Effects of TCDD on Ah receptor, ARNT, EGF, and TGF-alpha expression in embryonic mouse urinary tract.
Prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces hydronephrosis in C57BL/6N mice. The etiology of this response involves TCDD-induced hyperplasia of ureteric epithelium, which occludes the ureteric lumen, blocking the flow of urine. The present study localizes and examines the effects of TCDD on the expression of the Ah receptor (AhR), the Ah receptor nuclear translocator (ARNT), epidermal growth factor (EGF), and transforming growth factor-alpha (TGF-alpha) in the epithelial cells of the developing urinary tract, particularly the ureteric bud derivatives (ureter and tubules). Pregnant C57BL/6N mice were dosed on gestation day (GD) 10 with either corn oil or TCDD at 12 micrograms/kg; a dose of 24 micrograms/kg is expected to induce 100% hydronephrosis. The metanephric urinary tract is morphologically detectable as early as GD 12; thus, embryos were removed on GD 12, 13, and 14, and the lower dorsal torso was prepared for immunohistochemistry or in situ hybridization. Regardless of treatment, the expression of both AhR and ARNT increased in epithelial cells of the ureter and AhR increased in the metanephric tubules from GD 12-14. In situ hybridization localized the expression of AhR and ARNT mRNAs to these derivatives of the ureteric bud and levels of mRNA increased throughout the developmental period examined. There were no significant effects of TCDD treatment on expression of AhR, while TCDD significantly decreased levels of ARNT in tubules on GD 14. The epithelial cells of the ureter and tubules expressed TGF-alpha and EGF. EGF increased from GD 12 to 13 in the tubules and ureter, but there was no difference from GD 13 to 14. Treatment with TCDD reduced TGF-alpha significantly only in tubules on GD 13. TCDD exposure significantly decreased EGF in ureter and tubule cells on both GD 13 and 14. In summary, the epithelial cells of the embryonic mouse urinary tract expressed AhR, ARNT, EGF, and TGF-alpha in developmentally dependent patterns. These proteins are involved in the regulation of embryonic cell proliferation during normal urinary tract development and are probably involved in the hyperplastic response to TCDD.


Relationship between cytoplasmic free calcium and myosin light chain phosphorylation in intact platelets.
Human platelets were prepared and loaded with the fluorescent Ca2+ indicator quin2. The relation between cytoplasmic free calcium concentration, [Ca2+]i, and the extent of the phosphorylation of myosin light chains of Mr 20 000 could then be examined. When the calcium ionophore ionomycin is used to stimulate platelets, little phosphorylation is seen until [Ca2+]i exceeds 400 nM; half-maximal response occurs at 600 nM with a full response at about 1 microM-[Ca2+]i. Under optimal conditions, physiological stimuli such as platelet-activating factor and thrombin can increase [Ca2+]i to sufficiently high levels [Rink, Smith & Tsien (1982) FEBS Lett. 148, 21-26; Hallam, Sanchez & Rink (1984) Biochem. J. 218, 819-827] that Ca2+ ions could be the trigger for the myosin phosphorylation evoked by these agonists. However, in this paper we show that, in the absence of external calcium, platelet-activating factor and thrombin can stimulate myosin phosphorylation while [Ca2+]i remains at levels which are well below those needed when the calcium ionophore is the stimulus. This observation suggests that myosin light chain phosphorylation may be controlled by an additional pathway.


The use of Tranexamic Acid in Total Elbow Replacement to Reduce Post-Operative Wound Infection.
Background: Incidence of infection following total elbow replacement (TER) is recognised to be higher compared to hip or knee arthroplasty. Extensive swelling following TER can complicate the wound healing which might lead to infection. Tranexamic Acid (TXA) is proven to reduce blood loss peri-operatively which might contribute to better healing outcomes. Our aim is to assess the effect of TXA in wound healing following TER. Methods: A retrospective review of a single surgeon case series. 10 patients had TER mainly for complicated elbow fractures, four of them were relatively immune-supressed. All patients had 2 grams of TXA and antibiotics intra-operatively. All were reviewed at two weeks following surgery for wound check and removal of surgical clips. Results: Seven females and three males with a mean age of 81.5 had TER and TXA. The mean level of pre-operative haemoglobin was 134.40 g/l and the mean post-operative level was 122.70g/l. No patient in this series required blood transfusion. At two weeks and six weeks follow-up, all wound healed up with no signs of infection. Conclusion: TXA has been proven to be safe an effective way of reducing peri-operative bleeding. TXA maintains haemostasis after releasing the tourniquet and therefore reduces the swelling and wound complications post-operatively.


Accuracy of perceived risk of recurrence among patients with early-stage breast cancer.
Accurate breast cancer recurrence risk perceptions might motivate health-promoting behaviors and alleviate undue anxiety. Although a few studies have examined early-stage breast cancer survivors' perceived risk of recurrence, none have assessed the accuracy of survivors' perceived risk of recurrence. First primary ductal carcinoma in situ and early-invasive breast cancer survivors reported their perceived risk of recurrence during 6- and 12-month postsurgery interviews. We estimated the patients' 10-year risk of recurrence from published clinical trials, and for early-invasive breast cancer patients, risk of distant recurrence was based on their breast cancer-specific mortality calculated using Adjuvant! Online. Patients' perceived risk was compared with their calculated risk and categorized as "Accurate," "Underestimated," "Overestimated," and "Uncertain." Multinomial logit marginal effect models were fitted using Accurate as the reference. Only 17% of 531 patients accurately perceived their risk at 6 months, most of whom inaccurately perceived their risk at 12 months (P = 0.0143). Patients who were nonwhite [odds ratio (OR), 1.70; 95% confidence interval (95% CI), 1.12-2.56] and received radiation therapy (OR, 2.01; 95% CI, 1.07-3.77) were more likely to underestimate their risk. Patients with ductal carcinoma in situ (OR, 1.76; 95% CI, 1.11-2.79), [corrected] lower social support (OR, 0.71; 95% CI, 0.53-0.95), and anxiety (OR, 1.58; 95% CI, 1.01-2.47) were more likely to overestimate their risk. Few breast cancer survivors accurately perceived their risk of recurrence. The accuracy of perceived risk may be increased by better physician-patient communications about their prognosis, provision of social support, and treatment for coexisting anxiety.


Mitochondrial function and redox state in mammalian embryos.
Mitochondria play a central and multifaceted role in the mammalian egg and early embryo, contributing to many different aspects of early development. While the contribution of mitochondria to energy production is fundamental, other roles for mitochondria are starting to emerge. Mitochondria are central to intracellular redox metabolism as they produce reactive oxygen species (ROS, the mediators of oxidative stress) and they can generate TCA cycle intermediates and reducing equivalents that are used in antioxidant defence. A high cytosolic lactate dehydrogenase activity coupled with dynamic levels of cytosolic pyruvate is responsible for a very dynamic intracellular redox state in the oocyte and embryo. Mammalian embryos have a low glucose metabolism during the earliest stages of development, as both glycolysis and the pentose phosphate pathway are suppressed. The mitochondrial TCA cycle is therefore the major source of reducing equivalents in the cytosol so that any change in mitochondrial function in the embryo will be reflected in changes in the intracellular redox state. In the mouse, the metabolic substrates used by the oocyte and early embryo each have a different impact on the intracellular redox state. Pyruvate which oxidises the cytosolic redox state, acts as an energetic and redox substrate whereas lactate, which reduces the cytosolic redox state, acts only as a redox substrate. Mammalian early embryos are very sensitive to oxidative stress which can cause permanent developmental arrest before zygotic genome activation and apoptosis in the blastocyst. The oocyte stockpiles antioxidant defence for the early embryo to cope with exogenous and endogenous oxidant insults arising during early development. Mitochondria provide ATP for glutathione (GSH) production during oocyte maturation and also participate in the regeneration of NADPH and GSH during early development. Finally, a number of pathological conditions or environmental insults impair early development by altering mitochondrial function, illustrating the centrality of mitochondrial function in embryo development.


Chesapeake Bay Dissolved Oxygen Criterion Attainment Deficit: Three Decades of Temporal and Spatial Patterns.
Low dissolved oxygen (DO) conditions are a recurring issue in waters of Chesapeake Bay, with detrimental effects on aquatic living resources. The Chesapeake Bay Program partnership has developed criteria guidance supporting the definition of state water quality standards and associated assessment procedures for DO and other parameters, which provides a binary classification of attainment or impairment. Evaluating time series of these two outcomes alone, however, provides limited information on water quality change over time or space. Here we introduce an extension of the existing Chesapeake Bay water quality criterion assessment framework to quantify the amount of impairment shown by space-time exceedance of DO criterion ("attainment deficit") for a specific tidal management unit (i.e., segment). We demonstrate the usefulness of this extended framework by applying it to Bay segments for each 3-year assessment period between 1985 and 2016. In general, the attainment deficit for the most recent period assessed (i.e., 2014-2016) is considerably worse for deep channel (DC; n = 10) segments than open water (OW; n = 92) and deep water (DW; n = 18) segments. Most subgroups - classified by designated uses, salinity zones, or tidal systems - show better (or similar) attainment status in 2014-2016 than their initial status (1985-1987). Some significant temporal trends (p < 0.1) were detected, presenting evidence on the recovery for portions of Chesapeake Bay with respect to DO criterion attainment. Significant, improving trends were observed in seven OW segments, four DW segments, and one DC segment over the 30 3-year assessment periods (1985-2016). Likewise, significant, improving trends were observed in 15 OW, five DW, and four DC segments over the recent 15 assessment periods (2000-2016). Subgroups showed mixed trends, with the Patuxent, Nanticoke, and Choptank Rivers experiencing significant, improving short-term (2000-2016) trends while Elizabeth experiencing a significant, degrading short-term trend. The general lack of significantly improving trends across the Bay suggests that further actions will be necessary to achieve full attainment of DO criterion. Insights revealed in this work are critical for understanding the dynamics of the Bay ecosystem and for further assessing the effectiveness of management initiatives aimed toward Bay restoration.


Educational guidelines for achieving tight control and minimizing complications of type 1 diabetes.
Tight glucose control with intensive therapy in patients with type 1 diabetes (formerly known as juvenile-onset or insulin-dependent diabetes) can delay the onset and slow the progression of retinopathy, nephropathy and neuropathy. Optimal blood glucose control is defined by a target glycosylated hemoglobin level of less than 7 percent, a preprandial glucose level of 80 to 120 mg per dL (4.4 to 6.7 mmol per L) and a bedtime glucose level of 100 to 140 mg per dL (5.6 to 7.8 mmol per L). This article provides guidelines to help family physicians teach patients with type 1 diabetes how to achieve tight glucose control to help minimize complications. Guidelines include maintaining blood glucose levels at near normal by taking doses of short-acting insulin throughout the day supplemented by a nighttime dose of intermediate-acting insulin, monitoring blood glucose levels frequently, following a prudent diet, exercising regularly and effectively managing hypoglycemia, as well as empowering patients to lead their control efforts and rigorously controlling other risk factors for cardiovascular disease. Support from physicians, family members and friends is crucial to the success of a regimen of tight glucose control.


Past is prologue: host community assembly and the risk of infectious disease over time.
Infectious disease risk is often influenced by host diversity, but the causes are unresolved. Changes in diversity are associated with changes in community structure, particularly during community assembly; therefore, by incorporating change over time, host community assembly may provide a framework to resolve causation. In turn, community assembly can be driven by many processes, including resource enrichment. To test the hypothesis that community assembly causally links host diversity to future disease, we experimentally manipulated host diversity and resource supply to hosts, then allowed communities to assemble for 2 years (surveyed 2012-2014). Initially, host diversity increased disease. Subsequently, host diversity did not directly alter disease. However, host diversity determined the trajectory of host community assembly, altering colonisation by exotic host species and richness-independent host phylogenetic diversity, which together reversed the initial increase in disease. Ultimately, incorporating the temporal dimension of community assembly revealed novel mechanisms linking host diversity to future disease.


Biocueing and ambulatory biofeedback to enhance emotion regulation: A review of studies investigating non-psychiatric and psychiatric populations.
Over the last years, biofeedback applications are increasingly used to enhance interoceptive awareness and self-regulation, in psychiatry and beyond. These applications are used to strengthen emotion regulation skills by home training (ambulatory biofeedback) and real-time support in everyday life stressful situations (biocueing). Unfortunately, knowledge about the feasibility and effectivity of these applications is still scarce. Therefore, a systematic literature search was performed. In total, 30 studies (4 biocueing, 26 ambulatory biofeedback) were reviewed; 21 of these studies were conducted in non-psychiatric samples and 9 studies in psychiatric samples. Study characteristics, biofeedback characteristics, effectivity and feasibility outcomes were extracted. Despite the rapid advances in wearable technology, only a few biocueing studies were found. In the majority of the studies significant positive effects were found on self-reported (stress-related) psychological measures. Significant improvements on physiological measures were also reported, though these measures were used less frequently. Feasibility of the applications was often reported as sufficient, though not adequately assessed in most studies. Taken into account the small sample sizes and the limited quality of the majority of the studies in this recently emerging field, biocueing and ambulatory biofeedback interventions showed promising results. Future research is expected to be focusing on biocueing as a just-in-time adaptive intervention. To establish this research field, closer cooperation between research groups, use of more rigorous as well as individually tailored research designs and more valid feasibility and effectivity assessment are recommended.


Necrosis evolution during high-temperature hyperthermia through implanted heat sources.
A nonstationary model for high-temperature hyperthermic treatments is developed. The aim of this model is to describe the thermal propagation within a living tissue and to quantify its clinical effects as it regards the physiological status (necrosis) of a neoplastic body. Particular attention is turned to the description of the necrotic transition induced by heating. This leads to the introduction of a necrosis field and to an effective-medium approximation for the corresponding physiological status (vascularization, necrosis, etc.) of the exposed tissue. The resulting nonlinear, nonstationary model is applied to a multilayered spherical structure with a temperature-regulated implant, and to a clinical case of a solid liver tumor. Clinical data on the spatial extent of the necrotized region are in good agreement with model predictions.


Beyond episodic remembering: elaborative retrieval of lifetime periods in young and older adults.
Relative to young adults, cognitively normal older adults commonly generate more semantic details and fewer episodic details in their descriptions of unique life events. It remains unclear whether this reflects a specific change to episodic memory or a broader alteration to autobiographical narration. To explore age differences across different types of autobiographical narration, we created a lifetime period narrative task that involves describing extended events. For comparison, participants also described unique life events. All autobiographical narratives were scored for episodic, semantic, and other detail generation. Relative to young adults, older adults generated more detailed narratives for remote and recent lifetime periods, which was driven by their increased retrieval of personal and general semantic details. Older adults also generated more semantic details for unique life event narratives, along with reduced episodic detail. More broadly, in both groups lifetime period narratives were largely based on semantic details, whereas episodic details were more prominent in the descriptions of unique life events. These findings indicate that the elevated generation of semantic details associated with normal cognitive aging is reflected in multiple types of autobiographical narration. We suggest that lifetime period narration is a spared aspect of autobiographical memory among older adults.


Does social class predict diet quality?
A large body of epidemiologic data show that diet quality follows a socioeconomic gradient. Whereas higher-quality diets are associated with greater affluence, energy-dense diets that are nutrient-poor are preferentially consumed by persons of lower socioeconomic status (SES) and of more limited economic means. As this review demonstrates, whole grains, lean meats, fish, low-fat dairy products, and fresh vegetables and fruit are more likely to be consumed by groups of higher SES. In contrast, the consumption of refined grains and added fats has been associated with lower SES. Although micronutrient intake and, hence, diet quality are affected by SES, little evidence indicates that SES affects either total energy intakes or the macronutrient composition of the diet. The observed associations between SES variables and diet-quality measures can be explained by a variety of potentially causal mechanisms. The disparity in energy costs ($/MJ) between energy-dense and nutrient-dense foods is one such mechanism; easy physical access to low-cost energy-dense foods is another. If higher SES is a causal determinant of diet quality, then the reported associations between diet quality and better health, found in so many epidemiologic studies, may have been confounded by unobserved indexes of social class. Conversely, if limited economic resources are causally linked to low-quality diets, some current strategies for health promotion, based on recommending high-cost foods to low-income people, may prove to be wholly ineffective. Exploring the possible causal relations between SES and diet quality is the purpose of this review.


Characteristics of patients with increasing COPD assessment test scores within 3 years.
The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a subjective measure of quality of life. The aim of this study was to examine the characteristics of COPD patients with increasing CAT scores within 3 years. Keio University and its affiliate hospitals conducted an observational COPD cohort study over 3 years. St. George's Respiratory Questionnaire (SGRQ) and CAT were completed at baseline and annually thereafter. Patients who had at least 3 CAT scores were included (n = 315). The ΔCAT score/year and ΔSGRQ score/year were calculated by the slope between each of the measures and the date of measurement. The median ΔCAT score/year was 0.4, and ΔCAT score/year was significantly correlated with ΔSGRQ total score/year. Using an annual cut-off CAT score of +2 points, patients who deteriorated (n = 79) were older, had lower %FEV1, and more severe emphysema on computed tomography scan at baseline than patients who did not deteriorate. The baseline value was not a determinant of subsequent changes in the CAT score. Longitudinal changes in the CAT score were positively correlated with those in the SGRQ score. Old age and severe COPD, not the CAT score at one time point, predicted worsening quality of life.


Advanced Coats' disease treated with intravitreal bevacizumab combined with laser vascular ablation.
To evaluate the impact of intravitreal bevacizumab combined with laser vascular ablation in the management of advanced Coats' disease presenting with exudative retinal detachment. This was a retrospective review of 24 children that presented with exudative retinal detachments associated with advanced Coats' disease. Mean patient age was 62 months (range 9-160 months). Presenting signs included retinal detachment in 24 children (100%), vascular telangiectasia in 24 children (100%), and retinal ischemia in 24 children (100%). Twenty of 24 children presented with elevated, vascular leakage in the fovea (83%). Two children presented with sub-retinal fibrosis associated with presumed long-standing retinal detachment without evidence of rhegmatogenous retinal detachment. Ten patients exhibited vascular alterations in the periphery of the second eye without clinical evidence of exudation. All 24 children were treated with a large-spot-size diode laser directly to areas of abnormal telangiectatic vasculature. All 24 children received intravitreal bevacizumab injection. All 24 children had resolution of exudative retinal detachment, ablation of vascular telangiectasia, and anatomic improvement of the retina. No child exhibited progressive retinal detachment and no eye required enucleation. No cases of neovascular glaucoma were seen. Fellow eyes with peripheral vascular alterations showed no progression to exudative vasculopathy during the observation period. Intravitreal bevacizumab injection was not associated with endophthalmitis or systemically-observed complications. Repetitive intravitreal bevacizumab combined with laser vascular ablation may be utilized effectively for advanced Coats' disease presenting with exudative retinal detachment.


Gene expression of plasminogen activation cascade components in human term gestational tissues with labour onset.
The plasminogen activation cascade is thought to play a critical role in labour-associated remodelling events, such as fetal membrane rupture and placental separation. The aim of this study was to quantify, by Northern analysis, the gene expression of urokinase plasminogen activator (UPA), urokinase receptor (UPAR) and plasminogen activator inhibitor type-2 (PAI-2) in human gestational tissues. Amnion, choriodecidua and placenta were collected from women before, during and after spontaneous-onset labour at term. The expression of UPAR mRNA was significantly (P < 0.05) increased in amnion tissue during and after labour and delivery, compared with the before-labour group. In contrast, UPAR gene expression in choriodecidua and placenta was not significantly altered in association with labour onset. PAI-2 mRNA expression was also significantly (P < 0.05) increased in amnion after labour. No statistically significant differences were observed in choriodecidua or placenta PAI-2 mRNA with labour onset. Neither was any significant effect of labour status on UPA mRNA identified in any of the tissues examined. This study is the first to describe a significant increase in UPAR and PAI-2 gene expression in human amnion tissue with labour. These data are consistent with the hypothesis that, during labour, up-regulation of UPAR expression in amnion serves to localize active UPA at the cell surface, thereby increasing proteolytic activity in fetal membranes. Increased PAI-2 in amnion after labour may provide a regulatory 'switch' to cease further proteolysis in this tissue type. In conclusion, the data obtained support the proposal that the plasminogen activation cascade contributes to the rupture of fetal membranes during active labour.


Socio-demography and medical history as predictors of health-related quality of life of breast cancer survivors.
Even after completion of conventional treatment, breast cancer survivors continue to exhibit a variety of psychological and physical symptoms, affecting their quality of life. The study aimed to investigate the relationship between socio-demography, medical characteristics and health-related quality of life (HR-QOL) of a sample of breast cancer survivors in Malaysia. This pilot cross-sectional survey was conducted among breast cancer survivors (n=40) who were members of Breast Cancer Support Group Centre Johor Bahru. A validated self-administered questionnaire was used to identify the relationships between socio-demography, medical characteristics and HR-QOL of the participants. Living with family and completion of treatment were significant predictive factors of self-rated QOL, while living with family and ever giving birth significantly predicted satisfaction with health and physical health. Psychological health had moderate correlations with number of children and early cancer stage. Survivors' higher personal income (>MYR4,500) was the only significant predictor of social relationship, while age, income more than MYR4,500 and giving birth significantly predicted environment domain score. The findings suggested the survivors coped better in all four HR-QOL domains if they were married, lived with family, had children and were employed.


Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana.
Preexposure prophylaxis with antiretroviral agents has been shown to reduce the transmission of human immunodeficiency virus (HIV) among men who have sex with men; however, the efficacy among heterosexuals is uncertain. We randomly assigned HIV-seronegative men and women to receive either tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or matching placebo once daily. Monthly study visits were scheduled, and participants received a comprehensive package of prevention services, including HIV testing, counseling on adherence to medication, management of sexually transmitted infections, monitoring for adverse events, and individualized counseling on risk reduction; bone mineral density testing was performed semiannually in a subgroup of participants. A total of 1219 men and women underwent randomization (45.7% women) and were followed for 1563 person-years (median, 1.1 years; maximum, 3.7 years). Because of low retention and logistic limitations, we concluded the study early and followed enrolled participants through an orderly study closure rather than expanding enrollment. The TDF-FTC group had higher rates of nausea (18.5% vs. 7.1%, P<0.001), vomiting (11.3% vs. 7.1%, P=0.008), and dizziness (15.1% vs. 11.0%, P=0.03) than the placebo group, but the rates of serious adverse events were similar (P=0.90). Participants who received TDF-FTC, as compared with those who received placebo, had a significant decline in bone mineral density. K65R, M184V, and A62V resistance mutations developed in 1 participant in the TDF-FTC group who had had an unrecognized acute HIV infection at enrollment. In a modified intention-to-treat analysis that included the 33 participants who became infected during the study (9 in the TDF-FTC group and 24 in the placebo group; 1.2 and 3.1 infections per 100 person-years, respectively), the efficacy of TDF-FTC was 62.2% (95% confidence interval, 21.5 to 83.4; P=0.03). Daily TDF-FTC prophylaxis prevented HIV infection in sexually active heterosexual adults. The long-term safety of daily TDF-FTC prophylaxis, including the effect on bone mineral density, remains unknown. (Funded by the Centers for Disease Control and Prevention and the National Institutes of Health; TDF2 ClinicalTrials.gov number, NCT00448669.).


What We Know (and Do not Know) Regarding the Pathogenesis of Pulmonary Thrombosis in COVID-19.
The clinical course of coronavirus disease 2019 (COVID-19) is often complicated by the onset of venous thrombosis and thromboembolism (VTE), encompassing also pulmonary thrombosis. Recent statistics attests that the cumulative frequency of VTE can be as high as 30% in COVID-19 hospitalized patients, increasing to nearly 40 to 70% (depending on systematic screening) in those with severe illness, mechanical ventilation, or intensive care unit admission. The risk of venous thrombosis seems mostly limited to the active phase of disease, and is directly associated with some genetic (i.e., inherited prothrombotic predisposition) and demographical factors (male sex, overweight/obesity), disease severity (risk increasing progressively from hospitalization to development of severe illness, being the highest in patients needing mechanical ventilation and/or intensive care), presence and extent of pulmonary disease, coexistence of multiple risk factors (immobilization, mechanical ventilation, co- or superinfections), along with increased values of inflammatory and thrombotic biomarkers. At least three different phenotypes of pulmonary thrombosis may develop in COVID-19 patients, one caused by typical embolization from peripheral venous thrombosis (e.g., deep vein thrombosis), a second type triggered by local inflammation of nearby pulmonary tissue, and a third one mostly attributable to the prothrombotic state consequent to the pronounced systemic inflammatory response (i.e., the so-called cytokine storm) that is frequently observed in COVID-19. Although the pathogenesis of these three conditions has different features, their discrimination is essential for diagnostic and therapeutic purposes. The prognosis of COVID-19 patients who develop pulmonary thrombosis is also considerably worse than those who do not, thus probably needing frequent monitoring and more aggressive therapeutic management.


Highlights of the new recommendations for hypercholesterolemia.
The patient who benefits most by aggressive efforts to reduce elevated LDL cholesterol is the one who is at greatest risk for a coronary event in the next 5 to 10 years. Thus, treatment decisions are based on risk-factor analysis and personal history.


Comparison of the Clinico-Microbiological Characteristics of Culture-Positive and Culture-Negative Septic Pulmonary Embolism: A 10-Year Retrospective Study.
Septic pulmonary embolism (SPE) is a rare yet serious infectious disorder with nonspecific clinical findings due to microorganism-containing emboli disseminating from extrapulmonary infectious foci. It is unknown whether a positive blood culture correlates with a worse clinical outcome. We compared the clinical and microbiologic characteristics of patients with SPE divided into the culture-positive group and the culture-negative one. This study was a retrospective observational study of the patients diagnosed with SPE and treated in an academic hospital from April 2010 to May 2020. We identified six culture-positive and four culture-negative patients with SPE during the study period. The culture-positive group had significantly longer periods of hospitalization (median: 75 days, range: 45-125 days) than the culture-negative group (median: 14.5 days, range: 3-43 days) (p < 0.05), as well as significantly elevated serum C-reactive protein and procalcitonin. Patients with culture-negative SPE more commonly had odontogenic infections as the primary infectious foci. Our study highlights the importance of giving extra attention to SPE patients who have a positive blood culture, as they may have worse clinical outcomes. Physicians need to collaborate with dentists when faced with patients with culture-negative SPE, since they may have primary odontogenic infections.


Noninvasive Brain Stimulation in Epilepsy.
Neurostimulation in epilepsy is a long standing established concept, and through experimental and clinical uses, our understanding of neurostimulation and neuromodulation has grown substantially. Noninvasive brain stimulation techniques use electromagnetic principles to noninvasively modulate brain activity in a spatiotemporally targeted manner. This review focused on the two predominant forms of noninvasive neurostimulation: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, and their current applications in the diagnosis and management of epilepsy. A number of small randomized sham-controlled studies suggest that both TMS and transcranial direct current stimulation may have a beneficial effect in decreasing seizure frequency in patients with medically refractory epilepsy, without significant side effects. Small pilot studies also suggest that TMS in combination with EEG may be used to develop quantitative biomarkers of cortical hyperexcitability in patients with epilepsy. Furthermore, TMS is already Food and Drug Administration-cleared for presurgical mapping of eloquent cortex, and preliminary studies suggest that navigated TMS represents a highly valuable clinical supplement for preoperative functional planning. Transcranial magnetic stimulation and transcranial direct current stimulation have shown great potential benefit for patients with epilepsy; however, further large multicenter randomized sham-controlled studies are needed to better optimize stimulation settings and protocols, define mechanisms of action, assess long-term effects, and clearly define roles and determine efficacy.


Lung Ultrasound-Implemented Diagnosis of Acute Decompensated Heart Failure in the ED: A SIMEU Multicenter Study.
Lung ultrasonography (LUS) has emerged as a noninvasive tool for the differential diagnosis of pulmonary diseases. However, its use for the diagnosis of acute decompensated heart failure (ADHF) still raises some concerns. We tested the hypothesis that an integrated approach implementing LUS with clinical assessment would have higher diagnostic accuracy than a standard workup in differentiating ADHF from noncardiogenic dyspnea in the ED. We conducted a multicenter, prospective cohort study in seven Italian EDs. For patients presenting with acute dyspnea, the emergency physician was asked to categorize the diagnosis as ADHF or noncardiogenic dyspnea after (1) the initial clinical assessment and (2) after performing LUS ("LUS-implemented" diagnosis). All patients also underwent chest radiography. After discharge, the cause of each patient's dyspnea was determined by independent review of the entire medical record. The diagnostic accuracy of the different approaches was then compared. The study enrolled 1,005 patients. The LUS-implemented approach had a significantly higher accuracy (sensitivity, 97% [95% CI, 95%-98.3%]; specificity, 97.4% [95% CI, 95.7%-98.6%]) in differentiating ADHF from noncardiac causes of acute dyspnea than the initial clinical workup (sensitivity, 85.3% [95% CI, 81.8%-88.4%]; specificity, 90% [95% CI, 87.2%-92.4%]), chest radiography alone (sensitivity, 69.5% [95% CI, 65.1%-73.7%]; specificity, 82.1% [95% CI, 78.6%-85.2%]), and natriuretic peptides (sensitivity, 85% [95% CI, 80.3%-89%]; specificity, 61.7% [95% CI, 54.6%-68.3%]; n = 486). Net reclassification index of the LUS-implemented approach compared with standard workup was 19.1%. The implementation of LUS with the clinical evaluation may improve accuracy of ADHF diagnosis in patients presenting to the ED. Clinicaltrials.gov; No.: NCT01287429; URL: www.clinicaltrials.gov.


A Systematic Review and Meta-Analysis Baduanjin Qigong for Health Benefits: Randomized Controlled Trials.
Objective. To investigate the effects of practicing Baduanjin Qigong on different health outcomes. Methods. Six electronic databases were used for literature search through entering the following key words: Baduanjin Qigong, quality of life, sleep quality, and health-related outcomes. Results. Nineteen randomized controlled trials were used for meta-analysis. The aggregated results from this systematic review have shown significant benefits in favour of Baduanjin Qigong on quality of life (SMD, -0.75; 95% CI -1.26 to -0.24; P = 0.004), sleep quality (SMD, -0.55; 95% CI -0.97 to -0.12; P = 0.01), balance (SMD, -0.94; 95% CI -1.59 to 0.30; P = 0.004), handgrip strength (SMD, -0.69; 95% CI -1.2 to -0.19; P = 0.007), trunk flexibility (SMD, -0.66; 95% CI -1.13 to -0.19; P = 0.006), systolic (SMD, -0.60; 95% CI -0.94 to -0.27; P = 0.0004) and diastolic blood pressure (SMD, -0.46; 95% CI -0.73 to -0.20; P = 0.0005), and resting heart rate (SMD, -0.87; 95% CI -1.47 to -0.27; P = 0.005). The aggregated results of meta-analyses examining the effect of Baduanjin Qigong on leg power, cardiopulmonary endurance, and pulmonary function remain unclear because of a small number of studies. Conclusions. The aggregated results from this systematic review show that Baduanjin Qigong practice is beneficial for quality of life, sleep quality, balance, handgrip strength, trunk flexibility, systolic and diastolic blood pressure, and resting heart rate. Further studies are necessary to confirm the effects of Baduanjin Qigong on leg power, cardiopulmonary endurance, and pulmonary function (e.g., vital capacity), while considering a long-term follow-up. Registration Number. This trial is registered with International Prospective Register of Systematic Reviews (PROSPERO): CRD42016036966.


Segregation, discrimination and mortality in U.S. blacks.
Theoretically, segregation and discrimination could affect mortality among blacks (African Americans) not only through their impact on social class (including the concentration of blacks in high-poverty areas) but also by influencing health care and psychosocial factors. This paper reviews evidence that variation in mortality rates for black infants and young adults living in large metropolitan areas is associated with the level of black-white segregation. A few metropolitan areas in California with relatively low levels of segregation are shown to have low black death rates and small black-white differences in mortality rates for infants and young adult males (15-44 years old). In-depth studies are needed in these areas. Longitudinal studies of potential "risk factors" for disease and death among blacks should include: personal histories of experiences with discrimination, psychological reactions to discrimination, segregation indexes, quality of life in residential areas, and social class indicators.


Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice.
Using an environmentally sensitized genetic screen we identified mutations that cause inflammatory colitis in mice. The X-linked Klein-Zschocher (KLZ) mutation created a null allele of Yipf6, a member of a gene family believed to regulate vesicular transport in yeast, but without known functions in mammals. Yipf6 is a five transmembrane-spanning protein associated with Golgi compartments. Klein-Zschocher mutants were extremely sensitive to colitis induced by dextran sodium sulfate (DSS) and developed spontaneous ileitis and colitis after 16 mo of age in specific pathogen-free housing conditions. Electron microscopy, gene expression, and immunocytochemistry analyses provided evidence that impaired intestinal homeostasis stemmed from defective formation and secretion of large secretory granules from Paneth and goblet cells. These studies support a tissue- and organ-specific function for Yipf6 in the maintenance of intestinal homeostasis and implicate the orthologous human gene as a disease susceptibility locus.


CD45 expression discriminates waves of embryonic megakaryocytes in the mouse.
Embryonic megakaryopoiesis starts in the yolk sac on gestational day 7.5 as part of the primitive wave of hematopoiesis, and it continues in the fetal liver when this organ is colonized by hematopoietic progenitors between day 9.5 and 10.5, as the definitive hematopoiesis wave. We characterized the precise phenotype of embryo megakaryocytes in the liver at gestational day 11.5, identifying them as CD41++CD45-CD9++CD61+MPL+CD42c+ tetraploid cells that express megakaryocyte-specific transcripts and display differential traits when compared to those present in the yolk sac at the same age. In contrast to megakaryocytes from adult bone marrow, embryo megakaryocytes are CD45- until day 13.5 of gestation, as are both the megakaryocyte progenitors and megakaryocyte/erythroid-committed progenitors. At gestational day 11.5, liver and yolk sac also contain CD41+CD45+ and CD41+CD45- cells. These populations, and that of CD41++CD45-CD42c+ cells, isolated from liver, differentiate in culture into CD41++CD45-CD42c+ proplatelet-bearing megakaryocytes. Also present at this time are CD41-CD45++CD11b+ cells, which produce low numbers of CD41++CD45-CD42c+ megakaryocytes in vitro, as do fetal liver cells expressing the macrophage-specific Csf receptor-1 (Csf1r/CD115) from MaFIA transgenic mice, which give rise poorly to CD41++CD45-CD42c+ embryo megakaryocytes both in vivo and in vitro In contrast, around 30% of adult megakaryocytes (CD41++CD45++CD9++CD42c+) from C57BL/6 and MaFIA mice express CD115. We propose that differential pathways operating in the mouse embryo liver at gestational day 11.5 beget CD41++CD45-CD42c+ embryo megakaryocytes that can be produced from CD41+CD45- or from CD41+CD45+ cells, at difference from those from bone marrow.


Infant feeding practices in western Tanzania and Uganda: implications for infant feeding recommendations for HIV-infected mothers.
Current infant feeding guidelines of UNICEF/UNAIDS/WHO for HIV-infected women recommend the avoidance of breastfeeding or to breastfeed exclusively. In the context of a prevention of HIV mother-to-child transmission programme we assessed the feeding practices in peripheral areas of Tanzania and Uganda. A total of 237 mothers in south-western Tanzania and 424 mothers in western Uganda attending urban and rural antenatal care services as well as village women were interviewed with regard to duration of breastfeeding, time of introduction of additional nutrients and type of solid and liquid nutrients. The average reported duration of breastfeeding was 24 months in Tanzania but 18 months in Uganda (P < 0.001). Solid nutrients were added on average at month 6 in both areas while liquids were given significantly earlier in Tanzania (month 4) than in Uganda (month 5; P < 0.001). A total of 19% and 48% of the study participants, respectively, stated to breastfeed their infants exclusively at the age of 4 months in Tanzania and Uganda. Age between 26 and 35 years, urban residence and ethnic group were the risk factors for earlier introduction of nutrients in Uganda. In Tanzania, solid maize porridge was the most frequent (94%) and often single nutrient given during breastfeeding, while in Uganda combinations of nutrients such as bananas, millet and beans were used. Milk was the most frequently added fluid in Uganda whereas in Tanzania various liquids such as liquid maize porridge, milk, juice or water were used. Feeding practices differed considerably in the two countries. According to the interviewees, exclusive breastfeeding was rarely practiced in Tanzania. Our findings underline the necessity to promote exclusive breastfeeding if infant feeding recommendations are to be realized and emphasize the need to assess the local situation in order to ensure that locally appropriate information and recommendations are given to the target groups.


Effect of small interfering RNAs on in vitro replication and gene expression of feline coronavirus.
To evaluate the ability of small interfering RNAs (siRNAs) to inhibit in vitro viral replication and gene expression of feline coronavirus (FCoV). Cell cultures of Crandell-Rees feline kidney cells. 5 synthetic siRNAs that each targeted a different region of the FCoV genome were tested individually and in various combinations for their antiviral effects against 2 strains of FCoV (feline infectious peritonitis virus WSU 79-1146 and feline enteric coronavirus WSU 79-1683) in cell cultures. Tested combinations targeted the FCoV leader and 3' untranslated region, FCoV leader region and nucleocapsid gene, and FCoV leader region, 3' untranslated region, and nucleocapsid gene. For each test condition, assessments included relative quantification of the inhibition of intracellular viral genomic RNA synthesis by means of real-time, reverse-transcription PCR analysis; flow cytometric evaluation of the reduction of viral protein expression in infected cells; and assessment of virus replication inhibition via titration of extracellular virus with a TCID₅₀ infectivity assay. The 5 siRNAs had variable inhibitory effects on FCoV when used singly. Combinations of siRNAs that targeted different regions of the viral genome resulted in more effective viral inhibition than did individual siRNAs that targeted a single gene. The tested siRNA combinations resulted in approximately 95% reduction in viral replication (based on virus titration results), compared with findings in negative control, nontargeting siRNA-treated, FCoV-infected cells. In vitro replication of FCoV was specifically inhibited by siRNAs that targeted coding and noncoding regions of the viral genome, suggesting a potential therapeutic application of RNA interference in treatment of feline infectious peritonitis.


Dissociation of innate immune responses in microglia infected with Listeria monocytogenes.
Microglia, the innate immune cells of the brain, plays a central role in cerebral listeriosis. Here, we present evidence that microglia control Listeria infection differently than macrophages. Infection of primary microglial cultures and murine cell lines with Listeria resulted in a dual function of the two gene expression programmes involved in early and late immune responses in macrophages. Whereas the bacterial gene hly seems responsible for both transcriptional programmes in macrophages, Listeria induces in microglia only the tumor necrosis factor (TNF)-regulated transcriptional programme. Listeria also represses in microglia the late immune response gathered in two clusters, microbial degradation, and interferon (IFN)-inducible genes. The bacterial gene actA was required in microglia to induce TNF-regulated responses and to repress the late response. Isolation of microglial phagosomes revealed a phagosomal environment unable to destroy Listeria. Microglial phagosomes were also defective in several signaling and trafficking components reported as relevant for Listeria innate immune responses. This transcriptional strategy in microglia induced high levels of TNF-α and monocyte chemotactic protein-1 and low production of other neurotoxic compounds such as nitric oxide, hydrogen peroxide, and Type I IFNs. These cytokines and toxic microglial products are also released by primary microglia, and this cytokine and chemokine cocktail display a low potential to trigger neuronal apoptosis. This overall bacterial strategy strongly suggests that microglia limit Listeria inflammation pattern exclusively through TNF-mediated responses to preserve brain integrity.


Dynamic Cleft Maxillary Orthopedics and Periosteoplasty.
In 1985 this cleft team, dissatisfied with the treatment and results from cleft lip and palate repair, began a longitudinal long-term study using dynamic maxillary orthopedics and periosteoplasty as was originally described by Drs Millard and Latham. All cases were carefully documented through adolescence, including clinical assessments, orthodontic, radiographic, and cephalometric analyses. In 1998, in this journal, we published our data on 35 complete unilateral and 10 complete bilateral cleft patients. At that time facial growth was following normal cephalometric patterns. Crossbites were dental and treated with orthodontics. There was radiologic evidence of bone within the alveolus with elimination of the oronasal fistula, and facial aesthetics revealed soft faded scars and balanced noses.That publication was a preliminary study with the intent to provide long-term results when full facial growth was achieved. This article reports on 25 patients from the initial cohort (20 unilateral and 5 bilateral) that we were able to closely follow up for 25 years, with the same clinical team, making it the longest study of its kind.At this stage, data revealed continued growth of the midface both vertically and horizontally. Secondary alveolar cleft bone grafting when required was in small aliquots placed into well-healed tissue, and orthodontic movement of teeth was through a consolidated alveolus. Orthognathic procedures were performed in 2 of 5 bilateral and 0 of 20 unilateral cases.We concluded that in this cohort, dynamic maxillary orthopedics and periosteoplasty, despite controversy in the literature, did not negatively impact facial growth and provided the benefit of early structural normalization and social integration by consolidation of the maxilla, closure of the oronasal fistula, tension free closure of the lip, and by balancing the nose.


Kidney regeneration in fish.
Age-related diseases, such as kidney diseases, are becoming more prevalent in aging societies. Currently, patients with reduced kidney function require dialysis or organ transplants. Those who suffer from kidney disease would benefit from regenerative therapies. Thus, one of the ultimate goals of regeneration research is to enhance an individual's capacity of self-repairing damaged tissue; something that fish models can contribute towards. Kidney structures are conserved among vertebrates highlighting the opportunities for fish to act as human disease models. Here, different species can offer respective advantages. An understanding of the different modes of regeneration can help to visualize the differences in mammalian and fish regenerative capacity. The remarkable regenerative capacity of fish is well known, but kidney regeneration is an understudied area. The kinetics of kidney regeneration allows one to investigate early damage responses, as well as the initiation and completion of repair. Age-related reductions in regeneration are an additional societal problem; again an area where fish models can be of help. Age-matched experiments between varied vertebrate species will help us to learn from those that do or do not exhibit age-related phenotypes. The goal of such experiments is not only to outline important age-related factors and pathways, but, in addition, to see if age-related decreases in regenerative capacity can be reduced. Widening our knowledge of this very complex process will help to address many of the unanswered questions in the field.


The Effects of Calorie Restriction and Exercise on Age-Related Alterations in Corpus Cavernosum.
Aging is an important risk factor for erectile dysfunction (ED). Both calorie restriction (CR) and physical exercise (PE) have been established as a non-medical method for the improvement of detrimental changes in aging. It is well documented that both CR and PE influence on sympathetic and parasympathetic systems; however, there are few studies on non-adrenergic non-cholinergic pathways. This study aims to investigate the NO-mediated mechanisms of CR and PE on corpus cavernosum in aged rats. 3 and 15 month-old rats were divided into five experimental groups: young rats fed ad libitum (Y-C), aged rats fed ad libitum (O-S), aged rats with CR (O-CR), aged rats with PE (O-PE), and aged rats with CR and PE (O-CR-PE). CR was applied to animals as a 40% reduction of daily food intake for 6 weeks. PE was moderate swimming at 30 min at 3 days/week. The effects of CR and PE were evaluated by histologic, biologic, and in-vitro tissue bath studies. The outcomes in CR and PE groups (characterized by decreased nitrosative damage together with increased antioxidant capacity) were improved in comparison to the O-S. Apoptotic biomarkers were also lower and both endothelial and smooth muscle cell' functions were preserved too. There was no statistical difference between apoptosis, antioxidant capacity, and nitrosative damage parameters. Contractile responses to phenylephrine and relaxation responses to carbachol were: O-CR > O-PE > O-CR-PE. In these groups, NOS protein levels determined by western-blot were: eNOS: O-CR = O-CR + PE > O-PE; iNOS: O-CR = O-PE > O-CR-PE; nNOS: O-PE > O-CR-PE > O-CR. In our study, both CR and PE prevented age-related changes in the corpus cavernosum of rats. Reducing nitrosative damage in the neurovascular structure was the main mechanism. CR and exercise restored the endothelial and smooth muscle cells in corpus cavernosum by decreasing apoptosis. The mechanism of enhancing functional response in corpus cavernosum with CR was the improvement of endothelial function via eNOS activation however it involves increases in the NO-cGMP signaling pathway by an endothelium-independent mechanism with PE. This might be a direct stimulation of smooth muscle cells by NO, which released from the cavernous nerve endings via nNOS activation.


[Endothelial function in patients with arterial hypertension and impaired uric acid metabolism].
The aim of the study was to investigate endothelial function in patients with arterial hypertension and impaired uric acid metabolism in comparison with patients having arterial hypertension and normal uric acid metabolism. 46 patients aged 32-56 yr with grade I-II AH were included in the study. A group of 36 patients (27 male, 9 female) presented with AH and impaired uric acid metabolism (hyperuricemia), the control group included 10 patients with AH and unaffected uric acid metabolism. Inclusion criteria in the two groups were identical. Endothelial dysfunction was documented in all patients and confirmed by increased levels of serum endothelin-1 and microalbuminuria, qualitative and quantitative changes in the intima-media complex and its thickening. These changes were much more pronounced in patients with hyperuricemia It is concluded that impaired uric acid metabolism in patients with AH leads to rapid onset and progression of endothelial dysfunction. This fact should be taken into consideration by doctors practicing antihypertensive treatment and for the evaluation of cardiovascular risks.


Inflammation, lipids and aortic intima-media thickness in newborns following chorioamnionitis.
This study investigated whether chorioamnionitis was associated with increased inflammation, dyslipidaemia and adverse cardiovascular phenotypes in the immediate postnatal period. This prospective case-control study included preterm infants (30(+0) -35(+6) weeks gestational age, GA) whose mothers did not have pregnancy-related conditions that may influence outcomes. Chorioamnionitis was diagnosed by placental histology, and infants were divided retrospectively into cases (chorioamnionitis-exposed) and controls (unexposed). Serum high-sensitivity C-reactive protein (hsCRP), lipid profile, far-wall abdominal aortic intima-media thickness (aIMT) and blood pressure (BP) were measured in the first week of life. There were 20 (16 male, mean GA 32.4 weeks) cases and 31 (12 male, mean GA 32.6 weeks) controls. Histological chorioamnionitis was associated with a significant increase in hsCRP and a non-significant trend towards an adverse lipid profile. There was no evidence of differences in aIMT or BP. Preterm infants exposed to chorioamnionitis have greater postnatal inflammation. There were no early postnatal differences in aIMT or BP. The inflammatory stimulus of chorioamnionitis late in gestation may be of insufficient intensity and duration to result in immediate postnatal alterations to arterial structure. Cardiovascular follow-up of infants exposed to chorioamnionitis may identify differential risk trajectories and subsequent inflammatory responses.


Fluorination as tool to improve bioanalytical sensitivity and COX-2-selective antitumor activity of cobalt alkyne complexes.
The cobalt alkyne complex [(prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS) is an auspicious lead, which exhibits its anticancer activity mainly by inhibition of both cyclooxygenases (COX-1 and COX-2). Since COX-2 participates in carcinogenesis, a selective inhibition of that isoenzyme is aimed. To study if fluorination increases the COX-2/COX-1 inhibition ratio of the lead, substitution was respectively performed in the positions 3, 4, 5, and 6 of the aromatic moiety. The complexes 3/4/5F-Co-ASS and to a much lower extent also 6F-Co-ASS showed cytotoxic, antimetabolic, and apoptotic effects in COX-1/2-positive HT-29 and MDA-MB-231 cells and remarkably less activity in the COX-1/2-negative MCF-7 cell line. The metabolic activity in MCF-7 cells was even unaffected up to a concentration of 40 μM. With exception of 6F-Co-ASS, the complexes strongly reduced the PGE2 synthesis in HT-29 cells and all complexes inhibited COX-2 more effectively than COX-1 in an assay at isolated enzymes. These findings point to an interference in the COX cascade as part of the mode of antitumor action. The limited cellular effects of 6F-Co-ASS are related to its poor uptake as determined by HR CS AAS/MAS. Moreover, the cellular uptake studies confirm fluorination as beneficial tool for bioanalytical labeling. The higher quantification of fluorine by HR CS MAS makes this method about 5-fold more sensitive than HR CS AAS measuring cobalt. As a further positive result, 3/4/5/6-Co-ASS demonstrated high selectivity to tumor cells due to lack of antimetabolic activity against the non-tumorigenic bone marrow stromal cell line HS-5.


Impact of platelet transfusion on hematoma expansion in patients receiving antiplatelet agents before intracerebral hemorrhage.
Patients receiving antiplatelet medications are reported to be at increased risk for hematoma enlargement and worse clinical outcomes following intracerebral hemorrhage (ICH). While platelet transfusions are frequently administered to counteract qualitative platelet defects in the setting of ICH, conclusive evidence in support of this therapeutic strategy is lacking. In fact, platelet transfusions may be associated with adverse effects, and represent a finite resource. We sought to determine the clinical efficacy of platelet transfusion and its impact on systemic complications following ICH in a cohort of patients receiving antiplatelet medications. We retrospectively analysed the medical records of 66 patients admitted to our institution from June 2003 to July 2008 who suffered a primary ICH while receiving antiplatelet (acetylsalicylic acid and/or clopidogrel) therapy. The primary outcome was the rate of significant (>25% increase from admission) hematoma expansion in transfused (n=35) versus non-transfused (n=31) patients. Discharge modified-Rankin score (mRS) and the rates of systemic complications were also assessed. There were no statistically significant differences in rates of hematoma expansion between cohorts, nor were there differences in demographic variables, systemic complications or discharge mRS. Subgroup analysis revealed that there was a higher rate of hematoma expansion in the clopidogrel cohort (p=0.034) than in the cohort of patients receiving aspirin alone. This study suggests that platelet administration does not reduce the frequency of hematoma expansion in ICH patients receiving antiplatelet medications. This lack of efficacy may relate to transfusion timing, as a significant proportion of hematoma expansion occurs within 6 hours post-ictus. Additionally, the increased rates of hematoma expansion in the clopidogrel cohort may relate to its prolonged half-life. A larger, prospective study is warranted.


Recycling and consumption reduction following the COVID-19 lockdown: The effect of threat and coping appraisal, past behavior and information.
The COVID-19 pandemic has created sudden, rapid, and unprecedented change in almost every possible aspect of the general population's behavior. Despite its devastating consequences, the COVID-19 pandemic can alter individual behavior towards responsible environmental actions. This study provides an in-depth analysis of how the COVID-19 pandemic has changed pro-environmental beliefs and behavior. We compare pre-COVID-19 recycling and consumption reduction with post-COVID-19 intentions, focusing on the COVID-19 pandemic's role in catalyzing the change. The protection motivation theory is applied to investigate threat appraisal and coping appraisal as potential motivators for taking climate change more seriously and engaging in pro-environmental behavior. A tailor-made survey carried out during the national lockdown imposed in March-April 2020 in Israel served for the analysis. A generalized ordered probit estimated on a sample of 296 respondents served to validate the behavioral model. The results confirm that threat and coping appraisal are drivers of behavioral change towards pro-environmental behavior. The results show that: i) 40% of low-intensity recyclers are likely to increase recycling compared to 20% of high-intensity recyclers; ii) following the COVID-19 outbreak, 40% intend to consume less; iii) the changes are catalyzed by threat and coping appraisal; iv) taking climate change more seriously following the pandemic is a function of the individual's perceived association between COVID-19 and climate change, external knowledge, income loss due to the pandemic, self-resilience, and ecocentric beliefs; v) self-resilient attitudes lead to positive behavioral change, while anthropocentric beliefs impede changes towards sustainable behavior.


Improvement of Metabolic Parameters Resulted from Levothyroxine Therapy in Hypothyroid Type 2 Diabetes Mellitus Patient.
This is a case of 51 year-old woman with uncontrolled type 2 diabetes mellitus which was diagnosed 1.5 year earlier, obesity with body mass index 32.2 kg/m2, waist circumference of 113 cm, diffuse goiter with neck circumference 40 cm, and hypertension with blood pressure >140/90 mmHg. Since 6 months ago, she often seemed like having less concentration or daydreaming, chronic fatigue, depression, and low food intake. Her body weight had been increasing over time. Her hypothyroidism clinical scoring Billewicz and Zulewski criterias were 17 and 8 respectively, showing that she tended to experience hypothyroidism. From laboratory examination, fasting blood glucose was 216 mg/dL and 2-hour postprandial blood glucose was 320 mg/dL with level of HbA1c was 9.9%, triglyceride level was 486 mg/dL, HDL cholesterol 46 mg/dL, LDL cholesterol 157 mg/dL, and total cholesterol was 269 mg/dL. Thyroid ultrasound showed a diffuse goiter in both lobes of her thyroid gland.


Assessment of high-risk opioid use metrics among individuals with spinal cord injury: A brief report.
To examine high-risk opioid prescription metrics among individuals with chronic spinal cord injury (SCI) living in South Carolina. Cohort Study. Two statewide population-based databases, an SCI Surveillance Registry and state prescription drug monitoring program (PDMP). Linked data was obtained for 503 individuals with chronic (>1year-post injury) SCI who were injured in 2013 or 2014 and who survived at least 3 years post-injury. Not applicable. Opioid prescription metrics were obtained from the PDMP. Fill data during the period between January 1, 2014 and December 31, 2017 were analyzed to assess high-risk opioid use. Outcomes included: percentage of individuals prescribed chronic opioids, high-dose chronic opioid therapy (daily morphine milligram equivalents (MME) ≥50 and ≥90), and chronic concurrent opioids and benzodiazepines, sedatives, or hypnotics (BSH). Over half (53%) of the individuals filled an opioid in years 2-3 after injury. Of those, 38% had a concurrent BSH fill during the study period, 76% of which were for benzodiazepines. In any given quarter over the two-year timeframe, over half of the opioid prescriptions were for 60 days or more (chronic opioid prescriptions). Of those, roughly 40% of the individuals had high-dose chronic opioid prescriptions ≥50 MME/d and 25% were ≥90 MME/d. Over 33% had a concurrent BSH prescription for ≥60 days. While the number of individuals receiving high-risk opioid prescriptions may not be large, it is a concerning number of prescriptions. The findings suggest a need for more cautious opioid prescribing and monitoring of high-risk use in adults with chronic SCI.


Probiotics at War Against Viruses: What Is Missing From the Picture?
Our world is now facing a multitude of novel infectious diseases. Bacterial infections are treated with antibiotics, albeit with increasing difficulty as many of the more common causes of infection have now developed broad spectrum antimicrobial resistance. However, there is now an even greater challenge from both old and new viruses capable of causing respiratory, enteric, and urogenital infections. Reports of viruses resistant to frontline therapeutic drugs are steadily increasing and there is an urgent need to develop novel antiviral agents. Although this all makes sense, it seems rather strange that relatively little attention has been given to the antiviral capabilities of probiotics. Over the years, beneficial strains of lactic acid bacteria (LAB) have been successfully used to treat gastrointestinal, oral, and vaginal infections, and some can also effect a reduction in serum cholesterol levels. Some probiotics prevent gastrointestinal dysbiosis and, by doing so, reduce the risk of developing secondary infections. Other probiotics exhibit anti-tumor and immunomodulating properties, and in some studies, antiviral activities have been reported for probiotic bacteria and/or their metabolites. Unfortunately, the mechanistic basis of the observed beneficial effects of probiotics in countering viral infections is sometimes unclear. Interestingly, in COVID-19 patients, a clear decrease has been observed in cell numbers of Lactobacillus and Bifidobacterium spp., both of which are common sources of intestinal probiotics. The present review, specifically motivated by the need to implement effective new counters to SARS-CoV-2, focusses attention on viruses capable of co-infecting humans and other animals and specifically explores the potential of probiotic bacteria and their metabolites to intervene with the process of virus infection. The goal is to help to provide a more informed background for the planning of future probiotic-based antiviral research.


Green tobacco sickness in Poland.
Green tobacco sickness (GTS) is an illness associated with exposure to nicotine originating directly from the growing tobacco plant. The exposure takes place in the course of activities during tobacco farming. Nausea, vomiting, headache and dizziness are the symptoms typical of GTS. The GTS cases have been most commonly reported in the USA, Japan, India and Italy. The first case of GTS in Poland has been diagnosed in a young man working on a Virginia bright tobacco plantation. The patient had symptoms typical of GTS. The toxicological analysis of urine demonstrated the presence of cotinine at the level of 869 ng/ml. Intravenous fluids, anticholinergic agents and potassium supplementation were used in the treatment. Interestingly, diplopia at the initial stage of tobacco poisoning and horizontal nystagmus, which resolved on the 2nd day of hospital stay were observed. We believe that cases of GTS occur in Poland; however patients do not seek medical care. Given that the majority of activities during tobacco farming in Poland are performed manually, it seems necessary to launch a public awareness campaign on GTS and decontamination methods.


[Incidence of de novo neoplasms after liver transplantation].
De novo malignancy developing after transplantation constitutes a well-known complication or organ transplantation, mainly described among renal recipients. To determine the incidence of de novo internal malignancies (excluding therefore skin cancers and recurrent hepatocellular carcinoma) in a cohort of 183 patients undergoing liver transplantation (OLT) between 6/1/1991 and 12/1/1996 with a minimum follow-up of 12 months and under cyclosporine-azathioprine-prednisone. The study comprised 183 patients (mean age: 53 [8] years, with 70% males) whose charts were reviewed retrospectively. Rejection, steroids treatment, methyl-prednisolone bolus and OKT3 use were compared in the cases and in the matched control group. Seven malignancies were detected: 3 lung carcinomas, 1 larynx, 1 prostate, 1 colon and 1 ovarian. The mean age was 53 (8) years. The diagnosis of cancer was made at an average time of 24 (17) months (range, 10-54) post-OLT. Three patients died with a mean survival of 31 (16) months. OLT indication was mainly for viral liver disease (5/7). Although not statistically significant, immunosuppression data were higher among patients with cancer than in the matched group. Two additional patients developed post-transplantation lymphoproliferative diseases at 2 and 9 months, respectively. We observed a wide variety of malignancies after OLT, but no associated factor was found, even though there was a trend to higher doses of immunosuppression in patients with cancers. The institution of preventive measures and surveillance programs may allow for early institution of therapy, improving therefore the survival.


Synaptic activity controls localization and function of CtBP1 via binding to Bassoon and Piccolo.
Persistent experience-driven adaptation of brain function is associated with alterations in gene expression patterns, resulting in structural and functional neuronal remodeling. How synaptic activity-in particular presynaptic performance-is coupled to gene expression in nucleus remains incompletely understood. Here, we report on a role of CtBP1, a transcriptional co-repressor enriched in presynapses and nuclei, in the activity-driven reconfiguration of gene expression in neurons. We demonstrate that presynaptic and nuclear pools of CtBP1 are interconnected and that both synaptic retention and shuttling of CtBP1 between cytoplasm and nucleus are co-regulated by neuronal activity. Finally, we show that CtBP1 is targeted and/or anchored to presynapses by direct interaction with the active zone scaffolding proteins Bassoon and Piccolo. This association is regulated by neuronal activity via modulation of cellular NAD/NADH levels and restrains the size of the CtBP1 pool available for nuclear import, thus contributing to the control of activity-dependent gene expression. Our combined results reveal a mechanism for coupling activity-induced molecular rearrangements in the presynapse with reconfiguration of neuronal gene expression.


An early cytoplasmic step of peptidoglycan synthesis is associated to MreB in Bacillus subtilis.
MreB proteins play a major role during morphogenesis of rod-shaped bacteria by organizing biosynthesis of the peptidoglycan cell wall. However, the mechanisms underlying this process are not well understood. In Bacillus subtilis, membrane-associated MreB polymers have been shown to be associated to elongation-specific complexes containing transmembrane morphogenetic factors and extracellular cell wall assembly proteins. We have now found that an early intracellular step of cell wall synthesis is also associated to MreB. We show that the previously uncharacterized protein YkuR (renamed DapI) is required for synthesis of meso-diaminopimelate (m-DAP), an essential constituent of the peptidoglycan precursor, and that it physically interacts with MreB. Highly inclined laminated optical sheet microscopy revealed that YkuR forms uniformly distributed foci that exhibit fast motion in the cytoplasm, and are not detected in cells lacking MreB. We propose a model in which soluble MreB organizes intracellular steps of peptidoglycan synthesis in the cytoplasm to feed the membrane-associated cell wall synthesizing machineries.


Plant-made trastuzumab (herceptin) inhibits HER2/Neu+ cell proliferation and retards tumor growth.
Plant biotechnology provides a valuable contribution to global health, in part because it can decrease the cost of pharmaceutical products. Breast cancer can now be successfully treated by a humanized monoclonal antibody (mAb), trastuzumab (Herceptin). A course of treatment, however, is expensive and requires repeated administrations of the mAb. Here we used an Agrobacterium-mediated transient expression system to produce trastuzumab in plant cells. We describe the cloning and expression of gene constructs in Nicotiana benthamiana plants using intron-optimized Tobacco mosaic virus- and Potato virus X-based vectors encoding, respectively, the heavy and light chains of trastuzumab. Full-size antibodies extracted and purified from plant tissues were tested for functionality and specificity by (i) binding to HER2/neu on the surface of a human mammary gland adenocarcinoma cell line, SK-BR-3, in fluorescence-activated cell sorting assay and (ii) testing the in vitro and in vivo inhibition of HER-2-expressing cancer cell proliferation. We show that plant-made trastuzumab (PMT) bound to the Her2/neu oncoprotein of SK-BR-3 cells and efficiently inhibited SK-BR-3 cell proliferation. Furthermore, mouse intraperitoneal PMT administration retarded the growth of xenografted tumors derived from human ovarian cancer SKOV3 Her2+ cells. We conclude that PMT is active in suppression of cell proliferation and tumor growth.


Dendritic Cells Are the Intriguing Players in the Puzzle of Idiopathic Pulmonary Fibrosis Pathogenesis.
Idiopathic pulmonary fibrosis (IPF) is the most devastating progressive interstitial lung disease that remains refractory to treatment. Pathogenesis of IPF relies on the aberrant cross-talk between injured alveolar cells and myofibroblasts, which ultimately leads to an aberrant fibrous reaction. The contribution of the immune system to IPF remains not fully explored. Recent evidence suggests that both innate and adaptive immune responses may participate in the fibrotic process. Dendritic cells (DCs) are the most potent professional antigen-presenting cells that bridge innate and adaptive immunity. Also, they exert a crucial role in the immune surveillance of the lung, where they are strategically placed in the airway epithelium and interstitium. Immature DCs accumulate in the IPF lung close to areas of epithelial hyperplasia and fibrosis. Conversely, mature DCs are concentrated in well-organized lymphoid follicles along with T and B cells and bronchoalveolar lavage of IPF patients. We have recently shown that all sub-types of peripheral blood DCs (including conventional and plasmacytoid DCs) are severely depleted in therapy naïve IPF patients. Also, the low frequency of conventional CD1c+ DCs is predictive of a worse prognosis. The purpose of this mini-review is to focus on the main evidence on DC involvement in IPF pathogenesis. Unanswered questions and opportunities for future research ranging from a better understanding of their contribution to diagnosis and prognosis to personalized DC-based therapies will be explored.


Adolescent Self-Consent for Biomedical Human Immunodeficiency Virus Prevention Research.
The Adolescent Medicine Trials Network Protocol 113 (ATN113) is an open-label, multisite demonstration project and Phase II safety study of human immunodeficiency virus (HIV) preexposure prophylaxis with 15- to 17-year-old young men who have sex with men that requires adolescent consent for participation. The purpose of this study was to examine factors related to the process by which Institutional Review Boards (IRBs) and researchers made decisions regarding whether to approve and implement ATN113 so as to inform future biomedical HIV prevention research with high-risk adolescent populations. Participants included 17 researchers at 13 sites in 12 states considering ATN113 implementation. Qualitative descriptive methods were used. Data sources included interviews and documents generated during the initiation process. A common process for initiating ATN113 emerged, and informants described how they identified and addressed practical, ethical, and legal challenges that arose. Informants described the process as responding to the protocol, preparing for IRB submission, abstaining from or proceeding with submission, responding to IRB concerns, and reacting to the outcomes. A complex array of factors impacting approval and implementation were identified, and ATN113 was ultimately implemented in seven of 13 sites. Informants also reflected on lessons learned that may help inform future biomedical HIV prevention research with high-risk adolescent populations. The results illustrate factors for consideration in determining whether to implement such trials, demonstrate that such protocols have the potential to be approved, and highlight a need for clearer standards regarding biomedical HIV prevention research with high-risk adolescent populations.


New living evidence resource of human and non-human studies for early intervention and research prioritisation in anxiety, depression and psychosis.
In anxiety, depression and psychosis, there has been frustratingly slow progress in developing novel therapies that make a substantial difference in practice, as well as in predicting which treatments will work for whom and in what contexts. To intervene early in the process and deliver optimal care to patients, we need to understand the underlying mechanisms of mental health conditions, develop safe and effective interventions that target these mechanisms, and improve our capabilities in timely diagnosis and reliable prediction of symptom trajectories. Better synthesis of existing evidence is one way to reduce waste and improve efficiency in research towards these ends. Living systematic reviews produce rigorous, up-to-date and informative evidence summaries that are particularly important where research is emerging rapidly, current evidence is uncertain and new findings might change policy or practice. Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis (GALENOS) aims to tackle the challenges of mental health science research by cataloguing and evaluating the full spectrum of relevant scientific research including both human and preclinical studies. GALENOS will also allow the mental health community-including patients, carers, clinicians, researchers and funders-to better identify the research questions that most urgently need to be answered. By creating open-access datasets and outputs in a state-of-the-art online resource, GALENOS will help identify promising signals early in the research process. This will accelerate translation from discovery science into effective new interventions for anxiety, depression and psychosis, ready to be translated in clinical practice across the world.


Least-Squares Solutions of Eighth-Order Boundary Value Problems Using the Theory of Functional Connections.
This paper shows how to obtain highly accurate solutions of eighth-order boundary-value problems of linear and nonlinear ordinary differential equations. The presented method is based on the Theory of Functional Connections, and is solved in two steps. First, the Theory of Functional Connections analytically embeds the differential equation constraints into a candidate function (called a constrained expression) containing a function that the user is free to choose. This expression always satisfies the constraints, no matter what the free function is. Second, the free-function is expanded as a linear combination of orthogonal basis functions with unknown coefficients. The constrained expression (and its derivatives) are then substituted into the eighth-order differential equation, transforming the problem into an unconstrained optimization problem where the coefficients in the linear combination of orthogonal basis functions are the optimization parameters. These parameters are then found by linear/nonlinear least-squares. The solution obtained from this method is a highly accurate analytical approximation of the true solution. Comparisons with alternative methods appearing in literature validate the proposed approach.


Lumbar sympathectomy in occlusive diseases.
To assess the real value of Lumbar Sympathectomy it is of prime importance to be aware of both the mechanisms of the neurogenic vasomotricity in a normal limb, and the effect of a sympathetic interruption on a normal and arteriopathetic limb. These mechanisms are studied and discussed by means of different vascular functional tests and results of operative procedure. It leads to identify the patients who are likely to respond well to sympathectomy either for distal skin troubles, or for claudication.


Two heme-dependent terminal oxidases power Staphylococcus aureus organ-specific colonization of the vertebrate host.
Staphylococcus aureus is a significant cause of infections worldwide and is able to utilize aerobic respiration, anaerobic respiration, or fermentation as the means by which it generates the energy needed for proliferation. Aerobic respiration is supported by heme-dependent terminal oxidases that catalyze the final step of aerobic respiration, the reduction of O2 to H2O. An inability to respire forces bacteria to generate energy via fermentation, resulting in reduced growth. Elucidating the roles of these energy-generating pathways during colonization of the host could uncover attractive therapeutic targets. Consistent with this idea, we report that inhibiting aerobic respiration by inactivating heme biosynthesis significantly impairs the ability of S. aureus to colonize the host. Two heme-dependent terminal oxidases support aerobic respiration of S. aureus, implying that the staphylococcal respiratory chain is branched. Systemic infection with S. aureus mutants limited to a single terminal oxidase results in an organ-specific colonization defect, resulting in reduced bacterial burdens in either the liver or the heart. Finally, inhibition of aerobic respiration can be achieved by exposing S. aureus to noniron heme analogues. These data provide evidence that aerobic respiration plays a major role in S. aureus colonization of the host and that this energy-generating process is a viable therapeutic target. Staphylococcus aureus poses a significant threat to public health as antibiotic-resistant isolates of this pathogen continue to emerge. Our understanding of the energy-generating processes that allow S. aureus to proliferate within the host is incomplete. Host-derived heme is the preferred source of nutrient iron during infection; however, S. aureus can synthesize heme de novo and use it to facilitate aerobic respiration. We demonstrate that S. aureus heme biosynthesis powers a branched aerobic respiratory chain composed of two terminal oxidases. The importance of having two terminal oxidases is demonstrated by the finding that each plays an essential role in colonizing distinct organs during systemic infection. Additionally, this process can be targeted by small-molecule heme analogues called noniron protoporphyrins. This study serves to demonstrate that heme biosynthesis supports two terminal oxidases that are required for aerobic respiration and are also essential for S. aureus pathogenesis.


Precise measurement of the neutrino mixing parameter θ23 from muon neutrino disappearance in an off-axis beam.
New data from the T2K neutrino oscillation experiment produce the most precise measurement of the neutrino mixing parameter θ23. Using an off-axis neutrino beam with a peak energy of 0.6 GeV and a data set corresponding to 6.57×10(20) protons on target, T2K has fit the energy-dependent νμ oscillation probability to determine oscillation parameters. The 68% confidence limit on sin(2)(θ23) is 0.514(-0.056)(+0.055) (0.511±0.055), assuming normal (inverted) mass hierarchy. The best-fit mass-squared splitting for normal hierarchy is Δm32(2)=(2.51±0.10)×10(-3) eV(2)/c(4) (inverted hierarchy: Δm13(2)=(2.48±0.10)×10(-3) eV(2)/c(4)). Adding a model of multinucleon interactions that affect neutrino energy reconstruction is found to produce only small biases in neutrino oscillation parameter extraction at current levels of statistical uncertainty.


Early stage visual-orthographic processes predict long-term retention of word form and meaning: a visual encoding training study.
Adult learners of Chinese learned new characters through writing, visual chunking or reading-only. Following training, ERPs were recorded during character recognition tasks, first shortly after the training and then three months later. We hypothesized that the character training effects would be seen in ERP components associated with word recognition and episodic memory. Results confirmed a larger N170 for visual chunking training than other training and a larger P600 for learned characters than novel characters. Another result was a training effect on the amplitude of the P100, which was greater following writing training than other training, suggesting that writing training temporarily lead to increased visual attention to the orthographic forms. Furthermore, P100 amplitude at the first post-test was positively correlated with character recall 3 months later. Thus the marker of early visual attention (P100) was predictive of retention of orthographic knowledge acquired in training.


Impact of chronic disease self-management programs on type 2 diabetes management in primary care.
To assess the effectiveness of the Chronic Disease Self-Management Program (CDSMP) on glycated hemoglobin A1c (HbA1c) and selected self-reported measures. We compared patients who received a diabetes self-care behavioral intervention, the CDSMP developed at the Stanford University, with controls who received usual care on their HbA1c and selected self-reported measures, including diabetes self-care activities, health-related quality of life (HRQOL), pain and fatigue. The subjects were a subset of participants enrolled in a randomized controlled trial that took place at seven regional clinics of a university-affiliated integrated healthcare system of a multi-specialty group practice between January 2009 and June 2011. The primary outcome was change in HbA1c from randomization to 12 mo. Data were analyzed using multilevel statistical models and linear mixed models to provide unbiased estimates of intervention effects. Demographic and baseline clinical characteristics were generally comparable between the two groups. The average baseline HbA1c values in the CDSMP and control groups were 9.4% and 9.2%, respectively. Significant reductions in HbA1c were seen at 12 mo for the two groups, with adjusted changes around 0.6% (P < 0.0001), but the reductions did not differ significantly between the two groups (P = 0.885). Few significant differences were observed in participants' diabetes self-care activities. No significant differences were observed in the participants' HRQOL, pain, or fatigue measures. The CDSMP intervention may not lower HbA1c any better than good routine care in an integrated healthcare system. More research is needed to understand the benefits of self-management programs in primary care in different settings and populations.


Collocation-based sparse estimation for constructing dynamic gene networks.
One of the open problems in systems biology is to infer dynamic gene networks describing the underlying biological process with mathematical, statistical and computational methods. The first-order difference equation-based models such as dynamic Bayesian networks and vector autoregressive models were used to infer time-lagged relationships between genes from time-series microarray data. However, two primary problems greatly reduce the effectiveness of current approaches. The first problem is the tacit assumption that time lag is stationary. The second is the inseparability between measurement noise and process noise (unmeasured disturbances that pass through time process). To address these problems, we propose a stochastic differential equation model for inferring continuous-time dynamic gene networks under the situation in which both of the process noise and the observation noise exist. We present a collocation-based sparse estimation for simultaneous parameter estimation and model selection in the model. The collocation-based approach requires considerably less computational effort than traditional methods in ordinary stochastic differential equation models. We also incorporate various biological knowledge easily to refine the estimation accuracy with the proposed method. The results using simulated data and real time-series expression data of human primary small airway epithelial cells demonstrate that the proposed approach outperforms competing approaches and can provide significant genes influenced by gefitinib.


Characterization of antigen-specific CD8+ T lymphocyte responses in skin and peripheral blood following intradermal peptide vaccination.
Immune responses to cancer vaccines are commonly tested by measuring cutaneous reactions to intradermal (i.d.) antigen. When well-characterized peptide epitopes are injected i.d., infiltrates of CD4+ and CD8+ T lymphocytes are frequently seen. In this study, we have further characterized T cells derived from vaccine-infiltrating lymphocyte (VIL) responses. We found that the infiltrates capable of producing IFN-gamma and cytolytic activity could recognize vaccine peptide, as well as antigen-positive melanoma cells. We studied antigen-specific T cell responses from VILs and peripheral blood in 10 patients who participated in a clinical trial. All patients received systemic Flt3 ligand (20 microg/kg/d) and i.d. peptides: Three NY-ESO-1 peptides, SLLMWITQCFL (157-167), SLLMWITQC (157-165), QLSLLMWIT (155-163); tyrosinase internal peptide YMDGTMSQV (368-376); Melan-A/MART-1 analogue peptide ELAGIGILTV (26-35, E27L substitution); and influenza matrix peptide GILGFVFTL (58-66). In 54 paired VIL and peripheral blood analyses, a good correlation was found between responses in skin and in blood. These cells could be rapidly expanded in a short-term assay and thus appear to be memory T cells. The demonstrated presence of antigen-specific T cells at vaccination sites validates this method of assessing the immune response to i.d. vaccines.


Use of Radiomics Combined With Machine Learning Method in the Recurrence Patterns After Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma: A Preliminary Study.
Objective: To analyze the recurrence patterns and reasons in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT) and to investigate the feasibility of radiomics for analysis of radioresistance. Methods: We analyzed 306 NPC patients treated with IMRT from Jul-2009 to Aug-2016, 20 of whom developed with recurrence. For the NPCs with recurrence, CT, MR, or PET/CT images of recurrent disease were registered with the primary planning CT for dosimetry analysis. The recurrences were defined as in-field, marginal or out-of-field, according to dose-volume histogram (DVH) of the recurrence volume. To explore the predictive power of radiomics for NPCs with in-field recurrences (NPC-IFR), 16 NPCs with non-progression disease (NPC-NPD) were used for comparison. For these NPC-IFRs and NPC-NPDs, 1117 radiomic features were quantified from the tumor region using pre-treatment spectral attenuated inversion-recovery T2-weighted (SPAIR T2W) magnetic resonance imaging (MRI). Intraclass correlation coefficients (ICC) and Pearson correlation coefficient (PCC) was calculated to identify influential feature subset. Kruskal-Wallis test and receiver operating characteristic (ROC) analysis were employed to assess the capability of each feature on NPC-IFR prediction. Principal component analysis (PCA) was performed for feature reduction. Artificial neural network (ANN), k-nearest neighbor (KNN), and support vector machine (SVM) models were trained and validated by using stratified 10-fold cross validation. Results: The median follow up was 26.5 (range 8-65) months. 9/20 (45%) occurred in the primary tumor, 8/20 (40%) occurred in regional lymph nodes, and 3/20 (15%) patients developed a primary and regional failure. Dosimetric and target volume analysis of the recurrence indicated that there were 18 in-field, and 1 marginal as well as 1 out-of-field recurrence. With pre-therapeutic SPAIR T2W MRI images available, 11 NPC-IFRs (11 of 18 NPC-IFRs who had available pre-therapeutic MRI) and 16 NPC-NPDs were subsequently employed for radiomic analysis. Results showed that NPC-IFRs vs. NPC-NPDs could be differentiated by 8 features (AUCs: 0.727-0.835). The classification models showed potential in prediction of NPC-IFR with higher accuracies (ANN: 0.812, KNN: 0.775, SVM: 0.732). Conclusion: In-field and high-dose region relapse were the main recurrence patterns which may be due to the radioresistance. After integration in the clinical workflow, radiomic analysis can be served as imaging biomarkers to facilitate early salvage for NPC patients who are at risk of in-field recurrence.


Inspiratory muscle training during pulmonary rehabilitation in chronic obstructive pulmonary disease: A randomized trial.
Although recommended by international guidelines, the benefit of inspiratory muscle training (IMT) in addition to rehabilitation remains uncertain. The objective was to demonstrate the effectiveness of IMT on dyspnea using Borg scale and multidimensional dyspnea profile questionnaire at the end of a 6-minute walk test (6MWT) in patients with chronic obstructive pulmonary disease (COPD) with preserved average maximum inspiratory pressure (PImax) of 85 cm H2O (95% of predicted (pred.) value) and admitted for a rehabilitation program in a dedicated center. In a randomized trial, comparing IMT versus no IMT in 32 COPD patients without inspiratory muscle weakness (PImax >60 cm H2O) who were admitted for pulmonary rehabilitation (PR) for 3 weeks, we evaluated the effect of IMT on dyspnea, using both Borg scale and multidimensional dyspnea profile (MDP) at the end of the 6MWT, and on functional parameters included inspiratory muscle function (PImax) and 6MWT. All testings were performed at the start and the end of PR. In unadjusted analysis, IMT was not found to be associated with an improvement of either dyspnea or PImax. After adjustment on confounders (initial Borg score) and variables of interaction (forced expiratory volume in 1 second (FEV1)), we found a trend toward an improvement of "dyspnea sensory intensity", items from MDP and a significant improvement on the variation in the 2 items of MDP ("tight or constricted" and "breathing a lot"). In the subgroup of patients with FEV1 < 50% pred., 5 items of MDP were significantly improved, whereas no benefit was observed in patients with FEV1 > 50% pred. IMT did not significantly improve dyspnea or functional parameter in COPD patients with PImax > 60 cm H2O. However, in the subgroup of patients with FEV1 < 50% pred., MDP was significantly improved.


Numerical classification of some Rhodococci, Corynebacteria and related organisms.
Nineteen strains of Corynebacterium sensu stricto, 23 received as Corynebacterium equi or Rhodococcus equi, marker cultures of Arthrobacter, Brevibacterium, Bacterionema matruchotii, Cellulomonas flavigena, Kurthia zopfii, Listeria denitrificans, Microbacterium lacticum, Rhodococcus rubropertinctus and 88 representatives of Mycobacterium, Nocardia, Rhodococcus and the 'aurantiaca' taxon were the subject of numerical phenetic analyses using 92 characters. The data were examined using the simple matching (SSM) and Jaccard (SJ) coefficients and clustering was achieved using the average linkage algorithm. With a single exception, strains containing meso-diaminopimelic acid, arabinose, galactose and mycolic acids were recovered in five aggregate clusters corresponding to Corynebacterium sensu stricto, Mycobacterium, Nocardia, Rhodococcus and the 'aurantiaca' taxon. Most of the Corynebacterium (Rhodococcus) equi strains formed a good taxospecies which included the type strain of Corynebacterium hoagii. The numerical data, and the results of earlier chemical and genetical studies, also provide sufficient evidence for the transfer of Bacterionema matruchotii to Corynebacterium sensu stricto as Corynebacterium matruchotii comb.nov. and for the recognition of Rhodococcus globerulus sp.nov. for some strains previously classified as Rhodococcus rubropertinctus (Hefferan) Goodfellow & Alderson. The classification of the remaining marker strains correlates well with other major developments in coryneform taxonomy.


Proactively modulating mechanical behaviors of materials at multiscale for mechano-adaptable devices.
How materials behave when subjected to mechanical stresses is studied by mechanics of materials. However, the application of flexible and stretchable devices exposes materials to dynamic mechanical environments. Therefore, mechano-adaptable materials and devices that can respond as pre-designed have been explored. There are two main ways to proactively modulate mechanical behaviors for materials, which involve molecular design and structural design. Molecular design has effectively integrated mechanically sensitive groups into synthetic materials for anticipated mechano-response. Structural design has broadened the boundary of conventional materials, generating mechanical metamaterials at multiscale with unique mechanical properties. Furthermore, molecular, structural plus systematic design for the application of mechano-adaptable devices have realized better electrical performance, human interaction, long-term sustainability, and even higher efficiency. Various devices based on design ideas are summarized and future challenges for proactively modulating mechanical behaviors of mechano-adaptable devices are discussed.