed that although the proportion of very preterm children with clinically significant ADHD did not differ from normative data after excluding those with neurodevelopmental disabilities, 32.7% met criteria for subthreshold ADHD inattentive type and 33.6% for combined type, which was higher than the expected 20% in normative samples. Higher ADHD symptom scores (all) were associated with greater executive dysfunction (inhibitory self-control, flexibility, and emergent metacognition, corrected p<0.001 for all tests). Higher inattentive ADHD symptom scores were associated with lower IQ (ρ = -0.245, p = 0.011) and higher perinatal clinical risk (more days on mechanical ventilation (ρ = 0.196, p = 0.032) and more days on parenteral nutrition (ρ = 0.222, p = 0.015). Higher hyperactive ADHD symptom scores instead were associated with lower socio-economic status (ρ = 0.259, p = 0.004). These results highlight the importance of monitoring and supporting the development of very preterm children throughout the school years, as subthreshold ADHD symptoms represent risk factors for psychosocial problems and for receiving a future clinical diagnosis of ADHD.


Human T-cell responses to HLA-A-restricted high binding affinity peptides of human papillomavirus type 18 proteins E6 and E7.
Human Papillomaviruses (HPVs) are sexually transmitted pathogens, which are implicated in the etiology of cervical cancer. The early proteins E6 and E7 of HPV have transforming capacity and interfere with the cell cycle control of infected host cells and are essential for the maintenance of the transformed state. Identification of MHC class I-restricted, immunogenic peptides derived from either the E6 or the E7 protein is essential for the design of vaccines as well as the monitoring of clinical trials and immunotherapeutic approaches for the treatment of HPV-18-induced carcinomas. We have determined the binding affinities for all possible 9-mer peptides spanning the entire E6 and E7 amino acid sequence for the HLA-A*0101, HLA-A*0201, HLA-A*0302, HLA-A*1102, and HLA-A*2402101 molecules by a competition assay with reference peptides, thereby establishing the binding peptides as potential cytotoxic T-cell epitopes. From the HLA-A*0201 binding peptides, we selected five E6-derived and one E7-derived peptide with high affinities for HLA-A*0201. These six peptides were tested for their immunogenicity by in vitro immunization assays with purified human CD8+ T cells. We identified three HPV-18 E6-derived peptides (ELTEVFEFA, KTVLELTEV, and KLPDLCTEL) and the E7-derived peptide TLQDIVLHL to be highly immunogenic. Overall, these results will help to design vaccines for the prevention or treatment of HPV-18-induced cervical cancer.


Is amalgam removal in patients with medically unexplained physical symptoms cost-effective? A prospective cohort and decision modelling study in Norway.
There are many patients in general practice with health complaints that cannot be medically explained. Some of these patients attribute their health complaints to dental amalgam restorations. This study examined the cost-effectiveness of the removal of amalgam restorations in patients with medically unexplained physical symptoms (MUPS) attributed to amalgam fillings compared to usual care, based on a prospective cohort study in Norway. Costs were determined using a micro-costing approach at the individual level. Health outcomes were documented at baseline and approximately two years later for both the intervention and the usual care using EQ-5D-5L. Quality adjusted life year (QALY) was used as a main outcome measure. A decision analytical model was developed to estimate the incremental cost-effectiveness of the intervention. Both probabilistic and one-way sensitivity analyses were conducted to assess the impact of uncertainty in costs and effectiveness. In patients who attribute health complaints to dental amalgam restorations and fulfil the inclusion and exclusion criteria, amalgam removal is associated with modest increase in costs at societal level as well as improved health outcomes. In the base-case analysis, the mean incremental cost per patient in the amalgam group was NOK 19 416 compared to the MUPS group, while mean incremental QALY was 0.119 with a time horizon of two years. Thus, the incremental costs per QALY of the intervention was NOK 162 680, which is usually considered cost effective in Norway. The estimated incremental cost per QALY decreased with increasing time horizon, and amalgam removal was found to be cost saving over both 5 and 10 years. This study provides insight into the costs and health outcomes associated with the removal of amalgam restorations in patients who attribute health complaints to dental amalgam fillings, which are appropriate instruments to inform health care priorities.


Co-administration of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine and atazanavir in treatment-experienced HIV patients.
We report the use of elvitegravir 150 mg/cobicistat 150 mg/tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (EVG/COBI/TDF/FTC) once daily, in addition to once-daily atazanavir (ATV) 300 mg, in treatment-experienced patients with human immunodeficiency virus (HIV). Due to limited data available on the co-administration of these agents, our objective was to evaluate and monitor safety and efficacy of this regimen in patients who developed resistance or intolerance to conventional antiretroviral therapy (ART). This short report included offenders incarcerated in the Illinois Department of Corrections who were ≥18 years, HIV-infected, had documented antiretroviral resistance, and received EVG/COBI/TDF/FTC + ATV once daily. Based on previous ART, resistance patterns and current medications, seven patients were initiated on once-daily therapy consisting of EVG/COBI/TDF/FTC and ATV. Due to extensive resistance, two of the seven patients were also started on abacavir (ABC) 600 mg daily in addition to EVG/COBI/TDF/FTC and ATV. Of the seven patients, one had ART changed due to concerns of resistance based on a genotype, one experienced a decline in renal function that warranted a change in therapy, and one is currently virologically suppressed on a combination of EVG/COBI/TDF/FTC, ATV, and ABC. The remaining four patients remain virologically suppressed on EVG/COBI/TDF/FTC + ATV. Therapy consisting of EVG/COBI/TDF/FTC and ATV may be a viable option for some treatment-experienced HIV-infected patients. Further studies evaluating the safety, efficacy, and pharmacokinetics of this therapy are warranted, given the lack of information currently available.


[Dialectics for humanized care in ICU's: contradictions between professional nursing discourse and practice].
This study attempts to unveil contradictions in humanized nursing care in ICUs. It is a qualitative, dialectic-based study involving 7 nurses, 4 family members and one patient of the Adult ICU of the Hospital of the Federal Universityof Santa Catarina. Participatory observation and semi-structured interviews were applied to collect the data. Marxist and Gramscian ideas of contradiction were used as the theoretical-philosophical reference. This study demonstrates that humanized care is part of a complex network, in which care knowledge seems to give way to closer network ties, while care practicefollows an impersonalized strategy within the logic of partitioned and routine health care production. The dissociation between knowledge and practice also contemplates the difficulties in dealing with the burdens of suffering and institutional-professional limitations. The conclusion is that knowledge of this reality should be a renewed, yet age-old challenge for the nurse in the search for the constant construction/ reconstruction of Nursing in terms of practice, knowledge and work relations.


The AT1/AT2 Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System.
The AT1 receptor has mainly been associated with the pathological effects of the renin-angiotensin system (RAS) (e.g., hypertension, heart and kidney diseases), and constitutes a major therapeutic target. In contrast, the AT2 receptor is presented as the protective arm of this RAS, and its targeting via specific agonists is mainly used to counteract the effects of the AT1 receptor. The discovery of a local RAS has highlighted the importance of the balance between AT1/AT2 receptors at the tissue level. Disruption of this balance is suggested to be detrimental. The fine tuning of this balance is not limited to the regulation of the level of expression of these two receptors. Other mechanisms still largely unexplored, such as S-nitrosation of the AT1 receptor, homo- and heterodimerization, and the use of AT1 receptor-biased agonists, may significantly contribute to and/or interfere with the settings of this AT1/AT2 equilibrium. This review will detail, through several examples (the brain, wound healing, and the cellular cycle), the importance of the functional balance between AT1 and AT2 receptors, and how new molecular pharmacological approaches may act on its regulation to open up new therapeutic perspectives.


Management and outcomes of pregnant ICU patients with severe COVID-19 pneumonia in Qatar: A retrospective cohort study.
Pregnant women are considered a high-risk group for COVID-19 due to their increased vulnerability to viral infections. The impact of COVID-19 on pregnant women is not well understood, and there is a need for data on managing severe COVID-19 in pregnant patients. This retrospective descriptive cohort study described the characteristics, hospital stay, interventions, and outcomes of pregnant patients admitted to the intensive care units (ICUs) with severe COVID-19 pneumonia in Qatar. Data were collected from medical records and chart reviews of pregnant women admitted to Hamad Medical Corporation (HMC) with COVID-19 pneumonia from March 01, 2020, to July 31, 2021. The inclusion criteria encompassed pregnant women with a positive polymerase chain reaction (PCR) antigen test or radiological changes at admission, requiring respiratory support, and hospitalized for more than 24 hours. A total of 43 pregnant women were included in this study. Most patients were admitted during the first wave of the pandemic, with a median gestational age of 212 days [interquartile range 178-242 days] at presentation. The most common respiratory support methods were high-flow nasal cannula, non-invasive positive pressure ventilation, and invasive positive pressure ventilation. Convalescent plasma therapy was administered to 58% of patients, and tocilizumab was used in 28%. Renal replacement therapy was required by 4.6% of patients and 7% required extracorporeal membrane oxygenation. This study provides valuable insights into the impact of COVID-19 on pregnant patients admitted to the ICUs in Qatar. The results suggest that pregnant patients with COVID-19 pneumonia require close monitoring and appropriate interventions to minimize adverse outcomes for both mother and fetus. The data may contribute to future guidelines and management strategies for severe COVID-19 in pregnant patients.


[Multiple births in The Netherlands, 1900-1988].
There are an estimated 120,000 twins and other multiples (all still alive) in The Netherlands. The age of this population (i.e. a quarter of a million persons, 1.6% of the total population) is slightly lower compared with The Netherlands as a whole. Alterations in the structure of mother's age and birth order can only partly explain the observed changes in multiple birth frequencies. The recent increase may be due to medical treatment of women with fertility problems. In addition dizygotic twin births appear to be largely responsible for the total development in multiple births. The changes in birth patterns which relate to the demographic variables age of mother and birth order, are hardly responsible for the decline of stillbirths, perinatal and infant mortality among twins and other multiples. This improvement can be ascribed mainly to progress in medical care. In spite of this improvement, the differences compared with singles are still considerable: the stillbirth rate for twins and other multiples is 2.5 times that for singles; the perinatal mortality rate and the infant mortality rate are about four times as high. However, in the first few years of life of twins and other multiples the age-specific mortality risk declines at such a rate that as early as the third year after birth there is hardly any difference with respect to the singles.


Optimization of competitively differentiated polymerase chain reaction in detection of HBV basal core promoter mutation.
To improve competitively differentiated polymerase chain reaction (CD-PCR) in detection of HBV basal core promoter mutation. Recombinant plasmid of double point mutation A1762T/G1764A in basal core promoter of HBV constructed by site-directed mutagenesis was used as mutant control. To reveal the deficiency mechanism of CD-PCR, relationship between the circle number of PCR and the increased speed of products of each competitive primer was comparatively studied. Diversified amount of dNTPs and mutual primer of the competitive primers were tried to optimize CD-PCR. Optimized CD-PCR was evaluated by detecting A1762T/G1764A mutation in recombinant plasmids and clinical sera from patients with HBV infection. The deficiency mechanism of CD-PCR was that the products of mismatched competitive primer grew fast when the amplification of matched primer entered into plateau stage, which led to decrease in or disappearance of the difference in the amount of their products. This phenomenon could be eliminated by reducing dNTPs to 10 micromol/L and mutual primer to about 100 nmol/L. Optimized CD-PCR could detect both mutant and wild strain independent of the amount of templates and the number of PCR cycles. Its detection limit was 10(3) copies/mL, about 50 copies/reaction. About 10% of mutant DNAs among wild type DNAs could be detected. A1762T/G1764A mutant was detected in 41.8% (51/122) of patients with HBV infection, but not detected in controls with negative HBsAg. Optimized CD-PCR can detect mutation independent of the amount of initial templates and the number of PCR cycles.


Impact of ICD-9-CM to ICD-10-CM coding transition on trauma hospitalization trends among young adults in 12 states.
We aimed to estimate the impact of the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) coding transition on traumatic injury-related hospitalization trends among young adults across a geographically and demographically diverse group of U.S. states. Interrupted time series analyses were conducted using statewide inpatient databases from 12 states and including traumatic injury-related hospitalizations in adults aged 19-44 years in 2011-2017. Segmented regression models were used to estimate the impact of the October 2015 coding transition on external cause of injury (ECOI) completeness (percentage of hospitalizations with a documented ECOI code) and on population-level rates of injury-related hospitalizations by nature, intent, mechanism, and severity of injury. The transition to ICD-10-CM was associated with a drop in ECOI completion in the transition month (- 3.7%; P < .0001), but there was no significant change in the positive trend in ECOI completion from the pre- to post-transition periods. There were significant increases post-transition in the measured rates of hospitalization for traumatic brain injury (TBI), unintentional injury, mild injury (injury severity score (ISS) < 9), and injuries caused by drowning, firearms, machinery, other pedestrian, suffocation, and unspecified mechanism. Conversely, there were significant decreases in October 2015 in the rates of hospitalization for assault, injuries of undetermined intent, injuries of moderate severity (ISS 9-15), and injuries caused by fire/burn, other pedal cyclist, other transportation, natural/environmental, and other specified mechanism. A significant increase in the percentage of hospitalizations classified as resulting from severe injury (ISS > 15) was observed when the general equivalence mapping maximum severity method for converting ICD-10-CM codes to ICD-9-CM codes was used. State-specific results for the outcomes of ECOI completion and TBI-related hospitalization rates are provided in an online supplement. The U.S. transition from ICD-9-CM to ICD-10-CM coding led to a significant decrease in ECOI completion and several significant changes in measured rates of injury-related hospitalizations by injury intent, mechanism, nature, and severity. The results of this study can inform the design and analysis of future traumatic injury-related health services research studies that use both ICD-9-CM and ICD-10-CM coded data. II (Interrupted Time Series).


Structure and speciation in hydrous silica melts. 2. Pressure effects.
The effect of pressure on structure and water speciation in hydrated liquid silica is examined over a range of temperatures and compositions. The Feuston-Garofalini (FG) potential is used in isobaric-isothermal Monte Carlo simulations carried out at four pressures (0.25, 1.0, 2.5, and 10 GPa) for seven temperatures (2000 < or = T < or= 9000 K) and five compositions (0.0 < or = x_w < or = 0.4). The FG potential yields a stable melt phase for p > or = 1.0 GPa and/or x_w < or = 0.1 for all temperatures. The volume minimum seen in previous simulations of pure and hydrated liquid silica using the FG potential persists up to 2.5 GPa but is no longer evident at 10 GPa. This is correlated with gradual structural changes of the liquid up to 2.5 GPa and with more significant changes at 10 GPa. Even at high overall concentrations of water (x_w = 0.4), only about 2% of oxygen atoms are present as molecular water species at the lowest temperature. This percentage decreases with increasing pressure and temperature.


Comparison of the tendon damage caused by four different anchor systems used in transtendon rotator cuff repair.
Objectives. The objective of this study was to compare the damage to the rotator cuff tendons caused by four different anchor systems. Methods. 20 cadaveric human shoulder joints were used for transtendon insertion of four anchor systems. The Healix Peek, Fastin RC, Bio-Corkscrew Suture, and Healix Transtend anchors were inserted through the tendons using standard transtendon procedures. The areas of tendon damage were measured. Results. The areas of tendon damage (mean ± standard deviation, n = 7) were 29.1 ± 4.3 mm(2) for the Healix Peek anchor, 20.4 ± 2.3 mm(2) for the Fastin RC anchor, 23.4 ± 1.2 mm(2) for the Bio-Corkscrew Suture anchor, 13.7 ± 3.2 mm(2) for the Healix Transtend anchor inserted directly, and 9.1 ± 2.1 mm(2) for the Healix Transtend anchor inserted through the Percannula system (P < 0.001 or P < 0.001, compared to other anchors). Conclusions. In a cadaver transtendon rotator cuff repair model, smaller anchors caused less damage to the tendon tissues. The Healix Transtend implant system caused the least damage to the tendon tissues. Our findings suggest that smaller anchors should be considered when performing transtendon procedures to repair partial rotator cuff tears.


Evaluation of two strategies to implement physical cancer rehabilitation guidelines for survivors of abdominopelvic cavity tumors: a controlled before-and-after study.
This study evaluates the effectiveness and feasibility of two strategies to implement physical cancer rehabilitation (PCR) guidelines for patients who have survived abdominopelvic cavity malignancies. We tested and compared two tailored strategies to implement PCR guidelines for survivors of gastrointestinal, female organ and urogenital organ malignancies, in a clustered controlled before-and-after study. A patient-directed (PD) strategy was tested in five cancer centers, aiming to empower survivors. A multifaceted (MF) strategy was tested in four cancer centers, aiming additionally to influence healthcare professionals and the healthcare organization. Data were collected from existing registration systems, patient questionnaires and professional questionnaires. We measured both implementation- and client outcomes. For insight into the effectiveness we measured indicators related to PCR guidelines: (1) screening with the Distress Thermometer (DT) (=primary outcome measure), (2) information provision concerning physical activity (PA) and physical cancer rehabilitation programs (PCRPs), (3) advice to take part in PA and PCRPs, (4) referral to PCRPs, (5) participation in PCRPs, (6) PA uptake (PAU); and patient reported outcomes (PROs) such as (7) quality of life, (8) fatigue, and (9) empowerment. Furthermore, survivor and center determinants were assessed as possible confounders. Multilevel analyses were performed to compare the scores of the indicators of the PD and MF strategies, as well as the differences between the characteristics of these groups. The use of and experiences with both strategies were measured using questionnaires and Google Analytics to assess feasibility. In total, 1326 survivors participated in the study, 673 in the before- and 653 in the after-measurement. Regarding our primary outcome measure, we found a significant improvement of screening with the DT between the before- and after-measurement for both strategies, respectively from 34.2 to 43.1% (delta=8.9%; odds ratio (OR)=1.6706; p=0.0072) for the PD strategy and from 41.5 to 56.1% (delta=14.6%; OR=1.7098; p=0.0028) for the MF strategy. For both the primary and secondary outcomes, no statistically significant effect of the MF strategy compared to the PD strategy was observed. We found good use of and positive experiences with both strategies. Implementation strategies containing tools enhancing patient empowerment seem to be effective in increasing the systematic screening with the DT for survivors of abdominopelvic cavity malignancies. Further research is needed to assess the additional effectiveness of strategies that stimulate compliance among healthcare professionals and healthcare organizations. Using implementation strategies containing tools enhancing patient empowerment seem to be effective in increasing the systematic screening with the DT and might improve the quality of care of patients who have survived abdominopelvic cavity malignancies.


Link technologies and BlackBerry mobile health (mHealth) solutions: a review.
The number of wearable wireless sensors is expected to grow to 400 million by the year 2014, while the number of operational mobile subscribers has already passed the 5.2 billion mark in 2011. This growth results in an increasing number of mobile applications including: Machine-to-Machine (M2M) communications, Electronic-Health (eHealth), and Mobile-Health (mHealth). A number of emerging mobile applications that require 3G and 4G mobile networks for data transport relate to telemedicine, including establishing, maintaining, and transmitting health-related information, research, education, and training. This review paper takes a closer look at these applications, specifically with regard to the healthcare industry and their underlying link technologies. The authors believe that the BlackBerry platform and the associated infrastructure (i.e., BlackBerry Enterprise Server) is a logical and practical solution for eHealth, mHealth, sensor and M2M deployments, which are considered in this paper.


Insertion of vaccinia virus C7L host range gene into NYVAC-B genome potentiates immune responses against HIV-1 antigens.
The highly attenuated vaccinia virus strain NYVAC expressing HIV-1 components has been evaluated as a vaccine candidate in preclinical and clinical trials with encouraging results. We have previously described that the presence of C7L in the NYVAC genome prevents the induction of apoptosis and renders the vector capable of replication in human and murine cell lines while maintaining an attenuated phenotype in mice. In an effort to improve the immunogenicity of NYVAC, we have developed a novel poxvirus vector by inserting the VACV host-range C7L gene into the genome of NYVAC-B, a recombinant virus that expresses four HIV-1 antigens from clade B (Env, Gag, Pol and Nef) (referred as NYVAC-B-C7L). In the present study, we have compared the in vitro and in vivo behavior of NYVAC-B and NYVAC-B-C7L. In cultured cells, NYVAC-B-C7L expresses higher levels of heterologous antigen than NYVAC-B as determined by Western blot and fluorescent-activated cell sorting to score Gag expressing cells. In a DNA prime/poxvirus boost approach with BALB/c mice, both recombinants elicited robust, broad and multifunctional antigen-specific T-cell responses to the HIV-1 immunogens expressed from the vectors. However, the use of NYVAC-B-C7L as booster significantly enhanced the magnitude of the T cell responses, and induced a more balanced cellular immune response to the HIV-1 antigens in comparison to that elicited in animals boosted with NYVAC-B. These findings demonstrate the possibility to enhance the immunogenicity of the highly attenuated NYVAC vector by the insertion of the host-range gene C7L and suggest the use of this modified vector as an improved vaccine candidate against HIV/AIDS.


Pediatric extracorporeal cardiopulmonary resuscitation for yew cardiotoxicity.
English yew is an evergreen conifer frequently planted in household gardens and, when ingested in large doses, results in severe cardiotoxicity characterized by difficult to control ventricular arrhythmias with high rates of mortality. A previously healthy teenage female presented as an out-of-hospital cardiac arrest with refractory ventricular arrhythmias and severe biventricular dysfunction. Due to rapid deterioration in her clinical status, she was cannulated onto venoarterial extracorporeal membrane oxygenation (ECMO) which resulted in rapid normalization of her rhythm and ventricular function. Our case highlights the importance of keeping a broad differential diagnosis when considering etiologies of ventricular arrhythmias in the pediatric population. The final diagnosis was not made until after discharge and implantable cardiac defibrillator (ICD) placement. The delayed diagnosis of this intentional English yew ingestion ultimately resulted subsequent ICD removal. Early ECMO activation in cases of English yew toxicity can be essential for patient survival.


Efficacy of a permethrin-based acaricide to reduce the abundance of Ixodes dammini (Acari: Ixodidae).
Permethrin-impregnated cotton was distributed to reduce abundance of immature Ixodes dammini Spielman, Clifford, Piesman & Corwin feeding upon white-footed mice (Peromyscus leucopus) and questing on vegetation at a private resort site (The Crane Reservation of The Trustees of Reservations in Ipswich, Mass.) located in coastal New England. This test constituted the first independent evaluation of the efficacy of this commercial product (Damminix). Over a 3-yr period, 2,000 applicator tubes containing treated cotton were distributed over the 7.3-ha site in 5 regularly scheduled applications. Mice removed treated fiber from the tubes and transported it to their nests. Within 3 wk of the first application, virtually all mice in the treated site were rendered free of ectoparasites. After the first season of application, no nymphal host-seeking I. dammini could be found on vegetation. Visitor and employee complaints about deer tick bites or ticks found on skin and clothing had been attributed to the site before treatment, but not thereafter. We confirmed the efficacy of Damminix for reduction of the abundance of vector ticks and thereby contributed to the protection of humans against Lyme disease at this site.


Rehmanniae Radix in osteoporosis: A review of traditional Chinese medicinal uses, phytochemistry, pharmacokinetics and pharmacology.
Emerging clinical usage and pharmacological effects have been achieved in using Rehmanniae Radix either singly or in combination with other herbs to treat skeletal diseases in traditional Chinese medicine (TCM) in the recent years. This study is aimed to provide a comprehensive review about the historical TCM interpretation of the action of Rehmanniae Radix in osteoporosis, its usage in clinical trials and osteoporotic models, its main phytochemical constituents, and its pharmacokinetics. Several databases included PubMed, China Knowledge Resource Integrated Database, China Science and Technology Journal Database, National Science and Technology Library and the Web of Science Database were consulted to locate the publications pertaining to Rehmanniae Radix. The initial inquiry was conducted for the presence of the following terms combinations in the abstracts: Rehmanniae Radix, Dihuang, phytochemistry, pharmacokinetics, osteoporosis, bone, osteoclast and osteoblast. About 330 research papers and reviews were consulted. In TCM, Rehmanniae Radix exerts the anti-osteoporotic effect via regulating the functions of kidney and liver as well as improving blood circulation. 107 clinical trials are identified that used Rehmanniae Radix in combination with other herbs to treat post-menopausal, senile and secondary osteoporosis. Most of the clinical trials are characterized by high efficacy and no obvious adverse effects. However, the efficacies of these clinical trials are limited because of small patient sample size, short treatment duration and poor clinical design. In addition, TCM herbs under the clinical study are not clear because of a lack of standardization and authentication. The pharmacokinetics data demonstrate that the ingredients of Rehmanniae Radix are widely distributed after administration, and that catalpol and ajugol as well as acetoside are supposed to be the active constituents. More than 140 individual compounds have been currently isolated from this plant and reported to show pleiotropic effects on various diseases. Rehmanniae Radix displays bone protecting features in the osteoporosis models via the delicate balance between osteoclastogenesis and osteoblastogenesis through single herb extracts and its isolated compounds. The successful inclusion of Rehmanniae Radix in clinical trials and preclinical studies for the management of osteoporosis has attracted rising attentions for identifying potential anti-osteoporotic candidates from this plant and clinical existing TCM formulas, which will further speed up anti-osteoporosis drug discovery processes. Properly designed and well controlled prospective studies are still needed to further demonstrate bone protective actions and safe use of this herb and its ingredients.


Chicken stem cell factor enhances primordial germ cell proliferation cooperatively with fibroblast growth factor 2.
An in vitro culture system of chicken primordial germ cells (PGCs) has been recently developed, but the growth factor involved in the proliferation of PGCs is largely unknown. In the present study, we investigated the growth effects of chicken stem cell factor (chSCF) on the in vitro proliferation of chicken PGCs. We established two feeder cell lines (buffalo rat liver cells; BRL cells) that stably express the putative secreted form of chSCF (chSCF1-BRL) and membrane bound form of chSCF (chSCF2-BRL). Cultured PGC lines were incubated on chSCF1 or chSCF2-BRL feeder cells with fibroblast growth factor 2 (FGF2), and growth effects of each chSCF isoform were investigated. The in vitro proliferation rate of the PGCs cultured on chSCF2-BRL at 20 days of culture was more than threefold higher than those cultured on chSCF1-BRL cells and more than fivefold higher than those cultured on normal BRL cells. Thus, use of chSCF2-BRL feeder layer was effective for in vitro proliferation of chicken PGCs. However, the acceleration of PGC proliferation on chSCF2-BRL was not observed without FGF2, suggesting that chSCF2 would act as a proliferation co-factor of FGF2. We transferred the PGCs cultured on chSCF2-BRL cells to recipient embryos, generated germline chimeric chickens and assessed the germline competency of cultured PGCs by progeny test. Donor-derived progenies were obtained, and the frequency of germline transmission was 3.39%. The results of this study demonstrate that chSCF2 induces hyperproliferation of chicken PGCs retaining germline competency in vitro in cooperation with FGF2.


Agnostic sampling transceiver.
Increasing demands for data centers, backbone, access, and wireless networks require inventive concepts to transmit and distribute digital or analog signal waveforms. We present a new, extremely simple transceiver concept, fundamentally different from conventional approaches. It does not rely on high-speed electronics and enables transmission of various time multiplexed analog waveforms or digital data signals with the maximum possible symbol rate in the same rectangular optical spectral band B. The aggregate symbol rate of N signal channels corresponds to B or twice the used modulator's electro-optical bandwidth. By a modification of the system, it can be increased to three times the modulator bandwidth. The rectangular spectra can be further multiplexed into wavelength-superchannels without guardbands. To time demultiplex single signal channel, just another intensity modulator and a detector with an electrical bandwidth corresponding to the channel's baseband width (B/(2N)) is required. No optical filter, high-speed signal processing, or unconventional photonic devices are needed; thus, it has the potential to be easily integrated into any platform and provides an economical and energy-efficient solution for future communication networks and microwave photonic links.


Predicting the efficacy of radiotherapy in individual glioblastoma patients in vivo: a mathematical modeling approach.
Glioblastoma multiforme (GBM) is the most malignant form of primary brain tumors known as gliomas. They proliferate and invade extensively and yield short life expectancies despite aggressive treatment. Response to treatment is usually measured in terms of the survival of groups of patients treated similarly, but this statistical approach misses the subgroups that may have responded to or may have been injured by treatment. Such statistics offer scant reassurance to individual patients who have suffered through these treatments. Furthermore, current imaging-based treatment response metrics in individual patients ignore patient-specific differences in tumor growth kinetics, which have been shown to vary widely across patients even within the same histological diagnosis and, unfortunately, these metrics have shown only minimal success in predicting patient outcome. We consider nine newly diagnosed GBM patients receiving diagnostic biopsy followed by standard-of-care external beam radiation therapy (XRT). We present and apply a patient-specific, biologically based mathematical model for glioma growth that quantifies response to XRT in individual patients in vivo. The mathematical model uses net rates of proliferation and migration of malignant tumor cells to characterize the tumor's growth and invasion along with the linear-quadratic model for the response to radiation therapy. Using only routinely available pre-treatment MRIs to inform the patient-specific bio-mathematical model simulations, we find that radiation response in these patients, quantified by both clinical and model-generated measures, could have been predicted prior to treatment with high accuracy. Specifically, we find that the net proliferation rate is correlated with the radiation response parameter (r = 0.89, p = 0.0007), resulting in a predictive relationship that is tested with a leave-one-out cross-validation technique. This relationship predicts the tumor size post-therapy to within inter-observer tumor volume uncertainty. The results of this study suggest that a mathematical model can create a virtual in silico tumor with the same growth kinetics as a particular patient and can not only predict treatment response in individual patients in vivo but also provide a basis for evaluation of response in each patient to any given therapy.


Hereditary macular dystrophy. A clinical and genetic study of two specific forms.
Four families with nine members affected with autosomal recessive macular dystrophy (Stargardt's Disease) and one family with six members affected with autosomal dominant macular dystrophy have been examined. Age of onset, rate of visual deterioration, fundus appearance, electroretinography and dark adaptometry have been compared in the various families. Some differences, particularly in the rate of visual deterioration and in the fundus appearance were noted between the recessive and dominant forms. Despite these differences in the clinical and related features, the genetic implications are of greater importance to the affected individuals. Genetic counselling which provides recurrence risks of the disorder in the affected individuals' siblings and children should be included in the assessment of patients with these forms of hereditary ocular disease.


Organizational and psychosocial risk factors for carpal tunnel syndrome: a cross-sectional study of French workers.
The aim of the study was to examine the organizational and psychosocial risk factors for carpal tunnel syndrome (CTS) in workers exposed to various levels of work-related constraints, with a special focus on factors related to the work organization. From 3,710 workers, representative of a French region's working population, trained occupational physicians diagnosed a total of 156 cases of CTS between 2002 and 2005. Diagnoses were established by standardized physical examination, while personal factors and work exposure were assessed by self-administered questionnaires. Statistical associations between CTS and personal and work-related factors were analyzed for each gender using logistic regression modeling. Among the factors related to work organization, working with temporary workers was associated with CTS for women (OR = 1.99, 95 % CI 1.23-3.25), but not for men. Task rotation during the job (OR = 2.45 95 % CI 1.41-4.24) and work pace dependent on quantified targets (OR = 1.93 95 % CI 1.08-3.46) were associated with CTS only for men. The work-related psychosocial factors highlighted by the logistic modeling were high psychological demand for women (OR = 1.90, 95 % CI 1.17-3.09) and low skill discretion (OR = 1.77, 95 % CI 1.01-3.11) for men. This study has identified some psychosocial factors and factors related to work organization associated with clinically diagnosed and symptom-only cases of CTS as well as personal and biomechanical factors. However, due to the cross-sectional design of the study, no causal conclusion could be drawn and longitudinal studies are necessary to confirm these results.


School Nutrition Professionals' Experiences with Food Safety and Special Diets in School Meals during the Initial COVID-19 Pandemic.
Federally funded school meals, such as the National School Lunch Program and School Breakfast Program, can help alleviate food insecurity. Meals served as part of these programs are required by law to be modified when medically necessary, such as food allergies and special diets. The coronavirus disease 2019 (COVID-19) pandemic caused many schools across the United States to close, but schools quickly modified meal-serving models. The purpose of this study was to understand the experiences of school nutrition professionals relative to food safety and providing special diets through modified serving models. A survey was distributed to a convenience sample of child nutrition professionals via social media recruitment and e-mails (n = 504). The survey had both closed-ended questions and one open-ended question exploring food safety and special diet accommodations. At the time of the survey, most respondents (68.3%) had been involved in COVID-19 emergency feeding for 3 to 4 weeks. Results indicated that although most child nutrition professionals did not find food safety easier or more difficult during the initial onset of COVID-19, 34.8% of respondents were not taking food temperatures for hot and cold meals during meal service and were not able to obtain (or did not have enough) equipment necessary for holding hot foods (53.0%). Most respondents (60.2%) also indicated that they were not accommodating children with special diets. Themes from the qualitative analysis indicated participants had challenges obtaining specialty items, had little time to make accommodations, or had a limited supply from vendors to accommodate these diets. To prevent food insecurity and to maintain health during the pandemic, specific solutions for at-risk populations, such as those who experience food allergies, must be considered.


A high hepatic concentration of free proline does not induce collagen synthesis in rat liver.
It has been reported that the concentration of free proline in the liver can be a limiting factor in the synthesis of hepatic collagen, and there has also been found to be a good correlation between the free proline and the amount of collagen in cirrhotic human livers. Since ethanol retards the breakdown of proline, it might be expected that ethanol-induced liver cirrhosis could be produced by the effect of ethanol on the hepatic proline level. In the present study the hepatic free proline level was increased more than three-fold by the administration of proline-rich diet to the rats used in the experiment. Administration of ethanol to the animals did not further increase the concentration of free proline of the liver. The high free proline level had no effect on the collagen formation, nor on the structure of the liver. It can therefore be assumed that the increased free proline levels observed in cirrhotic livers did not induce an increased collagen accumulation, and are a consequence of an altered proline metabolism.


The spacing principle for unlearning abnormal neuronal synchrony.
Desynchronizing stimulation techniques were developed to specifically counteract abnormal neuronal synchronization relevant to several neurological and psychiatric disorders. The goal of our approach is to achieve an anti-kindling, where the affected neural networks unlearn abnormal synaptic connectivity and, hence, abnormal neuronal synchrony, by means of desynchronizing stimulation, in particular, Coordinated Reset (CR) stimulation. As known from neuroscience, psychology and education, learning effects can be enhanced by means of the spacing principle, i.e. by delivering repeated stimuli spaced by pauses as opposed to delivering a massed stimulus (in a single long stimulation session). To illustrate that the spacing principle may boost the anti-kindling effect of CR neuromodulation, in this computational study we carry this approach to extremes. To this end, we deliver spaced CR neuromodulation at particularly weak intensities which render permanently delivered CR neuromodulation ineffective. Intriguingly, spaced CR neuromodulation at these particularly weak intensities effectively induces an anti-kindling. In fact, the spacing principle enables the neuronal population to successively hop from one attractor to another one, finally approaching attractors characterized by down-regulated synaptic connectivity and synchrony. Our computational results might open up novel opportunities to effectively induce sustained desynchronization at particularly weak stimulation intensities, thereby avoiding side effects, e.g., in the case of deep brain stimulation.


VALIDITY OF THE BRAZILIAN-PORTUGUESE VERSION OF MOOREHEAD-ARDELT QUALITY OF LIFE QUESTIONNAIRE II AMONG PATIENTS WITH SEVERE OBESITY.
Patients with obesity present multiple comorbid psychiatric conditions and experience impairments in health-related quality of life. Reliable and valid tools that evaluate health-related quality of life are essential for clinical practice. This study aimed to investigate the reliability and validity of the six-item Moorehead-Ardelt Quality of Life Questionnaire II among Brazilian patients with severe obesity. We assessed 387 patients (mean age 43 years, 78.8% women, mean body mass index of 46.5 kg/m²) on the waiting list of a bariatric surgery center. Trained research assistants concurrently applied the Moorehead-Ardelt Quality of Life-II, the Montgomery-Åsberg Depression Rating Scale, and the Global Assessment of Functioning for assessing health-related quality of life, comorbid depressive symptoms, and patient functioning level, respectively. The internal consistency of the Moorehead-Ardelt Quality of Life-II was considered acceptable. The total score was correlated with the severity of depressive symptoms and functioning level. The more body mass index increases, the more health-related quality of life worsens. The Moorehead-Ardelt Quality of Life-II presented a unidimensional structure. The unidimensional Moorehead-Ardelt Quality of Life-II is a reliable and valid measure for evaluating health-related quality of life in Brazilian patients with severe obesity. The questionnaire allows to quickly assess the health-related quality of life of patients in different bariatric contexts, considering depression and functional level.