Increased lung permeability following long-term use of free-base cocaine (crack).
The clearance of inhaled 99mTc DTPA aerosol from the lungs is used as an index of lung epithelial permeability. Using the radioaerosol method, we investigated the effects of long-term "crack" (free-base cocaine) inhalation on lung permeability in 23 subjects. Eighteen control subjects (12 nonsmokers and 6 cigarette smokers) with no history of drug use were also studied. Subjects inhaled approximately 150 muCi (approximately 5.6 MBq) of 99mTc DTPA aerosol and quantitative gamma camera images of the lungs were acquired at 1-min increments for 25 minutes. Regions of interest (ROIs) were selected to include the following: (1) both lungs; (2) each individual lung; and (3) the upper, middle, and lower thirds of each lung. 99mTc DTPA lung clearance was determined from the slopes of the respective time-activity plots for the different RIOs. Radioaerosol clearance half-times (T1/2) for the seven nonsmoking crack users (61.5 +/- 18.3 minutes) were longer than for the seven cigarette-smoking crack users (27.9 +/- 16.9 minutes) and nine cigarette-smoking crack plus marijuana users (33.5 +/- 21.6 minutes). T1/2 for the nonsmoking crack users was significantly shorter (p less than 0.001) than for the nonsmoking control group (123.8 +/- 28.7 minutes). T1/2 for the cigarette-smoking drug users was similar to that of the cigarette-smoking control group (33.1 +/- 17.8 minutes), suggesting a similar mechanism of damage from the smoke of crack and tobacco. From these groups, one nonsmoker and 11 cigarette smokers displayed biexponential 99mTc DTPA clearances, indicative of greater lung injury than found in the usual cases of monoexponential clearance. The upper lungs of all crack users groups cleared faster than the lower lungs. The faster and biexponential clearance properties of inhaled 99mTc DTPA aerosol were the principal functional abnormalities found in all the drug users. In contrast, 19 of 23 crack users had normal spirometry and gas exchange. These results indicate that 99mTc DTPA may provide a sensitive and useful assay to evaluate the physiologic effects of cocaine inhalation in the lung.


Towards a new moral paradigm in health care delivery: accounting for individuals.
For years, commentators have debated how to most appropriately allocate scarce medical resources over large populations. In this paper, I abstract the major rationing schema into three general approaches: rationing by price, quantity, and prioritization. Each has both normative appeal and considerable weakness. After exploring them, I present what some commentators have termed the "moral paradigm" as an alternative to broader philosophies designed to encapsulate the universe of options available to allocators (often termed the market, professional, and political paradigms). While not itself an abstraction of any specific viable rationing scheme, it provides a strong basis for the development of a new scheme that offers considerable moral and political appeal often absent from traditionally employed rationing schema. As I explain, the moral paradigm, in its strong, absolute, and uncompromising version, is economically untenable. This paper articulates a modified version of the moral paradigm that is pluralist in nature rather than absolute. It appeals to the moral, emotional, and irrational sensibilities of each individual person. The moral paradigm, so articulated, can complement any health care delivery system that policy-makers adopt. It functions by granting individuals the ability to appeal to an administrative adjudicatory board designated for this purpose. The adjudicatory board would have the expertise and power to act in response to the complaints of individual aggrieved patients, including those complaints that stem from the moral, religious, ethical, emotional, irrational, or other subjective positions of the patient, and would have plenary power to affirm the denial of access to medical care or to mandate the provision of such care. The board must be designed to facilitate its intended function while creating structural limitations on abuse of power and other excess. I make some specific suggestions on matters of structure and function in the hope of demonstrating both that this adjudicatory model can function and that it can do so immediately, regardless of the underlying health care delivery system or its theoretical underpinnings.


Cognitive impairments and recovery in patients with work-related stress complaints - four years later.
Patients on sick leave due to work-related stress often present with cognitive complaints. The primary aim of this prospective cohort study was to examine potential long-term consequences of previous ongoing work-related stress in terms of cognitive functioning four years after initial professional care seeking. We tested a group of patients with work-related stress complaints with a comprehensive neuropsychological test battery. Patients were examined at a department of occupational medicine and tested at baseline, one-year follow-up and four-year follow-up. At each time point, we compared the performance of patients with healthy controls matched pairwise on sex, age and length of education. This paper presents the results from the four-year follow-up. Patients improved on their neuropsychological test performance during the four years but the main improvements took place during the first year. At baseline, the main impairments in the patient group concerned executive function and mental speed. At four-year follow-up, patients displayed slightly lower scores on the neuropsychological tests relative to controls but only the difference on immediate memory was significant corresponding to a small effect size (Cohen's d). More than half of the patients who participated in the four-year follow-up reported that they felt only slightly or partially recovered. The level of work participation among the former patients improved considerably during the four-year follow-up period.Lay SummaryThis study examines the long-term consequences of work-related stress in terms of cognitive functioning and recovery four years after initial professional care seeking. After four years, patients continued to display significantly lower memory scores than controls but no other significant differences between the groups were found on neuropsychological tests. Levels of work participation among patients improved considerably over time, yet, more than half of the former patients who participated in the four-year follow-up did not feel completely recovered.


Dynamic landscape of the intracellular termini of acid-sensing ion channel 1a.
Acid-sensing ion channels (ASICs) are trimeric proton-gated sodium channels. Recent work has shown that these channels play a role in necroptosis following prolonged acidic exposure like occurs in stroke. The C-terminus of ASIC1a is thought to mediate necroptotic cell death through interaction with receptor interacting serine threonine kinase 1 (RIPK1). This interaction is hypothesized to be inhibited at rest via an interaction between the C- and N-termini which blocks the RIPK1 binding site. Here, we use two transition metal ion FRET methods to investigate the conformational dynamics of the termini at neutral and acidic pH. We do not find evidence that the termini are close enough to be bound while the channel is at rest and find that the termini may modestly move closer together during acidification. At rest, the N-terminus adopts a conformation parallel to the membrane about 10 Å away. The distal end of the C-terminus may also spend time close to the membrane at rest. After acidification, the proximal portion of the N-terminus moves marginally closer to the membrane whereas the distal portion of the C-terminus swings away from the membrane. Together these data suggest that a new hypothesis for RIPK1 binding during stroke is needed.


Down-regulation of type I Runx2 mediated by dexamethasone is required for 3T3-L1 adipogenesis.
Runx2, a runt-related transcriptional factor family member, is involved in the regulation of osteoblast differentiation. Interestingly, it is abundant in growth-arrested 3T3-L1 preadipocytes and was dramatically down-regulated during adipocyte differentiation. Knockdown of Runx2 expression promoted 3T3-L1 adipocyte differentiation, whereas overexpression inhibited adipocyte differentiation and promoted the trans-differentiation of 3T3-L1 preadipocytes to bone cells. Runx2 was down-regulated specifically by dexamethasone (DEX). Only type I Runx2 was expressed in 3T3-L1 preadipocytes. Using luciferase assay and chromatin immunoprecipitation-quantitative PCR analysis, it was found that DEX repressed this type of Runx2 at the transcriptional level through direct binding of the glucocorticoid receptor (GR) to a GR-binding element in the Runx2 P2 promoter. Further studies indicated that GR recruited histone deacetylase 1 to the Runx2 P2 promoter which then mediated the deacetylation of histone H4 and down-regulated Runx2 expression. Runx2 might play its repressive role through the induction of p27 expression, which blocked 3T3-L1 adipocyte differentiation by inhibiting mitotic clonal expansion. Taken together, we identified Runx2 as a new downstream target of DEX and explored a new pathway between DEX, Runx2, and p27 which contributed to the mechanism of the 3T3-L1 adipocyte differentiation.


Causes of death in patients with celiac disease in a population-based Swedish cohort.
Patients with celiac disease have an increased risk of death from gastrointestinal malignancies and lymphomas, but little is known about mortality from other causes and few studies have assessed long-term outcomes. Nationwide data on 10 032 Swedish patients hospitalized from January 1, 1964, through December 31, 1993, with celiac disease and surviving at least 12 months were linked with the national mortality register. Mortality risks were computed as standardized mortality ratios (SMRs), comparing mortality rates of patients with celiac disease with rates in the general Swedish population. A total of 828 patients with celiac disease died during the follow-up period (1965-1994). For all causes of death combined, mortality risks were significantly elevated: 2.0-fold (95% confidence interval [CI], 1.8-2.1) among all patients with celiac disease and 1.4-fold (95% CI, 1.2-1.6) among patients with celiac disease with no other discharge diagnoses at initial hospitalization. The overall SMR did not differ by sex or calendar year of initial hospitalization, whereas mortality risk in patients hospitalized with celiac disease before the age of 2 years was significantly lower by 60% (95% CI, 0.2-0.8) compared with the same age group of the general population. Mortality risks were elevated for a wide array of diseases, including non-Hodgkin lymphoma (SMR, 11.4), cancer of the small intestine (SMR, 17.3), autoimmune diseases (including rheumatoid arthritis [SMR, 7.3] and diffuse diseases of connective tissue [SMR, 17.0]), allergic disorders (such as asthma [SMR, 2.8]), inflammatory bowel diseases (including ulcerative colitis and Crohn disease [SMR, 70.9]), diabetes mellitus (SMR, 3.0), disorders of immune deficiency (SMR, 20.9), tuberculosis (SMR, 5.9), pneumonia (SMR, 2.9), and nephritis (SMR, 5.4). The elevated mortality risk for all causes of death combined reflected, for the most part, disorders characterized by immune dysfunction.


The hypolipidemic effects of peptides prepared from Cicer arietinum in ovariectomized rats and HepG2 cells.
The lack of estrogen in postmenopausal women is a key risk factor for disorders of lipid metabolism and for obesity. Except in cases where estrogen replacement therapy (ERT) is being used, chickpea peptides (ChPs) may be a potential candidate for treating hyperlipidemia. In ovariectomized rats model, ChPs were found to decrease body weight, adipose tissue size, total cholesterol (TC), total triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and the atherogenic index (AI) in serum and liver TC and TG. Serum high-density lipoprotein cholesterol (HDL-C), bile acids in liver and feces, fecal TC and TG were observed to increase significantly (P < 0.05). ChPs play a role in inhibiting the activities of fatty acid synthetase (FAS) and HMG-CoA reductase (HMGR). The expression of peroxisome proliferator-activated receptors (PPAR)γ and sterol regulatory element-binding protein (SREBP)-1c were downregulated and the expression of liver X receptor (LXR) α, estrogen receptor(ER)α and ERβ were upregulated by ChPs. In HepG2 cell experiments, the cellular TC levels decreased and the uptake of NBD-cholesterol increased significantly after treatment with Mw < 1 kDa and Mw < 5 kDa ChPs fractions. Val-Phe-Val-Arg-Asn (VFVRN) could inhibit TC biosynthesis by decreasing the expression of HMGR. We demonstrated that ChPs could effectively regulate lipid metabolism disorders and restrain obesity caused by estrogen deficiency. Val-Phe-Val-Arg-Asn identified from ChPs could reduce the expression of HMGR to inhibit cholesterol biosynthesis. © 2018 Society of Chemical Industry.


Early endovascular aneurysm repair after percutaneous coronary interventions.
The objective of this study was to report long-term results of early endovascular aortic aneurysm repair after percutaneous coronary intervention (PCI). This was a retrospective analysis of all patients presenting with abdominal aortic aneurysm and coronary artery disease treated during the same hospitalization by endovascular aortic aneurysm repair performed soon after PCI. Primary outcomes were perioperative mortality, perioperative complications, survival after treatment, and freedom from reintervention. A total of 20 patients were included, and all completed both procedures. No deaths or abdominal aortic aneurysm ruptures occurred between the PCI and the aortic intervention. Perioperative mortality was 5% as one patient died of mesenteric ischemia after endovascular aneurysm repair. Major cardiovascular vascular complications occurred in four patients (20%) and included non-ST-segment elevation myocardial infarction (one) and access vessel complication (three). Mean follow-up was 94 (range, 1-164; standard deviation, 47) months. Estimated survival at 1 year, 2 years, 5 years, and 10 years was 90%, 90%, 90%, and 60%, respectively. A reoperation was required in six patients. Estimated freedom from reintervention at 1 year, 2 years, 5 years, and 10 years was 83%, 83%, 78%, and 72%, respectively. Our study indicates that early endovascular aneurysm repair performed within a week after PCI may be a reasonable approach in patients with large or symptomatic aneurysms.


Utilisation of hospital information systems for medical research in Saudi Arabia: A mixed-method exploration of the views of healthcare and IT professionals involved in hospital database management systems.
Although in recent times the Saudi government has paid much attention to the adaptation of hospital information systems (HIS) and electronic medical records (EMR), the importance of utilising HIS to enhance medical research has been neglected. We aimed to (i) investigate the current state of medical research in Saudi Arabia, (ii) identify possible issues that hinder improvement of medical research and (iii) identify possible solutions to enhance the role of HIS in medical research in Saudi Arabia. We used a questionnaire and structured interview approach. Questionnaires were distributed to Saudi healthcare professionals. One hundred responses to our questionnaire were captured by the online Google Form designed specifically for our survey. Structured interviews with two IT professionals were conducted regarding technical aspects of their hospital data management systems. Six themes contributing to the inefficacy of HIS in medical research in Saudi Arabia emerged from the data: incorrect datasets, difficult data collection and storage, poor data analytics, a lack of system interoperability across different HIS for universal access and negative perception of the usefulness of HIS for medical research. Our findings suggest (i) cloud-based HIS would support efficient, reliable and integrated data collection and storage across all hospitals in Saudi Arabia; (ii) EMR data sources should be seamlessly linked to avoid incomplete, fragmented or erroneous EMR in Saudi Arabia; and (iii) collaboration between all hospitals in Saudi Arabia to adopt a uniform standard to support interoperability and improve data exchange and integration is necessary.


Preexisting depression and COVID-19: a cohort study on the risk of susceptibility and hospitalization.
Depression can have negative effects on a person's physical health. However, the available evidence on the risk of susceptibility to COVID-19 and its adverse outcomes in people with mental disorders, including depression, is limited and inconsistent. Therefore, we investigated the relationship between major depressive disorder (MDD) and the risk of susceptibility to COVID-19 infection and hospitalization. The data used in the study were obtained from the Employees' Health Cohort Study of Iran (EHCSIR). We conducted a cohort study that included 3355 participants who had complete data on major depressive disorder at baseline assessment and two annual telephone follow-ups between January 2020 and March 2022. Trained psychologists used the Persian version of the Composite International Diagnostic Interview (CIDI-2.1) to identify major depressive disorders during the baseline assessment. We applied log binomial regression models to adjust for sociodemographic factors and background health conditions. We found that 11.4% of participants had lifetime MDD and 7.3% had MDD in the past 12 months. During the pandemic, 26.1% of participants were infected with COVID-19, and 14.4% of those who were infected were hospitalized. The risk of susceptibility to COVID-19 infection was significantly higher among participants with lifetime MDD than among those without MDD (adjusted risk ratio (ARR) = 1.24, 95% CI: 1.06-1.47). However, lifetime MDD or 12-month MDD was not independently associated with hospitalization among COVID-19 cases. Preexisting major depressive disorder may increase the risk of susceptibility to COVID-19.


MicroRNA profiling of human kidney cancer subtypes.
Although the functions of most of the identified microRNAs (miRNAs) have yet to be determined, their use as potential biomarkers has been considered in several human diseases and cancers. In order to understand their role in renal tumorigenesis, we screened the expression levels of miRNAs in four subtypes of human renal neoplasms: clear cell, papillary, and chromophobe renal cell carcinomas (RCC) as well as benign renal oncocytomas. We found a unique miRNA signature for each subtype of renal tumor. Furthermore, we identified unique patterns of miRNA expression distinguishing clear cell RCC cases with favorable vs. unfavorable outcome. Specifically, we documented the overexpression of miRs 424 and 203 in clear cell RCC relative to papillary RCC, as well as the inversion of expression of miR-203 in the benign oncocytomas (where it is underexpressed relative to normal kidney) as compared to the malignant chromophobe RCC (where it is overexpressed relative to normal kidney). Our results further suggest that overexpression of S-has-miR-32 is associated with poor outcome. While previous studies have identified unique miRNA expression pattern distinguishing tumors from different anatomical locations, here we extend this principle to demonstrate the utility of miRNA expression profiling to identify a signature unique to various tumor subtypes at a single anatomic locus.


A pilot study of inflammatory mediators in brain extracellular fluid in paediatric TBM.
Tuberculous meningitis (TBM) is the most fatal form of tuberculosis and frequently occurs in children. The inflammatory process initiates secondary brain injury processes that lead to death and disability. Much remains unknown about this cerebral inflammatory process, largely because of the difficulty in studying the brain. To date, studies have typically examined samples from sites distal to the site of disease, such as spinal cerebrospinal fluid (CSF) and blood. In this pilot study, we examined the feasibility of using direct brain microdialysis (MD) to detect inflammatory mediators in brain extracellular fluid (ECF) in TBM. MD was used to help guide neurocritical care in 7 comatose children with TBM by monitoring brain chemistry for up to 4 days. Remnant ECF fluid was stored for offline analysis. Samples of ventricular CSF, lumbar CSF and blood were collected at clinically indicated procedures for comparison. Inflammatory mediators were quantified using multiplex technology. All inflammatory markers, with the exception of interleukin (IL)-10 and IL-12p40, were detected in the ECF. Cytokine concentrations were generally lower in ECF than ventricular CSF in time-linked specimens. Individual cases showed ECF cytokine increases coinciding with marked increases in ECF glycerol or decreases in ECF glucose. Cytokine levels and glycerol were generally higher in patients with more severe disease. This is the first report of inflammatory marker analysis from samples derived directly from the brain and in high temporal resolution, demonstrating feasibility of cerebral MD to explore disease progression and possibly therapy response in TBM.


Differential investments and opportunities: How do neighborhood conditions moderate the relationship between perceived housing discrimination and social capital?
Though the adverse consequences of perceived housing discrimination have been documented, little is known about whether such experience undermines one's social capital in a neighborhood and even less is about whether and how this relationship is altered by neighborhood features. We proposed a framework that simultaneously considers within-individual and between-neighborhood processes. We applied multilevel structural equation models to data from Philadelphia (n = 9987) and found that (a) perceived housing discrimination was negatively associated with one's social capital even after other confounders were considered, (b) this negative association could be partly explained by the proliferated daily stress and anxiety mechanisms, (c) differential exposures to neighborhood social disadvantage accounted for the variation in social capital across neighborhoods, and (d) the adverse association between perceived housing discrimination and social capital could be attenuated by neighborhood stability. The findings suggested that appropriate interventions should buffer the negative association of perceived housing discrimination with social capital.


Aldolase A promotes cervical cancer cell radioresistance by regulating the glycolysis and DNA damage after irradiation.
Radioresistance is the major obstacle that affects the efficacy of radiotherapy which is an important treatment for cervical cancer. By analyzing the databases, we found that aldolase A (ALDOA), which is a key enzyme in metabolic reprogramming, has a higher expression in cervical cancer patients and is associated with poor prognosis. We detected the expression of ALDOA in the constructed cervical cancer radioresistance (RR) cells by repetitive irradiation and found that it was upregulated compared to the control cells. Functional assays were conducted and the results showed that the knockdown of ALDOA in cervical cancer RR cells inhibited the proliferation, migration, and clonogenic abilities by regulating the cell glycolysis. In addition, downregulation of ALDOA enhanced radiation-induced apoptosis and DNA damage by causing G2/M phase arrest and further promoted radiosensitivity of cervical cancer cells. The functions of ALDOA in regulating tumor radiosensitivity were also verified by the mouse tumor transplantation model in vivo. Therefore, our study provides new insights into the functions of ALDOA in regulating the efficacy of radiotherapy and indicates that ALDOA might be a promising target for enhancing radiosensitivity in treating cervical cancer patients.


Polymorphonuclear leukocyte chemotactic activity in rabbit serum and Guinea pig serum treated with immune complexes: evidence for c5a as the major chemotactic factor.
A number of polymorphonuclear leukocyte (PMN) chemotactic factors derived from complement components have been described. We sought to determine which of these factors accounted for the majority of PMN chemotactic activity in rabbit serum and guinea pig serum treated with preformed immune complexes. Normal rabbit sera, guinea pig sera, or rabbit sera deficient in C6 were treated with homologous antibovine serum-albumin-bovine serum-albumin complexes. Sera so treated contained one major PMN chemotactic factor which was heat-stable (56 C for 30 min), had a molecular weight of approximately 15,000, and did not require the presence of C6 for its generation. This factor appears to be analogous to C5a.


Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas.
MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy, and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA-eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B-cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (-)-SDS-1-021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.


Antheraea pernyi (Lepidoptera: Saturniidae) and Its Importance in Sericulture, Food Consumption, and Traditional Chinese Medicine.
Sericulture was developed in China in ancient times. Antheraea pernyi Guérin-Méneville was domesticated at least 2,000 yr ago, and Chinese farmers developed artificial rearing of A. pernyi before the 17th century. Today, >60,000 tons of cocoons are produced in China each year, which accounts for 90% of the world production. Despite the widespread utilization of A. pernyi in China and a long history of domestic research, the knowledge of A. pernyi outside China is limited. Therefore, we have in this paper summarized the production, usage, and breeding of A. pernyi. The foremost usage of A. pernyi is as silk producers; however, about 55-70% is used for other purposes. In this paper, we give examples of how the different developmental stages are used as a food source for human consumption and in traditional Chinese medicine, both directly in different preparations and also as a nutrient source for rearing medicinal fungi.


Activation changes of the left inferior frontal gyrus for the factors of construction and scrambling in a sentence.
Our previous functional magnetic resonance imaging (fMRI) studies have indicated that the left dorsal inferior frontal gyrus (L. dF3op/F3t) and left lateral premotor cortex (L. LPMC) are crucial regions for syntactic processing among the syntax-related networks. In the present study, we further examined how activations in these regions were modified by the factors of construction and scrambling (object-initial type). Using various sentence types, we clarified three major points. First, we found that the main effects of construction and scrambling consistently activated the L. dF3op/F3t and L. LPMC. Secondly, the main effects of scrambling clearly localized activation in the L. dF3op/F3t and L. LPMC, indicating the more narrowed down processing of syntax. Thirdly, step-wise percent signal changes were observed in the L. dF3op/F3t, demonstrating synergistic effects of construction and scrambling. These results demonstrate the abstract and intensive nature of syntactic processing carried out by these regions, i.e., the grammar center.


Effect of varying the time frame for COOP-WONCA functional health status charts: a nested randomised controlled trial in Bristol, UK.
To investigate whether changing the stated time frame for COOP-WONCA charts has any effect on responses. Specifically, to assess the effect of attempting to avoid the situation where the time frame crosses the onset of an acute episode. A randomised controlled trial of two time frames, nested within a main trial comparing early discharge with a hospital at home scheme against routine discharge policy. The time frames compared were the standard two weeks (four for the pain chart) and a shorter period of 48 hours for all seven charts. Acute hospital wards in Frenchay Healthcare Trust and the Avon Orthopaedic Centre in Bristol. Patients entered into the main trial, who were medically stable, in need of continued rehabilitative care but suitable for discharge to hospital at home. A total of 200 patients were randomised, 106 to the shorter time frame, 94 to the standard charts. No clear differences were observed between the two groups for the proportion failing to self complete the charts. For the (seven) chart scores, only pain was statistically significantly different between the time frames (Mann-Whitney p = 0.0085; proportion reporting moderate or severe pain 19% higher in the standard group, 95% confidence intervals 5% to 33%). For both this chart and that for change in health, however, there was evidence of greater differences between the versions of the chart among those admitted more recently (p values for relevant interactions 0.004 and < or = 0.001 respectively). While the present findings give some support for the wide applicability of the standard version, there is sufficient evidence here to indicate that the time frame may influence the results, particularly for patients with a recent acute episode. In the absence of further data, then, it would seem prudent to consider a shorter time frame for such patients, especially if the aim is to assess current health status or to measure changes over a comparatively short period of time, or both.


Nuclear and cytosolic distribution of metallothionein in the blue mussel Mytilus edulis L.
Four tissues from the blue mussel, Mytilus edulis L., were examined for the presence of nuclear metallothionein (MT), and the nuclear:cytosolic (N:C) MT ratios and nuclear MT:DNA ratios investigated. Gill, digestive gland, gonad and posterior adductor muscle tissues were dissected, homogenized and subjected to differential centrifugation in order to isolate the nuclear and cytosolic fractions, which were then analyzed for MT and DNA. MT was present in all samples of the nuclear fractions from all four tissues. The nuclear MT concentration was either lower or the same as the cytosolic MT concentration from the same tissue. The mean N:C MT ratio of the digestive gland was significantly lower than that of the gill. The mean nuclear MT:DNA ratio of the digestive gland was significantly higher than that of the gill and posterior adductor muscle. In addition to being the first report of nuclear MT in bivalves, we showed that N:C MT ratios and nuclear MT:DNA ratios differ among tissues of the same organism. This raises important questions concerning the regulation of nuclear MT concentrations and the role of nuclear MT in metal regulation and DNA protection.


The role of cyclin-dependent kinase 5 and a novel regulatory subunit in regulating muscle differentiation and patterning.
Cyclin-dependent kinase 5, coupled with its activator p35, is required for normal neuronal differentiation and patterning. We have isolated a novel member of the p35 family, Xp35.1, from Xenopus embryos which can activate cdk5. Xp35.1 is expressed in both proliferating and differentiated neural and mesodermal cells and is particularly high in developing somites where cdk5 is also expressed. Using dominant-negative cdk5 (cdk5 DN), we show that cdk5 kinase activity is required for normal somitic muscle development; expression of cdk5 DN results in disruption of somitic muscle patterning, accompanied by stunting of the embryos. Using explants of animal pole tissue from blastula embryos, which will differentiate into mesoderm in response to activin, we show that blocking cdk5 kinase activity down-regulates the expression of the muscle marker muscle actin in response to activin, whereas the pan-mesodermal marker Xbra is unaffected. Expression of MyoD and MRF4 (master regulators of myogenesis) is suppressed in the presence of cdk5 DN, indicating that these myogenic genes may be a target for cdk5 regulation, whereas the related factor Myf5 is largely unaffected. In addition, overexpression of Xp35.1 disrupts muscle organization. Thus, we have demonstrated a novel role for cdk5 in regulating myogenesis in the early embryo.


Volumetry and analysis of anatomical variants of the anterior portion of the petrous apex outlined by the kawase triangle using computed tomography.
Background Anterior petrosectomy has become an increasingly used approach for petroclival lesions. This study measures the volume and the anatomical variants of the anterior portion of the petrous apex outlined by the Kawase triangle using computed tomography (CT). Methods This was a transversal retrospective study. We assessed the anterior petrous apex portion outlined by the Kawase triangle in consecutive patients > 18 years of age from CT scans of temporal bone stored in an archive system. The volumetry was performed on a workstation. Results A total of 154 petrosal apex were analyzed in 77 patients (36 men). The average volume of the region outlined by the Kawase triangle was 1.89 ± 0.52 cm(3). The volume average in men was 2.01 ± 0.58 cm(3), and the average in women was 1.79 ± 0.41 cm(3). Intra- and interobserver agreement were both excellent, and there was little variance. Nineteen petrous apex demonstrated anatomical variations. In 18 cases it was pneumatized, and in one case a vascular or nerve-like structure was identified, a report we did not find in the literature. Conclusion The volumetry of the petrous apex anterior portion outlined by the Kawase triangle can be made by CT with excellent intra- and interobserver agreement and reproducibility. There are anatomical variants in this region that are relevant to surgery.


Use of ureteric stent related mobile phone application (UROSTENTZ App) in COVID-19 for improving patient communication and safety: a prospective pilot study from a university hospital.
During the COVID-19 led lockdown, a reliable system to monitor ureteral stent insertion and timely removal became an important facet of their use. This study looks at the use of 'Urostentz' smartphone application (app) for stent procedures and whether it improved patient communication and safety during the lockdown. The 'Urostentz' app was used for patients who underwent ureteric stent after ureteroscopy (URS) or percutaneous nephrolithotomy (PCNL) procedure. It is a smartphone app developed to improve patient safety, facilitate data collection, and provide an efficient interface to simplify ureteral stent tracking and patient communication. It also helps clinicians track stent-related symptoms (SRS) and provide digital remote assistance. A total of 33 patients registered with a mean age of 47.8 years (range:18-80) and a male: female ratio of 4.5:1. Of these, 29 (87.9%) used the Urostentz app, and 55.2% had SRS. The number of effective communication episodes ranged from 1-7/patient. Based on the symptoms and communication, stent was removed during lockdown (n = 2), within 1 week of lockdown lifted (n = 24) and within 2 weeks of lockdown lifted (n = 5). None of the patients suffered any stent-related complications and there were no cases of forgotten stents or readmissions despite the lockdown and lack of communication using standard practices. The Urostentz app proved to an effective medium of communication to provide guidance and personalized digital remote healthcare. It also allowed prompt removal of stents avoiding prolonged stent symptoms or forgotten stents. Such apps can have a much wider application in the post-COVID-19-era to reduce unnecessary post-procedural visits and reduce health care costs.


FADS genetic variants and omega-6 polyunsaturated fatty acid metabolism in a homogeneous island population.
Long-chain polyunsaturated fatty acids (PUFA) orchestrate immunity and inflammation through their capacity to be converted to potent inflammatory mediators. We assessed associations of FADS gene cluster polymorphisms and fasting serum PUFA concentrations in a fully ascertained, geographically isolated founder population of European descent. Concentrations of 22 PUFAs were determined by gas chromatography, of which ten fatty acids and five ratios defining FADS1 and FADS2 activity were tested for genetic association against 16 single nucleotide polymorphisms (SNP) in 224 individuals. A cluster of SNPs in tight linkage disequilibrium in the FADS1 gene (rs174537, rs174545, rs174546, rs174553, rs174556, rs174561, rs174568, and rs99780) were strongly associated with arachidonic acid (AA) (P = 5.8 x 10(-7) - 1.7 x 10(-8)) among other PUFAs, but the strongest associations were with the ratio measuring FADS1 activity in the omega-6 series (P = 2.11 x 10(-13) - 1.8 x 10(-20)). The minor allele across all SNPs was consistently associated with decreased omega-6 PUFAs, with the exception of dihomo-gamma-linoleic acid (DHGLA), where the minor allele was consistently associated with increased levels. Our findings in a geographically isolated population with a homogenous dietary environment suggest that variants in the Delta-5 desaturase enzymatic step likely regulate the efficiency of conversion of medium-chain PUFAs to potentially inflammatory PUFAs, such as AA.


Co-exposure to the food additives SiO2 (E551) or TiO2 (E171) and the pesticide boscalid increases cytotoxicity and bioavailability of the pesticide in a tri-culture small intestinal epithelium model: Potential health implications.
Many toxicity investigations have evaluated the potential health risks of ingested engineered nanomaterials (iENMs); however, few have addressed the potential combined effects of iENMs and other toxic compounds (e.g. pesticides) in food. To address this knowledge gap, we investigated the effects of two widely used, partly nanoscale, engineered particulate food additives, TiO2 (E171) and SiO2 (E551), on the cytotoxicity and cellular uptake and translocation of the pesticide boscalid. Fasting food model (phosphate buffer) containing iENM (1% w/w), boscalid (10 or 150 ppm), or both, was processed using a simulated in vitro oral-gastric-small intestinal digestion system. The resulting small intestinal digesta was applied to an in vitro tri-culture small intestinal epithelium model, and effects on cell layer integrity, viability, cytotoxicity and production of reactive oxygen species (ROS) were assessed. Boscalid uptake and translocation was also quantified by LC/MS. Cytotoxicity and ROS production in cells exposed to combined iENM and boscalid were greater than in cells exposed to either iENM or boscalid alone. More importantly, translocation of boscalid across the tri-culture cellular layer was increased by 20% and 30% in the presence of TiO2 and SiO2, respectively. One possible mechanism for this increase is diminished epithelial cell health, as indicated by the elevated oxidative stress and cytotoxicity observed in co-exposed cells. In addition, analysis of boscalid in digesta supernatants revealed 16% and 30% more boscalid in supernatants from samples containing TiO2 and SiO2, respectively, suggesting that displacement of boscalid from flocculated digestive proteins by iENMs may also contribute to the increased translocation.


The effect of tenofovir disoproxil fumarate on bone mineral density: a systematic review and meta-analysis.
We conducted a systematic review and meta-analysis (CRD#42017070552) to quantify the impact of oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) on bone mineral density (BMD) and the risk of osteoporosis, low bone mass and fractures, among people taking it as pre-exposure prophylaxis (PrEP), HIV treatment and HBV treatment. We searched MEDLINE and EMBASE for randomized controlled trials published from 1997-2018 reporting BMD, osteoporosis, low bone mass and/or fractures in treatment-naive patients taking compared with not taking TDF for 48 ±4 weeks. We pooled outcomes using DerSimonian random-effects models. Our search yielded 5,178 abstracts, representing 3,865 articles, with 25 meeting the inclusion criteria. TDF was associated with greater BMD decline when taken as PrEP (lumbar spine: mean difference [MD]=-0.82%, 95% CI=-1.28, -0.37%, I2=38%; total hip: MD=-0.81%, 95% CI=-1.22, -0.40%, I2=48%) and HIV treatment (lumbar spine: MD=-1.62%, 95% CI=-2.30, -0.95%, I2=93%; total hip: MD=-1.75%, 95% CI=-2.08, -1.42%, I2=83%; femoral neck: MD=-1.26%, 95% CI=-2.15, -0.38%, I2=43%) in comparison to those not taking TDF. Eight studies reported on incident osteoporosis or low bone mass, with variable results. Pooled results from five PrEP studies showed that TDF was not associated with increased fractures compared with no PrEP (RR=1.12, 95% CI=0.752, 1.74, I2=26%). TDF caused greater decreases in BMD than did comparators when used for all three indications and the magnitude of this decrease was larger for HIV treatment compared with PrEP. Fractures were not increased among PrEP patients. The clinically significant BMD decline caused by TDF and current expansion of PrEP use suggest attention to the adverse bone effects of TDF will increase in importance.


Enhancement of dynamin polymerization and GTPase activity by Arc/Arg3.1.
The Activity-regulated cytoskeleton-associated protein, Arc, is an immediate-early gene product implicated in various forms of synaptic plasticity. Arc promotes endocytosis of AMPA type glutamate receptors and regulates cytoskeletal assembly in neuronal dendrites. Its role in endocytosis may be mediated by its reported interaction with dynamin 2, a 100 kDa GTPase that polymerizes around the necks of budding vesicles and catalyzes membrane scission. Enzymatic and turbidity assays are used in this study to monitor effects of Arc on dynamin activity and polymerization. Arc oligomerization is measured using a combination of approaches, including size exclusion chromatography, sedimentation analysis, dynamic light scattering, fluorescence correlation spectroscopy, and electron microscopy. We present evidence that bacterially-expressed His6-Arc facilitates the polymerization of dynamin 2 and stimulates its GTPase activity under physiologic conditions (37°C and 100mM NaCl). At lower ionic strength Arc also stabilizes pre-formed dynamin 2 polymers against GTP-dependent disassembly, thereby prolonging assembly-dependent GTP hydrolysis catalyzed by dynamin 2. Arc also increases the GTPase activity of dynamin 3, an isoform of implicated in dendrite remodeling, but does not affect the activity of dynamin 1, a neuron-specific isoform involved in synaptic vesicle recycling. We further show in this study that Arc (either His6-tagged or untagged) has a tendency to form large soluble oligomers, which may function as a scaffold for dynamin assembly and activation. The ability of Arc to enhance dynamin polymerization and GTPase activation may provide a mechanism to explain Arc-mediated endocytosis of AMPA receptors and the accompanying effects on synaptic plasticity.


Emergence and localized circulation of a vaccine-derived poliovirus in an isolated mountain community in Guangxi, China.
From March to May 2006, type 1 circulating vaccine-derived poliovirus (cVDPV) was isolated from one case patient with acute flaccid paralysis (AFP) and six unimmunized healthy contacts in isolated mountain villages in Guangxi, China. We conducted epidemiological investigations in the affected communities and nucleotide sequence analyses of the cVDPV isolates. The results of the investigations showed that the AFP patient, an unimmunized 10-year-old boy, and five laboratory-confirmed contacts lived in the same village; one contact lived in a neighboring village. Only approximately 27% of children 5 to 10 years of age in the affected villages had received three or more doses of the trivalent oral poliovirus vaccine (OPV). Nucleotide sequence analyses revealed that the cVDPV isolates differed from the Sabin 1 (S1) isolate at 1.4 to 2.2% of VP1 nucleotide positions and shared 12 nucleotide substitutions within VP1. All isolates were S1/S2/S1/S3 recombinants sharing common recombination junctions. Key determinants of attenuation were replaced. Phylogenetic analysis suggested that the cVDPV circulated locally for approximately 12 months following the initiating OPV dose. No VDPVs were found after mass OPV immunizations, conducted from May to June 2006, that targeted all children <12 years of age. Our findings reinforce the point that VDPVs can emerge and spread in isolated communities with immunity gaps. Maintenance of sensitive AFP and poliovirus surveillance is essential to permit early detection and a rapid response to VDPV circulation.


Comparison of dorzolamide and timolol as suppressors of aqueous humor flow in humans.
To measure the effectiveness of topical 2% dorzolamide hydrochloride (Trusopt, Merck & Co Inc, Whitehouse Station, NJ) as a suppressor of aqueous humor flow in the human eye as compared with the effectiveness of 0.5% timolol maleate (Timoptic, Merck & Co Inc) and to measure the additivity of the 2 drugs. A randomized, double-masked, placebo-controlled study of 40 human subjects was carried out in 2 academic centers (Mayo Clinic, Rochester, Minn, and University of Uppsala, Uppsala, Sweden). The rate of aqueous flow was measured from 8 AM to 4 PM by means of fluorophotometry after administration of doses of each drug singly and both drugs together. Dorzolamide reduced aqueous flow from 3.07 +/- 0.63 microL/min (mean +/- SD) to 2.53 +/- 0.60 microL/min, a reduction of 18% (P < .001). Timolol reduced aqueous flow from the same beginning rate to 1.64 +/- 0.35 microL/min, a reduction of 47% (P < .001). The inhibitory effect of timolol was 2.6 times the inhibitory effect of dorzolamide (P < .001). The 2 drugs were almost completely additive, and together reduced the flow to 1.37 +/- 0.33 microL/min, a reduction of 55%. Consistent effects were observed on intraocular pressure. Timolol is more effective than dorzolamide as a suppressor of aqueous humor flow in the normal human eye. Timolol and dorzolamide are additive in their effects, both on aqueous flow and intraocular pressure.


Understanding The Rare Bone Tumor "ADAMANTINOMA".
Adamantinoma is a rare neoplastic bone tumor that has the potential to metastasize. The classic presentation is in the tibial region however; cases involving other bones of the body have been noticed. The tumour is very likely to be mistaken for other bone diseases and therefore it is important to investigate and study about its nature and thus differentiate it from other differentials. Nevertheless, literature on the presentation, findings, investigations and treatment options of adamantinomas are limited. In this case series, we report four cases from a local hospital in Karachi who were diagnosed, treated and followed up for adamantinoma. Studies regarding the disease will help us understand more about its features.


Arbitrarily Long Relativistic Bit Commitment.
We consider the recent relativistic bit commitment protocol introduced by Lunghi et al. [Phys. Rev. Lett. 115, 030502 (2015)] and present a new security analysis against classical attacks. In particular, while the initial complexity of the protocol scales double exponentially with the commitment time, our analysis shows that the correct dependence is only linear. This has dramatic implications in terms of implementation: in particular, the commitment time can easily be made arbitrarily long, by only requiring both parties to communicate classically and perform efficient classical computation.


Electrode materials for stretchable triboelectric nanogenerator in wearable electronics.
Stretchable Triboelectric Nanogenerators (TENGs) for wearable electronics are in significant demand in the area of self-powered energy harvesting and storage devices. Designing a suitable electrode is one of the major challenges in developing a fully wearable TENG device and requires research aimed at exploring new materials and methods to develop stretchable electrodes. This review article is dedicated to presenting recent developments in exploring new materials for flexible TENGs with special emphasis on electrode components for wearable devices. In addition, materials that can potentially deliver properties such as transparency, self-healability and water-resistance are also reviewed. Inherently stretchable materials and a combination of soft and rigid materials including polymers and their composites, inorganic and ceramic materials, 2D materials and carbonaceous nanomaterials are also addressed. Additionally, various fabrication strategies and geometrical patterning techniques employed for designing highly stretchable electrodes for wearable TENG devices are also explored. The challenges reflected in the present approaches as well as feasible suggestions for future advancements are discussed.


Magnetic resonance imaging and histologic study of hypertrophic cervical posterior longitudinal ligament. A case report.
Magnetic resonance imaging and histologic features of hypertrophic cervical posterior longitudinal ligament were determined in a cervical myelopathy patient. On T1-weighted images, the thickened ligament and the prolapsed nucleus pulposus showed isointensity shadows, making it impossible to differentiate these tissues. On T2-weighted images, the thickened ligament and prolapsed nucleus pulposus were visualized at high and low intensity, respectively. Sagittal T1-weighted images after gadolinium-diethylene triamine pentaacetic acid injection showed obvious enhancement of the thickened ligament.


Peroxisome proliferator-activated receptor-gamma-deficient heterozygous mice develop an exacerbated neural antigen-induced Th1 response and experimental allergic encephalomyelitis.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor transcription factor that regulates cell growth, differentiation, and homeostasis. PPARgamma agonists are potent therapeutic agents for type 2 diabetes, obesity, and inflammation. Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis. We have shown recently that PPARgamma agonists inhibit EAE by blocking IL-12 production, IL-12 signaling, and neural Ag-induced Th1 differentiation. In this study, we show that the PPARgamma-deficient heterozygous mice develop an exacerbated EAE with prolonged clinical symptoms than the wild-type littermates, following immunization with myelin oligodendrocyte glycoprotein (MOG) p35-55 peptide. The exacerbation of EAE in PPARgamma(+/-) mice associates with an increased expansion of CD4(+) and CD8(+) T cells and expression of CD40 and MHC class II molecules in response to MOGp35-55 Ag. The PPARgamma(+/-) mice also showed an increase in T cell proliferation and Th1 response to MOGp35-55 Ag than the wild-type littermates. These findings suggest that PPARgamma be a critical physiological regulator of CNS inflammation and demyelination in EAE and perhaps multiple sclerosis and other Th1 cell-mediated autoimmune diseases.


Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: preferential inhibition of CYP2D6.
The ability of antipsychotic drugs to inhibit the catalytic activity of five cytochrome P-450 (CYP) isoforms was compared using in vitro human liver microsomal preparations to evaluate the relative potential of these drugs to inhibit drug metabolism. The apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data. All antipsychotic drugs tested competitively inhibited dextromethorphan O-demethylation, a selective marker for CYP2D6, in a concentration-dependent manner. Thioridazine and perphenazine were the most potent, with IC(50) values (2.7 and 1.5 microM) that were comparable to that of quinidine (0.52 microM). The estimated K(i) values for CYP2D6-catalyzing dextrorphan formation were ranked in the following order: perphenazine (0.8 microM), thioridazine (1.4 microM), chlorpromazine (6.4 microM), haloperidol (7.2 microM), fluphenazine (9.4 microM), risperidone (21.9 microM), clozapine (39.0 microM), and cis-thiothixene (65.0 microM). No remarkable inhibition of other CYP isoforms was observed except for moderate inhibition of CYP1A2-catalyzed phenacetin O-deethylation by fluphenazine (K(i) = 40.2 microM) and perphenazine (K(i) = 65.1). The estimated K(i) values for the inhibition of CYP2C9, 2C19, and 3A were >300 microM in almost all antipsychotics tested. These results suggest that antipsychotic drugs exhibit a striking selectivity for CYP2D6 compared with other CYP isoforms. This may reflect a remarkable commonality of structure between the therapeutic targets for these drugs, the transporters, and metabolic enzymes that distribute and eliminate them. Clinically, coadministration of these medicines with drugs that are primarily metabolized by CYP2D6 may result in significant drug interactions.


Evaluation of venous thromboembolism (VTE) risk assessment and thrombo-prophylaxis practices in hospitalized medical and surgical patients at Aga Khan Hospital Dar es Salaam: single-centre retrospective study.
venous thromboembolism is a complication among admitted medical and surgical patients. International guidelines recommend patients are assessed upon admission and appropriate thromboprophylaxis should be initiated. However, studies have shown that thromboprophylaxis for patients at risk of venous thromboembolism is underutilized. this was a retrospective study conducted on hospitalized medical and surgical patients at Aga Khan Hospital Dar es salaam from January to June 2019. Patient's medical records were reviewed and data was collected for analysis of venous thromboembolism assessment and compliance with Caprini risk assessment model. The data was entered into statistical package for the social sciences (SPSS) 25 and categorized into risk groups, frequency of patients' demographic and clinical characteristics data was calculated and the main study outcomes were analyzed with Fisher´s exact test or Pearson chi-square test for categorical variables and student t-test for continuous variables. Regression analyses were done to identify significant risk factors where by P ≤ 0.05 was considered statistically significant. compliance of venous thromboembolism assessment among medical and surgical patients was similar at 78% and 80%, respectively, with a baseline 22% of all admitted patients considered at risk of venous thromboembolism, hence needing thromboprophylaxis following the Caprini risk assessment modelscore. Thromboprophylaxis practices was identified at just 25% of at-risk individuals received pharmacological prophylaxis with enoxaparin; the most commonly used agent (92%). Identified risk factors for venous thromboembolism were advancing age (>60 years), history of prior major surgery, Major surgery lasting > 60 minutes, obesity, and immobilization. risk assessment for venous thromboembolism should be emphasized upon admission of both surgical and medical patients. Adequate thromboprophylaxis should be prescribed upon identification of patients at risk.


The informed consent in the mature minor: Understanding and decision-making capacity.
The informed consent of the minor is a fundamental requirement of paediatric research. There is a lack of harmonisation as regards the age of the mature minor to consent, and there are no systematic tools available to assess competence in decision-making capacity. The objective of this work is to analyse the ethical and legal situation of consent by minors, as well as studies that use an objective assessment tool in the mature minor. Systematic review of scientific articles in PubMed, Embase and the Grey Literature, published with keywords "informed consent minors", without date restriction until March 2019. Abstracts and a selection of complete articles were reviewed following a protocol including identification, screening, eligibility, and inclusion. Of the 260 records identified, 139 were excluded. After categorising the resulting 121 publications, 13 were finally selected following the eligibility criteria, including 7 articles on international ethical and legal regulations and 6 on understanding and decision- making capacity assessment. The MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) semi-structured interview was used in 4 studies, including different age ranges (6-21 years) in healthy and sick children. The semi-structured MacArthur interview adapted to adolescents could be an appropriate tool with robust psychometric measures for assessing competence for the informed consent of minors between 9 and 12 years of age. The regulation of informed consent in paediatric research should consider this evidence.


Histone H1 variants are differentially expressed and incorporated into chromatin during differentiation and reprogramming to pluripotency.
There are seven linker histone variants in human somatic cells (H1.0 to H1.5 and H1X), and their prevalence varies as a function of cell type and differentiation stage, suggesting that the different variants may have distinct roles. We have revisited this notion by using new methodologies to study pluripotency and differentiation, including the in vitro differentiation of human embryonic stem (ES) and teratocarcinoma cells and the reprogramming of keratinocytes to induced pluripotent stem cells. Our results show that pluripotent cells (PCs) have decreased levels of H1.0 and increased levels of H1.1, H1.3, and H1.5 compared with differentiated cells. PCs have a more diverse repertoire of H1 variants, whereas in differentiated cells, H1.0 expression represents ∼80% of the H1 transcripts. In agreement with their prevalent expression in ES cells, the regulatory regions of H1.3 and H1.5 genes were found to be occupied by pluripotency factors. Moreover, the H1.0 gene promoter contains bivalent domains (H3K4me2 and H3K27me3) in PCs, suggesting that this variant is likely to have an important role during differentiation. Indeed, the knockdown of H1.0 in human ES did not affect self-renewal but impaired differentiation. Accordingly, H1.0 was recruited to the regulatory regions of differentiation and pluripotency genes during differentiation, confirming that this histone variant plays a critical role in the regulation of these genes. Thus, histone H1 variant expression is controlled by a variety of mechanisms that produce distinct but consistent H1 repertoires in pluripotent and differentiated cells that appear critical to maintain the functionality of such cells.


Dermal Hyperneury and Multiple Sclerotic Fibromas in Multiple Endocrine Neoplasia Type 2A Syndrome.
Multiple endocrine neoplasia type 2 (MEN 2) syndrome is an autosomal dominant, hereditary cancer disorder caused by germline mutations in the RET (formerly MEN2A, MEN2B) proto-oncogene located on chromosomal band 10q11.21. Two distinct clinical forms have been described as the following phenotypes: multiple endocrine neoplasia type 2A (MEN 2A) and multiple endocrine neoplasia type 2B (MEN 2B) syndromes. The common and necessary nexus that defines these 2 phenotypes is the presence of medullary thyroid carcinoma (MTC). The familial MTC type of MEN 2 syndrome was included within the spectrum of MEN 2A syndrome. Cutaneous manifestations of MEN 2A syndrome include macular amyloidosis, whereas MEN 2B syndrome is traditionally linked to multiple mucosal neuromas. To describe a family with cutaneous manifestations not previously described in patients with MEN 2A syndrome and to discuss the association of this disorder with Cowden syndrome. Clinicopathologic correlation of cutaneous lesions and genetic studies in 11 members of a family with familial MTC. Cutaneous lesions were histopathologically and immunohistochemically studied. Genetic screening for a germline mutation at the RET gene was performed in 11 family members. Identification of cutaneous lesions not previously described in patients with MEN 2A syndrome. This family of 11 individuals with familial MTC type of MEN 2A syndrome demonstrated the moderate risk RET p.Val804Met (protein valine at residue 804 replaced by methionine) genetic mutation, with 2 of the relatives presenting with dermal hyperneury, cutaneous lesions classically described in MEN 2B syndrome, and 1 relative also showing multiple sclerotic fibromas, a cutaneous manifestation of PTEN (phosphatase and tensin homologue) hamartoma-tumor syndrome. Dermal hyperneury and multiple sclerotic fibromas should be added to the list of cutaneous manifestations of patients with the familial MTC type of MEN 2A syndrome.


Charged domains in ferroelectric, polycrystalline yttrium manganite thin films resolved with scanning electron microscopy.
We have investigated ferroelectric charged domains in polycrystalline hexagonal yttrium manganite thin films (Y1Mn1O3, Y0.95Mn1.05O3, Y1Mn0.99Ti0.01O3, and Y0.94Mn1.05Ti0.01O3) by scanning electron microscopy (SEM) in secondary electron emission mode with a small acceleration voltage. Using SEM at an acceleration voltage of 1.0 kV otherwise homogenous surface charging effects are reduced, polarization charges can be observed and polarization directions (±Pz) of the ferroelectric domains in the polycrystalline thin films can be identified. Thin films of different chemical composition have been deposited by pulsed laser deposition on Pt/SiO2/Si structures under otherwise same growth conditions. Using SEM it has been shown that different charged domain density networks are existing in polycrystalline yttrium manganite thin films.


Sirt1 mediates improvement in cognitive defects induced by focal cerebral ischemia following hyperbaric oxygen preconditioning in rats.
Hyperbaric oxygen preconditioning (HBO-PC) has been proposed as a safe and practical approach for neuroprotection in ischemic stroke. However, it is not known whether HPO-PC can improve cognitive deficits induced by cerebral ischemia, and the mechanistic basis for any beneficial effects remains unclear. We addressed this in the present study using rats subjected to middle cerebral artery occlusion (MCAO) as an ischemic stroke model following HBO-PC. Cognitive function and expression of phosphorylated neurofilament heavy polypeptide (pNF-H) and doublecortin (DCX) in the hippocampus were evaluated 14 days after reperfusion and after short interfering RNA-mediated knockdown of sirtuin1 (Sirt1). HBO-PC increased pNF-H and DCX expression and mitigated cognitive deficits in MCAO rats. However, these effects were abolished by Sirt1 knockdown. Our results suggest that HBO-PC can protect the brain from injury caused by ischemia-reperfusion and that Sirt1 is a potential molecular target for therapeutic approaches designed to minimize cognitive deficits caused by cerebral ischemia.


Ab Interno Gel Implant for the Treatment of Glaucoma Patients With or Without Prior Glaucoma Surgery: 1-Year Results.
The purpose of this study is to evaluate IOP lowering effects and complication management of an ab interno gel implant for the treatment of patients refractory to antiglaucoma medication or glaucoma surgery. Retrospective analysis of the medical records of 242 consecutive eyes of 146 patients with uncontrolled intraocular pressure (IOP) despite maximum tolerated medical therapy or prior surgical intervention that underwent XEN45 implantation (as sole procedure or in combination with cataract surgery) between March 2014 and June 2015. Data included IOP, number of glaucoma medications, the need for additional surgery, needling, and complications. During the study period, mean IOP had decreased by 54.1% from 32.19 (±9.1) mm Hg to 14.24 (±4.0) mm Hg (P=0.00; Wilcoxon test). The number of antiglaucoma medications had decreased from a mean of 3.13±1.0 to 0.3±0.7 (P=0.00; Wilcoxon test). Needling was required between week 1 and months 3 in 27.7% of all eyes to enhance the outflow. Hypotony (IOP<6 mm Hg) was observed in 9 eyes (4.0%) at 1 month but normalized in all eyes at 12 months postoperatively. Two eyes experienced hypotony requiring the refill of the anterior chamber. Our data indicate that the XEN45 gel implant has a favorable safety profile and is an effective treatment option for controlling IOP in glaucoma patients with unregulated IOP despite IOP lowering medical therapy or prior surgical intervention. It offers an effective approach, both as sole procedure and in combination with cataract surgery.


Trends in the prevalence of depression in hospitalized patients with type 2 diabetes in Spain: analysis of hospital discharge data from 2001 to 2011.
This study aims to describe trends in the prevalence of depression among hospitalized patients with type 2 diabetes in Spain, 2001-2011. We selected patients with a discharge diagnosis of type 2 diabetes using national hospital discharge data. Discharges were grouped by depression status. Prevalence of depression globally and according to primary diagnoses based on the Charlson comorbidity index (CCI) were analyzed. We calculated length of stay (LOHS) and in-hospital mortality (IHM). Multivariate analysis was adjusted by age, year and comorbidity. From 2001 to 2011, 4,723,338 discharges with type 2 diabetes were identified (4.93% with depression). Prevalence of depression in diabetic patients increased from 3.54% in 2001 to 5.80% in 2011 (p<0.05). The prevalence of depression was significantly higher in women than in men in each year studied and increased from 5.22% in 2001 to 9.24% in 2011 (p<0.01). The highest prevalence was observed in the youngest age group (35-59 years). The median LOHS decreased significantly over this period. Men with diabetes and depression had higher IHM than women in all the years studied (p<0.05). Older age and greater comorbidity were significantly associated with a higher risk of dying, among diabetic patients with concomitant depression. Prevalence of depression increased significantly among hospitalized diabetic patients from 2001 to 2011 even if the health profile and LOHS have improved over this period. Programs targeted at preventing depression among persons with diabetes should be reinforced in Spain.


Phenomenology and theory of horizontally oscillated granular mixtures.
We overview the physics of a granular mixture subject to horizontal oscillations, recently investigated via experiments and molecular dynamics simulations. First we discuss the rich phenomenology exhibited by this system, which encompasses both segregation and dynamical instabilities. Then we show that the phenomenology can be explained via an effective interaction approach, by which the driven, non-thermal, granular mixture in mapped into a monodispersed thermal system of particles interacting via an effective potential. After determining the effective interaction we discuss its microscopic origin and investigate how it induces the observed phenomenology. Finally, as much as in thermal fluids, from the effective interaction we derive a Cahn-Hilliard dynamics equation, which appears to capture the essential characteristics of the dynamics of the granular mixture.


Clostridium difficile colitis following head and neck surgery. Report of cases.
Clostridium difficile, a toxin-producing, gram-positive anaerobe, has been implicated as the causative agent of pseudomembranous colitis, an acute inflammatory bowel disease that generally occurs in association with antimicrobial therapy. This subject has received extensive review in the general surgical, medical, and pediatric literature but has not been specifically addressed in the literature of our specialty. We present the report of four recent cases, including one that progressed to the clinical picture of peritonitis and toxin megacolon. The literature is reviewed regarding presentation, diagnosis, and treatment of C difficile colitis. Familiarity with this disease process may minimize morbidity and prevent disastrous complications following major head and neck surgery.


Validity of the current NCAA minimum weight protocol: a brief review.
Historically, collegiate wrestlers have been associated with utilizing rapid weight loss methods to reach a desired weight class. Following three deaths in 1997, the National Collegiate Athletic Association (NCAA) implemented a program which prevents wrestlers from wrestling below a minimum weight (MW) of 5% body fat. Although numerous studies have investigated adolescent wrestlers, few have investigated collegiate wrestlers using the methods outlined by the NCAA. The purpose of this review paper is to outline potential problems with the current NCAA protocol as well as critique studies investigating the validity of methods to assess MW.


AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling.
Toll-like receptor 4 (TLR4) is unique among the Toll-like receptors in its ability to utilize TLR/IL1R-domain-containing adaptor protein (TIRAP), which recruits TLR4-MyD88 to phosphatidylinositol 4,5-bisphosphate (PIP(2))-rich sites on the plasma membrane, to activate NF-kappaB and MAPK pathways. Here, we show that AIP1 disrupts formation of the TLR4- TIRAP-MyD88 complex without directly binding to any of the complex components. AIP1 via its pleckstrin homology and C2 domains binds to phosphatidylinositol 4-phosphate, a lipid precursor of PIP(2). Knock-out of AIP1 in cells increases and overexpression of AIP1 reduces cellular PIP(2) levels. We further show that AIP1 is a novel GTPase-activating protein (GAP) for Arf6, a small GTPase regulating cellular PIP(2) production and formation of the TLR4-TIRAP-MyD88 complex. Thus, deletion of the GAP domain on AIP1 results in a loss of its ability to mediate the inhibition of Arf6- and TLR4-induced signaling events. We conclude that AIP1 functions as a novel Arf6-GAP to negatively regulate PIP(2)-dependent TLR4-TIRAP-MyD88 signaling.


INCIDENCE OF PSEUDOEXFOLIATION SYNDROME AND GLAUCOMA IN A SET OF MORE THAN 14,000 EYES OF PATIENTS OPERATED FOR A CATARACT.
Evaluation of the incidence of pseudoexfoliation (PEX) syndrome and glaucoma in cataract patients operated at our Clinic, with an analysis of possible complications. Retrospective evaluation of medical records of PEX syndrome patients who have undergone cataract surgery at the Gemini Eye Clinic Ostrava-Hrusov was undertaken. The study period was from November 2016 to April 2021. The evaluated parameters were the incidence of PEX syndrome, age and gender of patients, intraocular pressure (IOP) before the surgery, pre-existing therapy of previously diagnosed secondary glaucoma and the occurrence of perioperative complications. In the study period of 4.5 years, out of the total number of 14 167 operated eyes with cataracts there were 852 eyes of 689 patients with PEX syndrome diagnosed at our Clinic, i.e. 6.0 %. The mean age was 76.9 years, the median 77 years, range 54-100 years. The observed pathology was more common in women at a ratio of 1.84: 1 (552: 300). Elevation of IOP above 21 mmHg was recorded in 118 eyes, in 14 of them IOP reached values over 30 mmHg. Diagnosed and long-term treated secondary glaucoma was confirmed by 153 patients (204 eyes), out of which 22 eyes have undergone antiglaucoma laser (19 eyes) and / or surgery (5 eyes) in the anamnesis. Perioperatively, we recorded the following pathological findings accompanying the occurrence of PEX syndrome in 231 eyes. Most often it was poor artificial mydriasis (189 eyes), then subluxation of the lens (31 eyes) or zonular fragility (17 eyes). To reduce the risk of perioperative and postoperative complications, implantation of a capsular tension ring was indicated in 20 eyes. Complications during the procedure occurred in 11 eyes, of which 8 eyes were diagnosed with advanced cataract. PEX syndrome and glaucoma are relatively common diseases that can complicate the lives of patients and eye surgeons. The incidence of PEX syndrome in our cataract patients was 6 %. Proper diagnosis of this disease is important not only for the possible occurrence of numerous complications during and after cataract surgery, but also for the possible presence of secondary glaucoma. It also serves to detect possible involvement of the contralateral eye. In addition, due to the involvement of practically all tissues in the body, the patient is endangered by numerous, especially vascular comorbidities. For these reasons, we find it appropriate that these patients are observed by other healthcare specialists. In our experience, early indication of cataract surgery is important to achieve a lower degree of zonular fragility and a softer lens core. In addition, lower levels of proinflammatory pseudoexfoliation material occur in the anterior segment of the eye in the early stages, which may have a beneficial effect on the postoperative healing.


Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial.
Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.


Associated criteria used in investigating suspected septic transfusion reactions: A scoping review.
Septic transfusion reactions (STRs) occur as a result of bacterial contamination of blood or blood products, resulting in sepsis. This scoping review aimed to identify, explore and map the available literature on the STR criteria triggering the investigation of STR. Four electronic databases (MEDLINE, Web of Science, Science Direct, Embase) were searched to retrieve scientific literature reporting such criteria, published from 1 January 2000 to 5 May 2022. Grey literature was also searched from open web sources. Of 1052 references identified, 43 (21 peer-reviewed and 22 grey literature) met the eligibility criteria for inclusion and data extraction after full article screening. Of them, most (27/43, 62.79%) were found to report a single set of criteria, and only two reported four or more sets of criteria. The analysis of 66 sets of criteria collected from the selected references revealed 57 different sets. A few sets of criteria used only one sign and symptom (s/s) (12.12%, n = 8), whereas 16 sets used 7-15 s/s (n = 16/66; 24.24%). Of the total 319 occurrences of s/s associated with the 66 sets of criteria, post-transfusion hyperthermia, body temperature increase and hypotension were the most common s/s categories. Of all the literature available, only one study tested the diagnostic accuracy of the STR criteria. This scoping review revealed a substantial variation in criteria used to identify suspected STR. Consequently, conducting further studies to enhance the diagnostic accuracy of these criteria, which trigger STR investigations, is imperative for advancing clinical practice.


The impact of 34 years of massive DEC chemotherapy on Wuchereria bancrofti infection and transmission: the Maupiti cohort.
Semi-annual mass DEC chemotherapy combined with vector control at the beginning of the programme, has been administered on the remote island of Maupiti (French Polynesia) since 1955 (except two periods in 1960-67 and 1970-74). The results of two surveys in 1985 and 1989, reporting 0% microfilaraemia, led to the hope that the eradication of lymphatic filariasis had been achieved. We combined parasitological criteria (microfilaraemia by membrane filtration), immunological (antigenaemia and serum levels of specific IgG antibodies) and molecular (PCR-based evaluation of infection in mosquitoes) techniques and found only good control of the parasite: We found residual microfilaraemia in 0.4% of the sample (mean level in carriers: 101.2 mf/ml), antigenaemia in 4.6% (mean level in positive persons: 714.4 units/ml) and specific IgG in 21.6% (including in one very young child). In addition, an infection rate of 1.4% was calculated in the Aedes polynesiensis vector population. These data, obtained in 1997 just before a hurricane, were partially confirmed in 1999 (0.1% of infection rate in the vector). Together with the possibility of some resistance to DEC, various epidemiological factors critical for the eradication of lymphatic filariasis are discussed.


Perceptions of Patient-Centered Care among First-Year Medical Students.
Phenomenon: Teaching patient-centered care (PCC) is a key component of undergraduate medical curricula. Prior frameworks of PCC describe multiple domains of patient-centeredness, ranging from interpersonal encounters to systems-level issues. Medical students' perceptions of PCC are thought to erode as they progress through school, but little is known about how students view PCC toward the beginning of training. This study explores the perceptions of PCC among 1st-year medical students to inform curricular development and evaluation. Approach: Medical students participated in semistructured, in-person interviews within 4 months of starting medical school as part of a longitudinal study. Transcripts were analyzed using a grounded theory approach and the constant comparative method to describe responses and characterize emergent themes. Transcripts were reviewed to compare codes and compile a final codebook. Findings: Thirty-eight students completed interviews. Students provided heterogeneous definitions of PCC, including perceptions that PCC is implicit and obvious. Many students were unable to provide a concrete definition of PCC, juxtaposing PCC with other priorities such as profit- or physician-centered care, whereas others thought the term was jargon. Some participants defined PCC as upholding patient values using hypothetical examples centered around physician behavior. Insights: Although students appeared to enter medical school with a range of perceptions about PCC, many of their descriptions were limited and only scratch the surface of existing frameworks. Rather than their perceptions of PCC eroding during medical school, students may never fully develop a foundational understanding of PCC. Our findings reinforce the need for authentic, clinically experiential learning opportunities that promote PCC from the earliest stages of medical education.


How do misassigned paternities affect the estimation of heritability in the wild?
Studies of birds have recently played an important role in the increasing success of quantitative genetics applied to natural populations. However, these studies mostly base their pedigree relationships on social information, despite the known widespread genetic polygamy in avian species. Here, we study the influence of misassigned paternities, combined with the effect of pedigree size and depth, on the estimation of heritability. First, we compute simulations of a polygenic trait for two levels of heritability (0.1 and 0.4), several extra-pair paternity rates (ranging from 5% to 40%), and varying sample sizes (20, 50 and 100 broods) or pedigree depth (2 or 4 generations). We compare heritability estimates from the social and the genetic pedigree, running a restricted maximum-likelihood 'animal model'. Social pedigree underestimates heritability by an average of 0-17% for 5-20% extra-pair paternities and by up to 18% for 40% extra-pair paternities and a heritability of 0.4. Second, we identifyied extra-pair offspring using microsatellite loci in two populations of blue tits (Parus caeruleus) showing high levels of extra-pair paternities (15% and 25% of extra-pair offspring). We compare heritabilities of tarsus length and body mass estimated with pedigrees of increasing accuracy. These analyses suggest that the bias induced by misassigned paternities on heritability estimation depends on the level of heritability and the rate of paternity error. Typical rates of extra-pair paternities in birds (around 20% of offspring) should result in an underestimation of heritability of less than 15% when estimated over a minimum of 100 broods.


Extracellular Signal-Regulated Kinase 1/2 Pathway Is Insufficiently Involved in the Neuroprotective Effect by Hydrogen Sulfide Supplement in Experimental Glaucoma.
Glaucoma is a neurodegenerative eye disease characterized by gradually impaired visual field and irreversible blindness due to retinal ganglion cell (RGC) loss. Our previous studies have confirmed that hydrogen sulfide (H2S) takes part in the glaucomatous process and contributes to RGC protection. The present study aimed to further investigate the role of extracellular signal-regulated kinase 1/2 (ERK 1/2) pathway underlying the impact of H2S, to better understand the mechanism through which H2S exerts neuroprotection in glaucoma. An established rat glaucoma model was used and 168 rats were qualified to undergo sodium hydrosulfide (NaHS, a H2S donor)/PD98059 (an ERK inhibitor) treatment. Then the survival and apoptosis of RGC were evaluated through retrograde labeling and TUNEL staining, along with activity evaluations of ERK 1/2 pathway, intrinsic apoptotic pathway, glial activation, nuclear factor kappa B (NF-κB) pathway, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, autophagy, and TNF-α production through immunohistochemistry, Western blotting, and ELISA. The study demonstrated that NaHS suppressed ERK 1/2 pathway activity similarly to PD98059 in retinas of experimental glaucoma rats, while PD98059 also similarly suppressed glial activation, NF-κB pathway, NADPH oxidase, and TNF-α production. However, PD98059 did not affect RGC survival, apoptotic regulation, or autophagy as NaHS did. Our study indicated that inhibition of ERK 1/2 pathway might partly contribute to the neuroprotection by H2S in experimental glaucoma; however, it was insufficient to initiate the therapeutic effect on its own.


Complement and coagulation crosstalk - Factor H in the spotlight.
The immune complement and the coagulation systems are blood-based proteolytic cascades that are activated by pathway-specific triggers, based on protein-protein interactions and enzymatic cleavage reactions. Activation of these systems is finely balanced and controlled through specific regulatory mechanisms. The complement and coagulation systems are generally viewed as distinct, but have common evolutionary origins, and several interactions between these homologous systems have been reported. This complement and coagulation crosstalk can affect activation, amplification and regulatory functions in both systems. In this review, we summarize the literature on coagulation factors contributing to complement alternative pathway activation and regulation and highlight molecular interactions of the complement alternative pathway regulator factor H with several coagulation factors. We propose a mechanism where factor H interactions with coagulation factors may contribute to both complement and coagulation activation and regulation within the haemostatic system and fibrin clot microenvironment and introduce the emerging role of factor H as a modulator of coagulation. Finally, we discuss the potential impact of these protein interactions in diseases associated with factor H dysregulation or deficiency as well as evidence of coagulation dysfunction.


Facial Reconstruction and Rehabilitation.
Extracranial infiltration of the facial nerve by salivary gland tumors is the most frequent cause of facial palsy secondary to malignancy. Nevertheless, facial palsy related to salivary gland cancer is uncommon. Therefore, reconstructive facial reanimation surgery is not a routine undertaking for most head and neck surgeons. The primary aims of facial reanimation are to restore tone, symmetry, and movement to the paralyzed face. Such restoration should improve the patient's objective motor function and subjective quality of life. The surgical procedures for facial reanimation rely heavily on long-established techniques, but many advances and improvements have been made in recent years. In the past, published experiences on strategies for optimizing functional outcomes in facial paralysis patients were primarily based on small case series and described a wide variety of surgical techniques. However, in the recent years, larger series have been published from high-volume centers with significant and specialized experience in surgical and nonsurgical reanimation of the paralyzed face that have informed modern treatment. This chapter reviews the most important diagnostic methods used for the evaluation of facial paralysis to optimize the planning of each individual's treatment and discusses surgical and nonsurgical techniques for facial rehabilitation based on the contemporary literature.


Implementation of fiber tract navigation.
To implement fiber tracking in a common neuronavigation environment for routine clinical use to visualize major white matter tracts intraoperatively. A single-shot, spin-echo diffusion weighted echo planar imaging sequence with six diffusion directions on a 1.5 T magnetic resonance scanner was used for diffusion tensor imaging. For three-dimensional (3-D) tractography, we applied a knowledge-based multiple volume of interest approach. Tracking was initiated in each voxel of the initial seed volume in retrograde and orthograde directions according to the direction of the major eigenvector by applying a tensor deflection algorithm. Tractography results were displayed as streamlines assigned direction encoding color. After selecting the fiber tract bundle of interest by defining inclusion and exclusion volumes, a 3-D object was generated automatically by wrapping the whole fiber tract bundle. This 3-D object was displayed along with other contours representing tumor outline and further functional data with the microscope heads-up display. In 16 patients (three cavernomas, 13 gliomas), major white matter tracts (pyramidal tract, n = 14; optic radiation, n = 2) were visualized intraoperatively with a standard navigation system. Three patients developed a postoperative paresis, which resolved in two in the postoperative course. Additional planning time for tractography amounted to up to 10 minutes. Comparing the tractography results with a fiber bundle generated on a different platform by applying a distortion-free sequence revealed a good congruency of the defined 3-D outlines in the area of interest. Fiber tract data can be reliably integrated into a standard neuronavigation system, allowing for intraoperative visualization and localization of major white matter tracts such as the pyramidal tract or optic radiation.


Does a pre-treatment diagnostic interview affect the outcome of internet-based self-help for social anxiety disorder? a randomized controlled trial.
Numerous studies suggest that Internet-based self-help treatments are effective in treating anxiety disorders. Trials evaluating such interventions differ in their screening procedures and in the amount of clinician contact in the diagnostic assessment phase. The present study evaluates the impact of a pre-treatment diagnostic interview on the outcome of an Internet-based treatment for Social Anxiety Disorder (SAD). One hundred and nine participants seeking treatment for SAD were randomized to either an interview-group (IG, N = 53) or to a non-interview group (NIG, N = 56). All participants took part in the same 10-week cognitive-behavioural unguided self-help programme. Before receiving access to the programme, participants of the IG underwent a structured diagnostic interview. Participants of the NIG started directly with the programme. Participants in both groups showed significant and substantial improvement on social anxiety measures from pre- to post-assessment (d IG = 1.30-1.63; d NIG = 1.00-1.28) and from pre- to 4-month follow-up assessment (d IG = 1.38-1.87; d NIG = 1.10-1.21). Significant between-groups effects in favour of the IG were found on secondary outcome measures of depression and general distress (d = 0.18-0.42). These findings suggest that Internet-based self-help is effective in treating SAD, whether or not a diagnostic interview is involved. However, the pre-treatment interview seems to facilitate change on secondary outcomes such as depression and general distress.


Pregnancy after breast cancer: Results from a prospective cohort of young women with breast cancer.
Many young women with newly diagnosed breast cancer are interested in future pregnancies. Prospective data regarding fertility interest and reproductive patterns after diagnosis are needed to counsel patients. The Young Women's Breast Cancer Study is a multicenter, prospective cohort of women who were diagnosed with breast cancer at age ≤40 years between 2006 and 2016. Women complete surveys at baseline, every 6 months for 3 years, then annually. Here, the authors describe fertility interest and pregnancies within 5 years of diagnosis for women with stage 0 through III breast cancer. Of 1026 eligible participants, 368 (36%) reported interest in future biologic children at least once within 5 years after diagnosis, including 16% at 5 years after diagnosis. Among 130 women who attempted to become pregnant, 90 (69.2%) conceived; and, among 896 women who did not attempt to conceive, 18 (2.0%) became pregnant, with a total of 152 pregnancies resulting in 91 live births. Factors associated with pregnancy included younger versus older age at diagnosis (aged ≤30 vs 36-40 years: odds ratio [OR], 6.63; 95% CI, 3.18-13.83; P < .0001; aged 31-35 vs 36-40 years: OR, 5.86; 95% CI, 3.37-10.17; P < .0001) and being nulliparous versus parous (OR, 2.66; 95% CI, 1.56-4.53; P = .001). The receipt of endocrine therapy versus no endocrine therapy (OR, 0.35; 95% CI, 0.20-0.59; P = .001) was inversely associated with pregnancy. Many women remain interested in future fertility in the 4 years after a breast cancer diagnosis, indicating that longitudinal fertility discussions are needed. Although a minority of those interested in having children attempted to become pregnant in the first 5 years, most who attempted to conceive did so and had live births.


A Chinese herbal medicine (Modified Guomin Decoction) Influences the differentiation of CD4+ T-cell subsets in OVA-induced asthmatic mice.
Modified Guomin Decoction (MGD) is an effective Chinese herbal medicine for treatment of various allergic diseases, especially allergic asthma. Its water decoction is conventionally used for treatment of allergic bronchitis in China. Up to date, the underlying mechanisms of this herbal combination have not been fully investigated yet. In the in vivo study, the mice were treated with Chicken egg ovalbumin (OVA) and aluminum hydroxide gel as the classic allergic asthma animal model. After treatment with MGD, the lung tissues were examined by Histological assessment. The flow cytometric analysis was used to classify the CD4+ T-cell subsets. RT-PCR, Real time fluorescence quota PCR and Western blotting were used to analyze the gene expression of IL-4, IL-5, IFN-γ T-bet/GAIA-3 and Foxp3 in lung tissues. MGD significantly reduced ovalbumin-specific IgE production in mouse serum and suppressed inflammatory cell infiltration, thus, improved the asthma symptoms. The mechanistic studies indicated that MGD treatment mainly modified the differentiation of CD4+ T-cell subsets and improved their functions. These included that MGD enhanced the proportion of Th1-cell, reduced Th2-cell subsets to CD4+ cell and balanced Treg/Th17 cell populations in the asthmatic mice spleen tissues. For Th1-cells, MGD upregulated the gene expression of their cytokine IFN-γ and its transcription factor T-bet while it downregulated the gene expression of their cytokines of IL-4 and IL-5. For Th2-cells, MGD mainly downregulated its transcription factor GATA-3 in lung tissues of asthmatic mice. MGD suppressed the Th17-cell subsets in CD4+ cells and upregulated the expression of Foxp3, a specific transcription factor of Treg-cell.


Longterm follow-up of childhood epilepsy with absences. II. Absence-epilepsy with initial grand mal.
The study deals with 83 patients with absence epilepsy which had started with generalized tonic clonic seizures. Only those patients were included, who could be followed up to an age older than eighteen years. The patient population is heterogeneous; it includes numerous older patients in whom therapy had been instituted at a time when the present standard medication with ethosuximide and valproate was not available. Therefore the data cannot be used as a basis for global statements concerning the prognosis of absence epilepsy with grand mal onset. About 80% of the patients treated with standard therapy became seizure free. An unfavourable course was mainly preceded by incorrect, irregular and quantitatively inadequate therapy. Standard therapy cannot prevent singular generalised tonic clonic seizures in the late course. The social status of adult patients is mainly favourable if they are seizure free. Sporadic attacks usually will not impair social integration. In all, absence epilepsy starting with grand mal responds not as well to therapy and has a more unfavourable social prognosis than epilepsy starting with absences.


Pediatric Asthma Health Care Utilization, Viral Testing, and Air Pollution Changes During the COVID-19 Pandemic.
The coronavirus disease 2019 (COVID-19) pandemic caused dramatic changes in daily routines and health care utilization and delivery patterns in the United States. Understanding the influence of these changes and associated public health interventions on asthma care is important to determine effects on patient outcomes and identify measures that will ensure optimal future health care delivery. We sought to identify changes in pediatric asthma-related health care utilization, respiratory viral testing, and air pollution during the COVID-19 pandemic. For the time period January 17 to May 17, 2015 to 2020, asthma-related encounters and weekly summaries of respiratory viral testing data were extracted from Children's Hospital of Philadelphia electronic health records, and pollution data for 4 criteria air pollutants were extracted from AirNow. Changes in encounter characteristics, viral testing patterns, and air pollution before and after Mar 17, 2020, the date public health interventions to limit viral transmission were enacted in Philadelphia, were assessed and compared with data from 2015 to 2019 as a historical reference. After March 17, 2020, in-person asthma encounters decreased by 87% (outpatient) and 84% (emergency + inpatient). Video telemedicine, which was not previously available, became the most highly used asthma encounter modality (61% of all visits), and telephone encounters increased by 19%. Concurrently, asthma-related systemic steroid prescriptions and frequency of rhinovirus test positivity decreased, although air pollution levels did not substantially change, compared with historical trends. The COVID-19 pandemic in Philadelphia was accompanied by changes in pediatric asthma health care delivery patterns, including reduced admissions and systemic steroid prescriptions. Reduced rhinovirus infections may have contributed to these patterns.


Timing of left heart base descent in dogs with dilated cardiomyopathy and normal dogs.
The identification and assessment of myocardial failure in canine idiopathic dilated cardiomyopathy (DCM) is achieved using a variety of two-dimensional and Doppler echocardiographic techniques. More recently, the availability of tissue Doppler imaging (TDI) has raised the potential for development of new ways of more accurately identifying a disease phenotype. Nevertheless, TDI has not been universally adapted to veterinary clinical cardiology primarily because of the lack of information on its utility in diagnosis. We assessed the application of timing of left heart base descent using TDI in the identification of differences between DCM and normal dogs. The times from the onset of the QRS complex on a simultaneously recorded electrocardiograph to the onset (Q--S'), peak (Q--peak S'), and end (Q--end S') of the systolic velocity peak were measured in the interventricular septum (IVS) and the left ventricular free wall. The duration of S' was also calculated. The Q--S' (FW), Q--end S' (FW), and duration S' (FW) were correlated with ejection fraction in the diseased group (P < 0.05). In addition, Q--S', Q--peak S', Q--end S', and the peak S' velocity were prolonged in the diseased dogs at both the free wall and in the IVS (P < 0.01). The duration of S' was unaffected by disease status. These findings provide insight into the electromechanical uncoupling that occurs in canine DCM and identifies new TDI parameters that can be added to the range of Doppler and echocardiographic parameters used for detecting myocardial failure in the dog.