Nomifensine-induced immune hemolytic anemia and posttransfusion purpura in the same patient.
A 53-year-old white woman had severe hemolytic anemia while taking nomifensine. A drop of hemoglobin to 61 g per I prompted the transfusion of two units of packed red cells. Nine days later, severe thrombocytopenia with multiple petechiae ensued. Both hemolysis and thrombocytopenia resolved promptly upon withdrawal of the drug and short-term prednisolone treatment. Serologic studies showed nomifensine-dependent, metabolite-specific red cell antibodies as the cause of immune-mediated hemolysis and, in serum samples obtained after purpura, strong platelet-specific PlA1 and weak HLA antibodies suggested a diagnosis of posttransfusion purpura.


Genotoxicity of selenite in diploid yeast.
Selenite, a chemical of industrial importance and also an antimutagenic/anticarcinogenic agent, was tested for mutagenic and recombinogenic effects in 2 diploid yeast strains, Saccharomyces cerevisiae BZ 34 and D7. Selenite induced gene conversion and toxicity in BZ 34 and a variety of genetic events, viz. back-mutation, gene conversion, mitotic crossing-over, aberrant colony formation and also toxicity in the D7 strain. In both strains, the genetic effects of selenite showed a peak and a decline during 5 h of treatment while its toxicity increased marginally during 1-5 h. In the BZ 34 strain, the presence of glutathione (GSH) during selenite treatment greatly enhanced the convertogenic and toxic effects of selenite.


Overexpression of BIRC6 driven by EGF-JNK-HECTD1 signaling is a potential therapeutic target for triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. The lack of targeted therapies and poor patient outcome have fostered efforts to discover new molecular targets to treat patients with TNBC. Here, we showed that baculoviral IAP repeat containing 6 (BIRC6) is overexpressed and positively correlated with epidermal growth factor (EGF) receptor (EGFR) in TNBC cells and tissues and that BIRC6 overexpression is associated with poor patient survival. Mechanistic studies revealed that BIRC6 stability is increased by EGF-JNK signaling, which prevents ubiquitination and degradation of BIRC6 mediated by the E3 ubiquitin ligase HECTD1. BIRC6 in turn decreases SMAC expression by inducing the ubiquitin-proteasome pathway, thereby antagonizing apoptosis and promoting the proliferation, colony formation, tumorsphere formation, and tumor growth capacity of TNBC cells. Therapeutically, the PEGylated cationic lipid nanoparticle (pCLN)-assisted delivery of BIRC6 small interfering RNA (siRNA) efficiently silences BIRC6 expression in TNBC cells, thus suppressing TNBC cell growth in vitro and in vivo, and its antitumor activity is significantly superior to that of the EGFR inhibitor gefitinib. Our findings identify an important regulatory mechanism of BIRC6 overexpression and provide a potential therapeutic option for treating TNBC.


Only coherent spiking in posterior parietal cortex coordinates looking and reaching.
Here, we report that temporally patterned, coherent spiking activity in the posterior parietal cortex (PPC) coordinates the timing of looking and reaching. Using a spike-field approach, we identify a population of parietal area LIP neurons that fire spikes coherently with 15 Hz beta-frequency LFP activity. The firing rate of coherently active neurons predicts the reaction times (RTs) of coordinated reach-saccade movements but not of saccades when made alone. Area LIP neurons that do not fire coherently do not predict RT of either movement type. Similar beta-band LFP activity is present in the parietal reach region but not nearby visual area V3d. This suggests that coherent spiking activity in PPC can control reaches and saccades together. We propose that the neural mechanism of coordination involves a shared representation that acts to slow or speed movements together.


Studies in the enhancement of tumour immunity by coupling strong antigens to tumour cells ('heterogenization of tumours'). Helper T cell clones against PPD help other T cells mount anti-tumour responses to PPD-coupled tumour cells.
PPD-reactive T cell clones have been used to analyse the nature of T lymphocytes that are involved in the 'heterogenization' of tumour cells. This is a phenomenon where coupling tumour cells to a strong antigen (in this case PPD) causes an enhanced immune response to tumour-specific antigens to be elicited providing that the host shows T cell immunity to the strong antigen (in this case is BCG positive). Clones of T cells with the Lyt1+2- phenotype which were unable to mediate delayed-type hypersensitivity but which provided efficient help to hapten-primed B cells were found to potentiate anti-tumour immunity in BCG-negative syngeneic mice when immunized with Con-A-PPD coupled, X-irradiated MC6A tumour cells. There therefore appears to be a mechanism whereby a helper T cell response to one antigen can provide help for the generation of a T cell response to a linked antigen which is analogous to the well-known phenomenon of help to hapten primed B cells. Furthermore the clones of T cells that help B cells the best are those that give maximal augmentation of T cell immunity.


Severe florid cemento-osseous dysplasia: a case report treated conservatively and literature review.
Florid cemento-osseous dysplasia (FCOD) has been described as a condition that characteristically affects the jaws of middle-aged black women. Radiographically, FCOD appears as dense, lobulated masses, often symmetrically located in various regions of the jaws. FCOD is usually asymptomatic. In severe cases, focal expansion may occur due to infection. Management of the symptomatic patient is more difficult due to the avascular nature of the lesion which contributes to susceptibility severe infection, bone sequestration, and osteomyelitis when surgery is performed. This paper presents a rare case of severe FCOD; the black woman patient was diagnosed based on clinical and radiographic findings and treated conservatively. The examination of panoramic radiographs revealed a multiple sclerotic masses with radiolucent borders, found in the mandible and maxilla which were symmetrical at presentation. The patient continuous with the follow-up. This report confirms that a diagnosis can be made with accurate clinical and radiographic assessment. The correct selection of treatment for FCOD depends on this information.


Dynamics of insulin release by perifused insulin-producing tumoral cells: effects of glucose, forskolin, leucine, barium and theophylline.
Perifused tumoral insulin-producing cells, of the RINm5F line, display a high basal insulin output relative to their hormonal content. D-Glucose (2.8 or 16.7 mmol/l) causes a modest and monophasic increase in insulin output. The secretory response to D-glucose (1.4 to 16.7 mmol/l) is enhanced by forskolin, which exerts little effect in the absence of exogenous nutrient. L-Leucine (10.0 mmol/l) also stimulates insulin release from the perifused cells. The secretory response to these nutrient secretagogues in much less marked, however, than that evoked, in the absence of Ca2+, by the association of Ba2+ and theophylline. It is concluded that the dynamics of insulin release by the tumoral cells, when compared to that of normal islet cells, are characterized by several anomalies, including a high basal ratio between secretion and content, a low threshold (less than or equal to 1.4 mmol/l) in the secretory response to D-glucose, and a lesser responsiveness to nutrient than nonnutrient secretagogues.


[Sarcoid-like granulomatosis associated with eosinophilic fasciitis].
Eosinophilic fasciitis (EF) is a rare condition characterized by swelling of the extremities, sclerodermatous evolution and frequent hypereosinophilia. Hematological disorders, including aplastic anemia, solid tumors and autoimmune diseases, may be associated with EF. EF is usually not associated with granulomatous diseases. Herein we describe the case of an 80-year-old man with symmetrical swelling and sclerosis of the legs, typical of EF, associated with skin and lymph node granulomas. Oral prednisone treatment resulted in complete clinical remission. Association of EF and granulomatous disease is uncommon. Our case highlights the possible association of EF with sarcoidosis-like reactions.


Natural history of pure ground-glass opacity after long-term follow-up of more than 2 years.
Pure ground-glass opacity (PGGO) is a new entity that has been clearly defined on high-resolution computed tomography (CT) during the last half decade. It is important to investigate the natural history of PGGO through long-term observation for the management of this new entity. We investigated 19 patients with PGGO(s) defined on high-resolution computed tomography and retained as PGGO for more than 2 years. The PGGOs of 11 patients were detected at annual mass screening by low-radiation-dose CT (low-dose CT), 7 at follow-up CT after cancer resection, and 1 incidentally on CT. After long-term observation, 10 of 19 patients underwent operation and 9 are currently being followed-up with CT. Their growth characteristics and histologic findings are reported. The median follow-up period was 32 months, ranging from 24 to 124 months. The sizes of PGGOs at the time of discovery were 4 to 18 mm in largest diameter (average 8.6 mm). During follow-up, the size of PGGO showed no change in 8 patients, increased slightly (up to 5 mm) in 6 patients, and increased by more than 5 mm in 5 patients. Ten patients had limited resection (segmentectomy or wide wedge resection) with negative surgical margin by intraoperative lavage cytology of the resection margin of the lung. Of them, 5 patients had adenocarcinoma, 3 pulmonary lymphoproliferative disorder, and 1 each atypical adenomatous hyperplasia and focal fibrosis. There was no clear tendency between the degree of size change and histology. In all but 1 of 9 patients with follow-up only, the PGGOs showed either no change or only a slight increase within 5 mm in largest diameter. These data suggest that some PGGOs will never progress to clinical disease and would be included in the category of overdiagnosis bias. However, a prior history of lung cancer should significantly raise the index of suspicion, as 4 of 5 proven cancer cases in this small series fell into that category. Because of the difficulties of preoperative and intraoperative histodiagnosis of PGGO, minimally invasive surgery may be appropriate from the viewpoints of both diagnosis and curability.


The use of multistage exercise testing with wheelchair ergometry and arm cranking in subjects with spinal cord lesions.
The primary aim of this investigation was to compare maximum wheelchair performance with arm cranking using a multistage progressive work load protocol. In five subjects with a wide range of neurological disability and two normal males the differences observed in maximum oxygen uptake, heart rate and ventilation during two forms of upper limbs exercise, were not significant.


Trace metals supplementation in anaerobic membrane bioreactors treating highly saline phenolic wastewater.
Biomass requires trace metals (TM) for maintaining its growth and activity. This study aimed to determine the effect of TM supplementation and partitioning on the specific methanogenic activity (SMA), with a focus on cobalt and tungsten, during the start-up of two lab-scale Anaerobic Membrane Bioreactors (AnMBRs) treating saline phenolic wastewater. The TM partitioning revealed a strong accumulation of sodium in the biomass matrix and a wash-out of the majority of TM in the reactors, which led to an SMA decrease and a low COD removal of about 30%. The SMA exhibits a maximum at about 6g Na+ L-1 and nearly complete inhibition at 34g Na+ L-1. The dose of 0.5mgL-1 of tungsten increases the SMA by 17%, but no improvement was observed with the addition of cobalt. The results suggested that TM were not bioavailable at high salinity. Accordingly, an increased COD removal was achieved by doubling the supply of TM.


Twenty-nail dystrophy: report of a case and review of the literature.
A case of twenty-nail dystrophy in an 7-year-old girl is presented. The histopathological findings were incompatible with lichen planus. The differential diagnosis is briefly discussed, and the literature reviewed.


Lymphocyte-C-reactive protein ratio as a novel prognostic index in intrahepatic cholangiocarcinoma: A multicentre cohort study.
The lymphocyte-C-reactive protein ratio (LCR) is a novel inflammatory-based score, based solely on the lymphocyte and C-reactive protein. We aimed to clarify the prognostic value of the LCR score in intrahepatic cholangiocarcinoma (ICC) patients after resection. We compared the prognostic accuracy of the LCR score with other inflammatory-based scores in this large, multicentre cohort study. The independent variables associated with overall survival (OS) were explored in both the primary (n = 228) and validation cohorts (n = 135). Harrell's concordance index (C-index) was used to compare the predictive ability of all the assessed inflammatory-based scores. The LCR score was differentiated two groups of ICC patients with distinct prognoses (1-, 3-, and 5-year OS rates: 94.4%, 66.3%, and 59.3%; and 66.6%, 45.6%, and 32.7%, respectively) (P < .001). Multivariate analysis showed that the LCR score, as well as the TNM stage and preoperative CA19-9 level, were independently associated with OS. The predictive accuracy of the LCR score (c score: 0.634) was superior to that of the other inflammatory-based scores (c scores: 0.508-0.615). These findings were supported by the external validation cohort. The LCR score is stable and consistently the best prognostic score and may offer as a simple, objective and discriminatory method in facilitating the risk stratification of ICC patients.


Observation of high and low passive ankle flexibility in stair descent.
Able-bodied people from the two extremes of the distribution of passive dorsiflexion exhibit biomechanical differences when descending stairs. Whether physical therapists could judge accurately the amount of ankle flexibility from observation of stair descent was examined with physical therapists (20 neurological 20 cardiothoracic) and 20 students. Subjects were 18 able-bodied men with high or low passive dorsiflexion. Raters viewed videotaped subjects descending stairs at normal playback speed and in slow motion and rated ankle flexibility on a 20-point scale. 'Flexible' or 'inflexible' subjects were classified correctly better than chance, but accuracy of rating flexibility was relatively poor. Both experience and slow motion playback improved accuracy. Physical therapists can detect extremes of normal flexibility in the ankle, based solely on observation of stair descent, and experienced therapists are better at this task than less experienced ones. Using slow motion videotape enhanced observational analysis.


Practical aspects of the preparation and filing of patent applications.
This chapter is intended to give a brief introduction into the most important patent basics. More importantly, it provides some practical advice to scientists on various considerations when contemplating and preparing the filing of a patent application, irrespective of whether this is assisted by a patent professional or not.


Streptococcus suis infections in Danish pigs and experimental infection with Streptococcus suis serotype 7.
During a two-year period, Streptococcus suis serotypes 1-8 were isolated from 108 pigs examined at the laboratory. S. suis serotypes 2 and 7 represented 75% of the isolates. S. suis serotype 7 was isolated more frequently than reported from other countries, and mostly from piglets less than 3 weeks of age. Experimental inoculation of 7-day-old piglets with S. suis serotype 7 provoked severe illness within a week in 6 out of 7 animals. By bacteriological and pathological examination it was found that S. suis serotype 7 was pathogenic to piglets, giving rise to septicemia with predilection for joints, serous membranes and meninges.


Polarization memory effect in the photoluminescence of nc-Si-SiOx light-emitting structures.
The polarization memory (PM) effect in the photoluminescence (PL) of the porous nc-Si-SiOx light-emitting structures, containing nanoparticles of silicon (nc-Si) in the oxide matrix and passivated in a solution of hydrofluoric acid (HF), has been investigated. The studied nc-Si-SiOx structures were produced by evaporation of Si monoxide (SiO) powder in vacuum and oblique deposition on Si wafer, and then the deposited silicon oxide (SiOx) films were annealed in the vacuum at 975 °C to grow nc-Si. It was found that the PM effect in the PL is observed only after passivation of nanostructures: during etching in HF solution, the initial symmetric nc-Si becomes asymmetric elongated. It was also found that in investigated nanostructures, there is a defined orientational dependence of the PL polarization degree (ρ) in the sample plane which correlates with the orientation of SiOx nanocolumns, forming the structure of the porous layer. The increase of the ρ values in the long-wavelength spectral range with time of HF treatment can be associated with increasing of the anisotropy of large Si nanoparticles. The PM effect for this spectral interval can be described by the dielectric model. In the short-wavelength spectral range, the dependence of the ρ values agrees qualitatively with the quantum confinement effect.


First experiences using transurethral ultrasound ablation (TULSA) as a promising focal approach to treat localized prostate cancer: a monocentric study.
To share our experience using transurethral ultrasound ablation (TULSA) treatment for focal therapy of localized prostate cancer (PCa). Between 10/2019 and 06/2021 TULSA treatment for localized PCa was performed in 22 men (mean age: 67 ± 7 years, mean initial PSA: 6.8 ± 2.1 ng/ml, ISUP 1 in n = 6, ISUP 2 in n = 14 and 2 patients with recurrence after previous radiotherapy). Patients were selected by an interdisciplinary team, taking clinical parameters, histopathology from targeted or systematic biopsies, mpMRI and patients preferences into consideration. Patients were thoroughly informed about alternative treatment options and that TULSA is an individual treatment approach. High-intensity ultrasound was applied using an ablation device placed in the prostatic urethra. Heat-development within the prostatic tissue was monitored using MR-thermometry. Challenges during the ablation procedure and follow-up of oncologic and functional outcome of at least 12 months after TULSA treatment were documented. No major adverse events were documented. In the 12 month follow-up period, no significant changes of urinary continence, irritative/obstructive voiding symptoms, bowel irritation or hormonal symptoms were reported according to the Expanded Prostate Cancer Index Composite (EPIC) score. Erectile function was significantly impaired 3-6 months (p < 0.01) and 9-12 months (p < 0.05) after TULSA. PSA values significantly decreased after therapy (2.1 ± 1.8 vs. 6.8 ± 2.1 ng/ml, p < 0.001). PCa recurrence rate was 23% (5/22 patients). Establishment of TULSA in clinical routine was unproblematic, short-term outcome seems to be encouraging. The risk of erectile function impairment requires elaborate information of the patient.


Evaluation of a combined, online intervention for binge-type eating disorders and high body weight in young adults.
Binge-type eating disorders (EDs; i.e., bulimia nervosa, binge eating disorder) are common among young adults with high body weight, yet few interventions target both conditions. This study tested an online guided self-help intervention that provided cognitive behavioral therapy (CBT) tools for EDs and behavioral weight loss (BWL) content to young adults with binge-type EDs and high body weight. 60 adults aged 18-39 with clinical/subclinical binge-type EDs and high body weight were randomized to a combined condition or a CBT-only condition. Participants received self-help content for 8 weeks and self-reported ED attitudes, frequency of binge eating and compensatory behaviors, and weight at baseline, 4-weeks, and 8-weeks. Linear mixed models and negative binomial models compared changes between conditions in ED attitudes, ED behaviors, and weight at each timepoint. Chi-square test and independent samples t-test compared program completion and session engagement between conditions. No significant differences in weight change or ED symptom change emerged between the conditions. Both conditions achieved significant reductions in ED attitudes, binge episodes, and compensatory behaviors from baseline to 8-weeks (ps < .05). Neither condition demonstrated significant weight loss from baseline to 8-weeks. Program completion (47 %) and session engagement (57 %) were equally high across conditions. Both conditions achieved ED symptom change; however, neither condition was associated with weight change. Research is needed to identify the types of strategies and doses of BWL that promote clinically significant weight and ED symptom change in young adults.


Application of a mandibular nerve block using an indwelling catheter for intractable cancer pain.
We report a case in which a mandibular nerve block using an indwelling catheter was employed for pain management in a terminal case of orofacial cancer. The patient was a 74-year-old female weighing 27 kg. She had a 27-month history of mouth floor and tongue cancer. The cancer recurred and spread to bilateral face and neck. The severest pain mainly originated from the right mandibular region. Two steps of pain relief were performed for the patient. First, pain control using 1% lidocaine or 0.25% bupivacaine administered intermittently or continuously through an indwelling catheter in the mandibular nerve was performed for 1 week to estimate the amount of pain relief thereby obtained. Second, a neurolytic block was applied to the mandibular nerve through the catheter. After the neurolytic block, the total dosage of morphine and diclofenac remained unchanged for 2 months. We conclude from the present case that this technique is an excellent means of obtaining long-term pain control in patients with intractable orofacial cancer pain.


Sufficient mesh polyhedral intralesional injection for treatment of keloids.
The recurrence of keloids after intralesional injections is significant, and a review of the literature shows an inconsistent range of success rates. In this study, the modified medical proportion and intralesional injection method were intended to enhance the treatment effect. Twenty patients completed the study. Regional block anesthesia (lidocaine, ropivacaine) was performed. Triamcinolone acetonide (40 mg/mL), 5-fluorouracil (25 mg/mL), and ropivacaine (7.5 mg/mL) were configured in a ratio of 2:1:4 and applied on the lesion by reticular injection (horizontal fan-shaped stratified and vertical shaking pressurized injection). The minimum volume of injection per square centimeter was approximately 3.5 mL. The outcome indicators were the Vancouver Scar Scale (VSS), Visual Analogue Scale (VAS), treatment frequency. The patients had an 82% ± 7% average reduction in VSS scores and 89% ± 13% and 93% ± 10% reductions in VAS scores of pain and pruritus, respectively, after an average of 2.5 ± 0.7 injections administered within 1 year. The sufficient mesh polyhedral intralesional injection can achieve excellent results for the treatment of keloid scars.


Within-person fluctuations over three years in depression, anxiety, fatigue, and health-related quality of life in multiple sclerosis.
Longitudinal studies of health-related quality of life (HRQoL) in multiple sclerosis (MS) are limited. Most have examined average changes within the population, rather than dynamic changes within individuals. To assess the between- and within-individual association between depression, anxiety, fatigue, cognition, physical functioning, and physical comorbidities and HRQoL. Adults with MS underwent physical and cognitive assessments and reported symptoms of fatigue (Daily Fatigue Impact Scale), depression and anxiety (Hospital Anxiety and Depression Scale (HADS)), and HRQoL (RAND-36) annually (n = 4 visits). We evaluated associations of elevated symptoms of anxiety (HADS-A) and depression (HADS-D), fatigue, physical function (timed-walk and nine-hole peg test), cognitive function and comorbidity count with physical (PCS-36) and mental (MCS-36) HRQoL using multivariable linear models-estimating between-person and within-person effects. Of 255 participants with MS enrolled, 81.6% were women. After adjustment, within-person increases in depression and fatigue were associated with decreases in physical HRQoL. Increases in depression, anxiety, and comorbidity count were associated with decreases in mental HRQoL. Within-person increases in symptoms of depression, anxiety and fatigue, and comorbidity count are associated with HRQoL decreases among adults with MS, highlighting the potential magnitude of individual benefit of intervention for these symptoms.


Pipeline Embolization device for intracranial aneurysms in a large Chinese cohort: factors related to aneurysm occlusion.
The Pipeline Embolization Device (PED, Covidien/Medtronic) is widely used to treat intracranial aneurysms. This PED in China post-market multi-center registry study (PLUS) investigated safety and effectiveness of the PED for intracranial aneurysms in the Chinese population. This was a panoramic, consecutive, real-world cohort registry study. Patients treated with PED with or without coils between November 2014 and October 2019 at 14 centers in China were included, and those treated by parent vessel occlusion or other stents were excluded. Study outcomes included angiographic evaluation of aneurysm occlusion, complications, in-stent stenosis, and predictors of aneurysm occlusion. A central committee reviewed all imaging and endpoint events. In total, 1171 patients with 1322 intracranial aneurysms were included. The total occlusion rate was 81.4% (787/967) at mean follow-up of 8.96 ± 7.50 months, with 77.1% (380/493) occlusion in the PED alone and 85.9% (407/474) in the PED plus coiling group. On multi-variate analysis, female sex, hyperlipidemia, vertebral aneurysms, PED plus coiling, and blood flow detained to venous phase were significant predictors of aneurysm occlusion. In posterior circulation cohort, there was no variable associated with aneurysm occlusion. In-stent stenosis predictors included current smoking and cerebral sclerosis/stenosis. In the largest series on PED of multi-center date of China, data suggest that treatment with the flow-diverting PED in intracranial aneurysms was efficacious. The treatment of PED combined coiling and blood flow detained to venous phase after PED implant were associated with aneurysmal occlusion. The occlusion rate of vertebral aneurysms was higher than other location aneurysms. ClinicalTrials.gov identifier: NCT03831672.


Induction of hepatic tumors with butylated hydroxyanisole in the self-fertilizing hermaphroditic fish Rivulus ocellatus marmoratus.
The three-day-old larvae of self-fertilizing hermaphroditic fish Rivulus ocellatus marmoratus were fed a diet containing the antioxidant butylated hydroxyanisole (BHA) at levels of 0.01-0.8% for 12 days. Six months after BHA administration, hepatic tumors were found in all groups of BHA-treated fish. The BHA-induced tumor incidences were clearly dose-dependent. These results show that dietary BHA is hepatocarcinogenic in Rivulus even at 0.01% dose.


Personalized predictive models for symptomatic COVID-19 patients using basic preconditions: Hospitalizations, mortality, and the need for an ICU or ventilator.
The rapid global spread of the SARS-CoV-2 virus has provoked a spike in demand for hospital care. Hospital systems across the world have been over-extended, including in Northern Italy, Ecuador, and New York City, and many other systems face similar challenges. As a result, decisions on how to best allocate very limited medical resources and design targeted policies for vulnerable subgroups have come to the forefront. Specifically, under consideration are decisions on who to test, who to admit into hospitals, who to treat in an Intensive Care Unit (ICU), and who to support with a ventilator. Given today's ability to gather, share, analyze and process data, personalized predictive models based on demographics and information regarding prior conditions can be used to (1) help decision-makers allocate limited resources, when needed, (2) advise individuals how to better protect themselves given their risk profile, (3) differentiate social distancing guidelines based on risk, and (4) prioritize vaccinations once a vaccine becomes available. To develop personalized models that predict the following events: (1) hospitalization, (2) mortality, (3) need for ICU, and (4) need for a ventilator. To predict hospitalization, it is assumed that one has access to a patient's basic preconditions, which can be easily gathered without the need to be at a hospital and hence serve citizens and policy makers to assess individual risk during a pandemic. For the remaining models, different versions developed include different sets of a patient's features, with some including information on how the disease is progressing (e.g., diagnosis of pneumonia). National data from a publicly available repository, updated daily, containing information from approximately 91,000 patients in Mexico were used. The data for each patient include demographics, prior medical conditions, SARS-CoV-2 test results, hospitalization, mortality and whether a patient has developed pneumonia or not. Several classification methods were applied and compared, including robust versions of logistic regression, and support vector machines, as well as random forests and gradient boosted decision trees. Interpretable methods (logistic regression and support vector machines) perform just as well as more complex models in terms of accuracy and detection rates, with the additional benefit of elucidating variables on which the predictions are based. Classification accuracies reached 72 %, 79 %, 89 %, and 90 % for predicting hospitalization, mortality, need for ICU and need for a ventilator, respectively. The analysis reveals the most important preconditions for making the predictions. For the four models derived, these are: (1) for hospitalization:age, pregnancy, diabetes, gender, chronic renal insufficiency, and immunosuppression; (2) for mortality: age, immunosuppression, chronic renal insufficiency, obesity and diabetes; (3) for ICU need: development of pneumonia (if available), age, obesity, diabetes and hypertension; and (4) for ventilator need: ICU and pneumonia (if available), age, obesity, and hypertension.


Herman Jan Phaff: professor, mentor, friend and colleague.
Herman Jan Phaff, the father of yeast ecology, was born in the Netherlands in 1913. In his early years, he spent much time in his family's winery, which sparked his interest in microbes. Trained in the famous Delft tradition, Phaff discovered many unrecognized ecological niches of yeast, such as shellfish, rabbit stomach, frass of bark beetles, tree exudates, cactus roots, Capri figs, sewage, Drosophila flies and shrimp. He is also remembered for his pioneering work on the coevolution of yeasts, insects and plants as well as for his work on yeast beta-glucanase, which resulted in major advances in the understanding of the nature of the yeast cell wall. Phaff's legacy includes research on pectin degradation by fungal enzymes and the application of molecular approaches to yeast systematics. He discovered and described many yeasts, such as the yeast named in his honor, Phaffia rhodozyma, which led to the establishment of a very important industrial fermentation process yielding high concentrations of the pigment astaxanthin, used throughout the world to provide a natural source of this important carotenoid.


Dysautonomia: Diagnosis and Management.
Dysautonomias are a heterogenous group of disorders that can cause variable symptoms ranging from isolated impairment of one autonomic function to multisystem failure. The causes are also diverse and can be central or peripheral and primary (owing to an intrinsic neurologic cause) or secondary (owing to a disorder that secondarily causes damage to the autonomic nervous system). This review covers common phenotypes of dysautonomias, primary and secondary causes, initial clinical workups, interpretation of common autonomic tests, and first-line treatments. A brief review of autonomic impairment associated with acute and long-COVID is also presented.


A tier approach for evaluating the respiratory allergenicity of low molecular weight chemicals.
A multi-level approach for evaluating low molecular weight chemicals as respiratory sensitizers is proposed. The approach involves four levels of testing that utilize both in vitro and in vivo methods. Tier 1 evaluates structure-activity information to determine if the chemical can covalently modify carrier molecules. It also includes a literature search to determine if the compound belongs to a family of chemicals that has been reported to induce hypersensitivity. Tier 2 tests the chemical's potential to haptenate carrier molecules (i.e., protein) under in vitro conditions. Positive results in Tiers 1 and 2 lead to testing in a guinea pig injection model to assess chemical immunogenicity (Tier 3). A positive result at this level leads to testing in a guinea pig inhalation model to address questions about relevant routes of chemical exposure and allergenicity (Tier 4). Tier 4 results are used in determining safe chemical exposure levels. We have evaluated three chemicals using this scheme: phthalic anhydride, reactive black b dye, and toluene diisocyanate. All three have reactive groups and haptenate protein in vitro. They induce a humoral immune response when injected into guinea pigs at equimolar concentrations, and they sensitize animals via inhalation exposure. The severity of the response (antibody titer and respiratory reactivity) can be used to rank-order the chemicals in terms of allergenic "potency." Our data indicate that this approach can detect chemical allergens and can be used to characterize them as moderate or strong respiratory sensitizers.


Synthesis of aligned porous poly(ε-caprolactone) (PCL)/hydroxyapatite (HA) composite microspheres.
We synthesized poly(ε-caprolactone) (PCL)/hydroxyapatite (HA) composite microspheres with an aligned porous structure and evaluated their potential applications in bone tissue engineering. A range of HA particles (0, 5, 10 and 20 wt.% in relation to the PCL polymer) were added to a PCL solution in order to improve the biocompatibility of the porous PCL/HA composite microspheres. All the synthesized microspheres showed that the HA particles were distributed well in the PCL matrix, while preserving their aligned porous structure. The average size of the PCL/HA composite microspheres increased from 62±7 to 179±95 μm with increasing HA content from 0 to 20 wt.%. The incorporation of the HA particles to the PCL polymer led to a considerable improvement in in vitro bioactivity, which was assessed by immersing the PCL/HA composite microspheres in simulated body fluid (SBF). A number of apatite crystals could be precipitated on the surface of the aligned porous PCL/HA composite microspheres after soaking in the SBF for 7 days.


Prognostic value of dialysis effluent leukocyte count in children on peritoneal dialysis with peritonitis.
Early prediction of the efficacy of treatment in peritonitis complicating peritoneal dialysis (PD) is the best way to reduce morbidity. We studied the prognostic value of the third-day dialysis effluent leukocyte count after antibiotic therapy for prediction of treatment outcomes. Medical records of 31 children on PD, younger than 15 years old, admitted in Ali-Asghar Children's Hospital because of PD-related peritonitis, were reviewed retrospectively. Peritonitis was defined by fever, abdominal pain, and cloudy effluent with a leukocyte count greater than 100/mm3 or a positive dialysis effluent culture for microorganisms. For each episode of peritonitis, the leukocyte count of the effluent was measured on the third day after initiation of empiric therapy and culture results were recorded. The receiver operating characteristic curve was used to perform predicting value assessments. Of 60 episodes of peritonitis, 68.3% were treated successfully. Of the remaining episodes, 15.8% resulted in mortality, 57.9% required catheter removal, and 26.3% led to both. The mean PD effluent leukocyte count on the third day after initiating empiric antibiotics was significantly higher in the group with treatment failure (2258 ± 796/mm3) than in the group with successful treatment (1325 ± 669/mm3; P < .001). The cutoff point of 1240/mm3 was found with optimized sensitivity (100%), specificity (63.4%), positive predictive value (55.9%), and negative predictive value (100%) for prediction of treatment failure (P < .001). This study showed that the third-day dialysis effluent leukocyte count predicted short outcomes of peritonitis.


Management of Cavernous Sinus Involvement in Sinonasal and Ventral Skull Base Malignancies.
Cavernous sinus (CS) involvement by sinonasal and ventral skull base malignancies is infrequently encountered in neurosurgical practice. Despite advancements in skull base microneurosurgery and endoscopic techniques, detailed knowledge and experience of the surgical management of these lesions are limited. This article elaborates on surgical strategies and approaches for CS involvement of malignant ventral skull base tumors. The article discusses the indications, techniques, nuances, advantages, limitations, and complications of minimally invasive CS biopsy, transcranial microscopic, and transfacial endoscopic approaches to the CS using illustrative diagrams and operative videos. The principles and nuances of a high-flow cerebral revascularization procedure are mentioned.


The conformation of fibrinogen and fibrin: an electron microscopy study.
A mica adsorption technique was used to prepare fibrinogen and early fibrin polymers for examination in the transmission electron microscope. Globular particles 10 +/- 3 nm in diameter were observed and a model for the process of aggregation of these globules into fibrous units is proposed. A comparison is made between the results obtained by the mica adsorption technique and those obtained by conventional preparation techniques involving fixation and staining.


Plasma persistence of 2-aminothiazoline-4-carboxylic acid in rat system determined by liquid chromatography tandem mass spectrometry.
2-Aminothiazoline-4-carboxylic acid (ATCA) was intravenously injected to rats in order to investigate its plasma distribution. ATCA was extracted from plasma samples by solid phase extraction (SPE) and molecularly imprinted polymer stir bar sorption extraction (MIP-SBSE). Detection and quantification of ATCA were achieved by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). It was found that the intravenously injected ATCA concentration quickly decreased to half within 2.5h in the rat system. However, after 2.5 h, the concentration of ATCA in plasma stayed constant at least 5 folds above the endogenous ATCA level for more then 48 h. This finding can be used for evaluating ATCA's diagnostic and forensic value as a biomarker for cyanide exposure.


Beneficial effects of amiodarone pretreatment on early ischemic ventricular arrhythmias relative to infarct size and regional myocardial blood flow in the conscious dog.
The effects of chronic pretreatment with amiodarone on ischemic ventricular arrhythmias were evaluated in fully conscious instrumented dogs. In control dogs (n = 14) with large myocardial infarcts, early (first 30 min) ventricular arrhythmias occurred in a bimodal distribution with peaks at 3-5 min and at 12-25 min, with only the former associated with epicardial conduction delay. Ventricular fibrillation occurred equally frequently during each peak of early ventricular arrhythmias. Amiodarone (30 mg/kg daily) for 3-4 weeks had no significant effect (n = 11) on anatomic infarct size (28 +/- 6 vs. 30 +/- 5% of left ventricular weight) nor on collateral blood flow in the center of the infarct (19 +/- 11 vs. 15 +/- 7 ml/min/100 g of tissue) or on the ratio of endocardial/epicardial perfusion (0.23 +/- 0.19 vs. 0.28 +/- 19). Despite significant lengthening of peak epicardial conduction delay (191 +/- 20 to 239 +/- 81 ms, p less than 0.05), the frequency of early ventricular arrhythmias, especially during the second peak of ectopic activity, were markedly attenuated by amiodarone pretreatment, with the extrasystole-free intervals often being as long as 6 h. The incidence of ventricular fibrillation was 9% in the treated animals compared with 29% in the controls. In the control animals, arrhythmias always supervened when epicardial fractionation was significant, and no ectopy-free interval was present in the first 6 h following coronary occlusion. The data indicate that chronic amiodarone pretreatment exerts a beneficial effect on the frequency and severity of such ventricular tachyarrhythmias, with reduction in the incidence of ventricular fibrillation and ectopic activity in the early phases following coronary occlusion.


Prevalence of antibiotic-resistant enterobacteriaceae isolated from chicken and pork meat purchased at the slaughterhouse and at retail in Bavaria, Germany.
The purpose of this study was to investigate chicken and pork meat sampled at the slaughterhouse and at retail for differences in the presence of antibiotic resistant Gram-negative bacteria. For this aim, Escherichia coli (n=677), Enterobacter spp. (n=167), Citrobacter spp. (n=83), Serratia spp. (n=116), Klebsiella spp. (n=125), and Salmonella spp. (n=89) were isolated from 500 chicken and 500 pork samples purchased at the slaughterhouse and at retail (in the same amounts) in Germany. Salmonella were present in 17% of the chicken, and in 0.4% of the pork meat samples. There was a clear shift in the spectrum of coliforms from slaughterhouse to retail: Enterobacter, Citrobacter and Klebsiella were the most frequently detected coliforms (other than E. coli) from slaughterhouse samples, whereas the prevalence of Serratia spp. was up to eight times higher in retail samples. The prevalence of E. coli was higher in slaughterhouse samples, whereas the prevalence of other coliforms and Salmonella spp. was higher in retail samples. E. coli strains were often resistant to penicillins, streptomycin, spectinomycin, doxycycline and sulfamethoxazole/trimethoprim. Resistance rates of the other coliforms were generally low. Resistant and multi-resistant isolates were significantly more common in chicken meat. Compared to samples from the slaughterhouse, the prevalence of resistant bacteria tended to be higher in retail samples, probably due to good conditions for resistant bacteria on the matrix meat and/or due to secondary contamination with resistant strains. Therefore, stringent hygiene measures should be observed to reduce the risk of transmission of resistant bacteria from food to humans.


Amide Proton Transfer-Weighted MR Imaging of Pediatric Central Nervous System Diseases.
Amide proton transfer-weighted (APTw) imaging is a molecular MR imaging technique that can detect the concentration of the amide protons in mobile cellular proteins and peptides or a pH change in vivo. Previous studies have indicated that APTw MR imaging can be used to detect malignant brain tumors, stroke, and other neurologic diseases, although the clinical application in pediatric patients remains limited. The authors briefly introduce the basic principles of APTw imaging. Then, they review early clinical applications of this approach to pediatric central nervous system diseases, including pediatric brain development, hypoxic-ischemic encephalopathy, intracranial infection, and brain tumors.


Overdose, opioid treatment admissions and prescription opioid pain reliever relationships: United States, 2010-2019.
"As part of the U.S. government's urgent response to the epidemic of overdose deaths (1)" the United States Centers for Disease Control and Prevention (CDC) issued the "CDC Guideline for Prescribing Opioids for Chronic Pain-United States, 2016 (2)" (guideline) followed by the "CDC Clinical Practice Guideline for Prescribing Opioids-United States, 2022 (3) (guideline update). " The guideline and guideline update cite a direct correlation between prescription opioids sales (POS) and opioid treatment admissions (OTA) and prescription opioid deaths (POD), which was based on data from 1999 to 2010. This paper updates those relationships and includes the correlations between prescription opioid sales (POS) and any opioid deaths (AOD) and total overdose deaths (TOD) from 2010 to 2019. Linear regression models were fit to each response separately. Opioid sales (measured as MME (morphine milligram equivalent) per capita) was the independent variable. Total overdose deaths (TOD), any opioid overdose deaths (AOD), prescription opioid overdose deaths (POD) and opioid treatment admissions (OTA) were the dependent, response variables. The models were assessed using three criteria: the statistical significance of the model (Overall P-Value), the quality of the fit (R 2), and the sign of the slope coefficient (positive or negative). The analyses revealed that the direct correlations (i.e., significant, positive slopes) reported by the CDC based on data from 1999 to 2010 no longer exist. Based on data from 2010 to 2019, the relationships either have reversed (i.e., significant, negative slopes) or are non-existent (i.e., no significant model). The guideline, guideline update, CDC's public, medical profession, and intergovernmental communications should be corrected/updated to state no direct correlation has existed between POS to OTA, POD, AOD, and TOD since 2010. Individualized patient care and public health policy should be amended accordingly.


Effect of a traditional Chinese medicine prescription Quzhuotongbi decoction on hyperuricemia model rats studied by using serum metabolomics based on gas chromatography-mass spectrometry.
Morbidity of hyperuricemia has constantly increased in population in decades, and hyperuricemia has proved to be an important risk factor for gout, cardiovascular diseases and others. Many urate-lowering drugs have unfavorable side effects and drug interactions. Quzhuotongbi decoction (QZTBD) is an empirical traditional Chinese medicine prescription for clinical therapy of hyperuricemia without serious adverse effects. In the study, we investigated the effects of QZTBD on urate and other metabolites in the sera of hyperuricemia model rats. Hyperuricemia model was established by orally administering yeast extract paste, and allopurinol served as a positive control drug. Serum metabolomics was performed by using a gas chromatography-mass spectrometry (GC-MS) method. Student's t-test and the principal component analysis (PCA) were employed to find the metabolic perturbations in hyperuricemia model rats. The levels of urate, lactate, pyruvate and ornithine were significantly increased, and xanthine, glyconic acids (ribonate, galactonate), amino acids (aspartate, proline, glutamine, serine, pyroglutamate, glutamate) and glucose were down-regulated greatly in the model rats. It demonstrated that nucleotide metabolism, amino acid metabolism and glycolytic pathway were disturbed by yeast administration. An orthogonal signal correction-partial least-squares discriminant analysis (OSC-PLS DA) was performed to assess the effects of yeast administering and drug treatment. 11 significantly distinctive metabolites among four groups were defined according to the variable importance for project values (VIP>1) and univariate ANOVA (p value<0.05). As compared to the model rats, the serum uric acid levels were lowered markedly under the treatment of allopurinol or QZTBD. Aspartate and glutamine involved in purine metabolism, were raised to normal level as well. The different influences on xanthine, glutamate pyroglutamate and galactonate suggested there were different mechanisms of two drugs in urate-lowering therapy. Our finding proved that QZTBD can efficiently lower the level of serum uric acid in a different way from allopurinol, which suggested that QZTBD based on the theory of TCM could be an effective therapeutic option for hyperuricemia.


Mechanistic formation of hazardous molecular heterocyclic amines from high temperature pyrolysis of model biomass materials: cellulose and tyrosine.
Research inventories on the co-pyrolysis of major biomass components such as cellulose with amino acid materials is scarce in literature despite the fact that such studies are critical in understanding toxic product relations from high temperature cooking, combustion of bio-fuels, cigarette smoking and forest fires. This paper explores, quantitatively, the yields of heterocyclic nitrogenated molecular reaction products of grave mutagenetic concern from the co-pyrolysis of model biomass materials; tyrosine and cellulose. Research has established that heterocyclic amines such as isocyanates are mutagens as well precursors for asthma, and other respiratory disorders. An equimassic mixture of tyrosine and cellulose (50 ± 2 mg) by weight were pyrolyzed in a tubular quartz reactor in flowing nitrogen at 1 atm. Besides, varying combinations of tyrosine and cellulose in the ratios 3:1 and 1:3 were also explored for comparison. The reaction time was set at 2 s so as to simulate combustions events in nature. The pyrolysate was collected over 5 mL dichloromethane and characterized using a gas chromatograph coupled to a mass spectrometer detector. Evidently, it was noted that 1-methylindazole was released in high yields at 300 °C, constituting ~ 300 µg in the entire pyrolysis temperature range (200-700 °C). Nonetheless, isoindazole gave the highest yield ~ 730 µg while 1-naphthyl isocyanate gave a total yield of ~ 336 µg in the same temperature range. Remarkably, the change in char yield between 300 and 450 °C for the pyrolysis of 25% tyrosine in 75% cellulose was found to be ~ 48% whereas the change in char yield for the pyrolysis of 75% tyrosine in 25% cellulose was 49%. The char and tar yields considered important residues of biomass burning have been reported in this study and found to be consistent with other research output in literature. The striking similarities of % yield of char across all temperatures for various combinations was the most significant observation in this investigation-char yield was independent of the mixing ratio during pyrolysis. From a mechanistic standpoint, it was noted that tyrosine inhibited cellulose based nitrogenated products. Thus N-products dominated the O-products.


Probiotic B420 and prebiotic polydextrose improve efficacy of antidiabetic drugs in mice.
Gut microbiota is now known to control glucose metabolism. Previous studies have shown that probiotics and prebiotics may improve glucose metabolism, but their effects have not been studied in combination with drug therapy. The aim of this study was to investigate whether probiotics and prebiotics combined with drug therapy affect diabetic outcomes. Two different study designs were used to test gut microbiota modulating treatments with metformin (MET) or sitagliptin (SITA) in male C57Bl/6J mice. In Design 1, diabetes was induced with four-week feeding with a ketogenic, 72 kcal% fat diet with virtually no carbohydrates. Mice were then randomly divided into four groups (n = 10 in each group): (1) vehicle, (2) Bifidobacterium animalis ssp. lactis 420 (B420) (10(9) CFU/day), (3) MET (2 mg/mL in drinking water), or (4) MET + B420 (same doses as in the MET and B420 groups). After another 4 weeks, glucose metabolism was assessed with a glucose tolerance test. Fasting glucose, fasting insulin and HOMA-IR were also assessed. In Design 2, mice were fed the same 72 kcal% fat diet to induce diabetes, but they were simultaneously treated within their respective groups (n = 8 in each group): (1) non-diabetic healthy control, (2) vehicle, (3) SITA [3 mg/(kg*day)] (4) SITA with prebiotic polydextrose (PDX) (0.25 g/day), (5) SITA with B420 (10(9) CFU/day), and (6) SITA + PDX + B420. Glucose metabolism was assessed at 4 weeks, and weight development was monitored for 6 weeks. In Design 1, with low-dose metformin, mice treated with B420 had a significantly lower glycemic response (area under the curve) (factorial experiment, P = 0.002) and plasma glucose concentration (P = 0.02) compared to mice not treated with B420. In Design 2, SITA + PDX reduced glycaemia in the oral glucose tolerance test significantly more than SITA only (area under the curve reduced 28 %, P < 0.0001). In addition, B420, PDX or B420+PDX, together with SITA, further decreased fasting glucose concentrations compared to SITA only (-19.5, -40 and -49 %, respectively, P < 0.01 for each comparison). The effect of PDX may be due to its ability to increase portal vein GLP-1 concentrations together with SITA (P = 0.0001 compared to vehicle) whereas SITA alone had no statistically significant effect compared to vehicle (P = 0.14). This study proposes that combining probiotics and/or prebiotics with antidiabetic drugs improves glycemic control and insulin sensitivity in mice. Mechanisms could be related to incretin secretion.


Systematic Identification and Classification of β-Lactamases Based on Sequence Similarity Criteria: β-Lactamase Annotation.
β-lactamases, the enzymes responsible for resistance to β-lactam antibiotics, are widespread among prokaryotic genera. However, current β-lactamase classification schemes do not represent their present diversity. Here, we propose a workflow to identify and classify β-lactamases. Initially, a set of curated sequences was used as a model for the construction of profiles Hidden Markov Models (HMM), specific for each β-lactamase class. An extensive, nonredundant set of β-lactamase sequences was constructed from 7 different resistance proteins databases to test the methodology. The profiles HMM were improved for their specificity and sensitivity and then applied to fully assembled genomes. Five hierarchical classification levels are described, and a new class of β-lactamases with fused domains is proposed. Our profiles HMM provide a better annotation of β-lactamases, with classes and subclasses defined by objective criteria such as sequence similarity. This classification offers a solid base to the elaboration of studies on the diversity, dispersion, prevalence, and evolution of the different classes and subclasses of this critical enzymatic activity.


Fatty acid pattern of tissue phospholipids in copper and iron deficiencies.
Because copper and iron have been reported to be essential cofactors in delta 9 desaturation of fatty acids, the effects of different dietary intakes of copper and iron on tissue fatty acids were studied. Male Long-Evans rats (ten per group) were fed diets containing adequate, deficient or excess copper or iron. On day 42 of the dietary regimen, the animals were killed and tissues and blood were removed for analysis of metals and fatty acids of phospholipids. Compared with the copper-adequate rats, the copper-deficient rats showed increased 18:0 in liver and decreased 16:1 omega 7 in liver, heart and serum. There were no differences for 16:0 or 18:1 omega 9. Intake of excess copper did not cause an increase in products of delta 9 desaturation. Comparisons between iron-deficient and iron-adequate rats showed that iron deficiency increased 18:2 omega 6 in liver and serum and decreased 20:4 omega 6 in serum only. Relative percentages of 16:0, 18:0, 16:1 omega 7 and 18:1 omega 9 in liver and serum phospholipids were similar for both groups. Intake of excess iron caused a decrease in 18:2 omega 6; and 16:0 and 18:1 omega 9 were higher in the liver of the iron-excess group than the iron-deficient group. This study did not support the requirement for copper or iron in the delta 9 desaturation of fatty acids as expressed in phospholipids of liver, heart and serum.


Molecular responses of a key Antarctic species to sedimentation due to rapid climate change.
Rapid regional warming causing glacial retreat and melting of ice caps in Antarctica leads benthic filter-feeders to be exposed to periods of food shortage and high respiratory impairment as a consequence of seasonal sediment discharge in the West Antarctic Peninsula coastal areas. The molecular physiological response and its fine-tuning allow species to survive acute environmental stress and are thus a prerequisite to longer-term adaptation to changing environments. Under experimental conditions, we analyzed here the metabolic response to changes in suspended sediment concentrations, through transcriptome sequencing and enzymatic measurements in a highly abundant Antarctic ascidian. We found that the mechanisms underlying short-term response to sedimentation in Cnemidocarpa verrucosa sp. A involved apoptosis, immune defense, and general metabolic depression. These mechanisms may be understood as an adaptive protection against sedimentation caused by glacial retreat. This process can strongly contribute to the structuring of future benthic filter-feeder communities in the face of climate change.


Simple and rapid physico-chemical methods to examine action of antimalarial drugs with hemin: its application to Artemisia annua constituents.
Malaria is a major health problem in many countries and according to an estimate of the WHO, more than 500 million infections occur per year. Artemisinin, a sesquiterpene from Artemisia annua L., has received considerable attention as a promising and potent antimalarial drug for its stage speciticity, its rather low toxicity, effectiveness against drug-resistant Plasmodium species and activity against cerebral malaria. From recent studies it seems that hemin is primarily involved in the antimalarial activity of the constituents of Artemisia annua L. Thus, the interaction of a compound with hemin may represent a crucial screening test to define its efficacy. In this study the interaction between artemisinin and hemin was investigated by UltraViolet/Visible (UV/Vis) spectrophotometry and High Performance Liquid Chromatography/Diode Array Detector/Mass Spectrometry (HPLC/DAD/MS). In addition, some flavonols isolated from Artemisia annua L. were also tested to investigate their possible role in the interaction between artemisinin and hemin. These two simple physico-chemical methods can be useful as rapid and widespread screening methods for the search of other alkylating antimalarial constituents from natural sources or for the evaluation of the activity of semisynthetic analogues of artemisinin.


Persistent hyperlactatemia in decompensated type I diabetes with hepatic glycogenosis and hepatomegaly: Mauriac syndrome: a case report.
We describe a case of Mauriac syndrome, which is a rare complication of poorly controlled type I diabetes that combines glycogenosis, hepatomegaly, growth retardation with a Cushingoid appearance that is most often present in children but also in young adults. Here we also describe another finding with this syndrome, which is hyperlactatemia. The case is of a 16-year-old female of North African ethnicity with history of poorly controlled type I diabetes who was brought to the emergency department for dyspnea and tachycardia, treated initially for diabetic ketoacidosis. Her persistent hyperlactatemia helped to reveal a more subtle condition known as Mauriac syndrome after multiple examinations and follow-up. This case reports shows that Mauriac syndrome is a rare condition that should be considered in a setting of poorly controlled type I diabetes, hepatomegaly, Cushingoid appearance, and hyperlactatemia. The current treatment of this condition is a strict control of blood glucose levels with an attempt to achieve an acceptable glycated hemoglobin value.


[Opposable medical references in pediatrics].
Recommended guidelines for medical practice are instituted in France as a contribution to a reduction of health care expenses. The methodology, applications, and implications in pediatrics, are presented.


Phase III, large-scale chemoprevention trials. Approach to chemoprevention clinical trials and phase III clinical trial of tamoxifen as a chemopreventive for breast cancer--the US National Cancer Institute experience.
Clinical trials to evaluate interventions for cancer prevention are designed as early (phase I, IIa, and IIb) or late-phase studies. Whereas the former are small and generally rely on intermediate endpoint biomarkers of carcinogenesis, the latter are large-scale, long-term, randomized, phase III studies that address endpoints such as cancer incidence. The Breast Cancer Prevention Trial, P-1, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), is discussed as an example of a large, extended, phase III trial designed to answer the question of whether tamoxifen reduces the incidence of breast cancer in women who are at increased risk for the disease.


Crystal structure and function of C-terminal Sau3AI domain.
Sau3AI is a type II restriction enzyme that recognizes the 5'-GATC-3' sequence in double-strand DNA and cleaves at 5' to the G residue. The C-terminal domain of Sau3AI (Sau3AI-C), which contains amino acids from 233 to 489, was crystallized and its structure was solved by using the Multi-wavelength Anomalous Diffraction method. The Sau3AI-C structure at 1.9 A resolution is similar to the structure of MutH, a DNA mismatch repair protein that shares high sequence similarity with the N-terminal Sau3AI domain. The functional analysis shows that Sau3AI-C can bind DNA with one recognition sequence but has no cleavage activity. These results indicate that Sau3AI is a pseudo-dimer belonging to the type IIe restriction enzymes and the Sau3AI-C is the allosteric effector domain that assists DNA binding and cleavage.


Development and psychometric properties of the Pandemic-Related Postpartum Stress Scale (PREPS-PP).
Postpartum experiences have been adversely affected by the burdens of the COVID-19 pandemic. However, there are no well-tested measures of pandemic-specific postpartum stress. We developed a modified, postpartum version of the Pandemic-Related Pregnancy Stress Scale (PREPS) and examined the psychometric properties of this novel measure. Online questionnaires were administered at 3-4 month intervals throughout pregnancy and postpartum to women pregnant at the start of the pandemic. This study reports psychometric properties of the Pandemic-Related Postpartum Stress Scale (PREPS-PP) among women who were administered this instrument at either of two postpartum timepoints. At both timepoints (n = 1301 and n = 1009), CFAs revealed good model fit of the same three-factor structure identified for the prenatal PREPS (Preparedness Stress, Infection Stress, and Positive Appraisal). All PREPS-PP subscales demonstrated good reliability (α's .78-87). Higher levels of Preparedness Stress and Infection Stress were associated with greater health and financial burdens and psychological distress. The PREPS-PP is a reliable and valid measure of postpartum stress related to the COVID-19 pandemic. It is a valuable tool for future research into how pandemic-related postpartum stress may affect families in the short- and long-term.


Peripheral electrophysiological responses decrease in response to repetitive painful stimulation of the human nasal mucosa.
The study aimed to investigate the relation of both negative mucosal potentials (NMP) obtained from respiratory epithelium, and pain ratings to repetitive stimulation with CO2 (21 subjects). Trains of four stimuli of identical intensity (70% v/v) were applied at a constant interseries interval (approximately 60 s) but different interstimulus intervals (ISI) of 2 s or 6 s. At an ISI of 6 s, ratings decreased while they increased at an interval of 2 s (P < 0.01). This change was accompanied by the buildup of burning pain probably relating to the 'wind-up' of spinal neurons. In contrast, the decrease of NMP amplitudes was stronger the shorter the ISI (P < 0.01). These findings are in line with the view that the NMP reflects activation of epithelial nociceptors (C-fibers and/or A delta-fibers).


Nitrification in vitro by a range of filamentous fungi and yeasts.
A wide range of fungi including yeasts, growing on Czapek Dox medium, nitrified added ammonium and the ammonium released by urea hydrolysis. Phanerochaete chrysosporium and Hymenoscyphus ericiae were the only fungi tested which failed to nitrify. A soil yeast (isolate 1) was the most active nitrifier of ammonium in vitro, forming 0.80 microgram nitrate mg-1 biomass over the 7 d incubation period.


Interaction of tetrabromobisphenol A (TBBPA) with microplastics-sediment (MPs-S) complexes: A comparison between binary and simple systems.
The presence of microplastics (MPs) and the associated organic pollutants in the aquatic environment has attracted growing concern in recent years. MPs could compete with chemicals for adsorption sites on the surface of sediment, affecting the sorption processes of pollutants on sediment. However, few studies focused on the binary system of microplastics-sediment (MPs-S), which appear much common in aquatic environment. Herein, we investigated the interactions between a continuously used flame retardant tetrabromobisphenol A (TBBPA) and four MPs-S complexes (PVC-S, PE-S, PP-S and PS-S). The equilibrium adsorption capacities were 17.1, 15.6, 15.4, and 14.0 mg/kg for PVC-S, PS-S, PE-S, and PP-S, respectively. Kinetics suggest that adsorption behavior of TBBPA was fitted by pseudo-second-order model. Co-adsorption of TBBPA in binary systems were much lower than the sum of each simple system, which may be due to the mutually occupied adsorption sites. Higher ionic strength and lower dissolved organic matter strengthened the sorption of TBBPA onto MPs-S complexes. The enhanced sorption capacities for TBBPA were observed with elevated proportion and small particle size of MPs in the MPs-S complexes. This study contributes to the knowledge on the impact of MPs in partitioning of organic pollutants in-between solid and aqueous phases in the aquatic environment.


Small RNAs establish gene expression thresholds.
The central role of small RNAs in regulating bacterial gene expression has been elucidated in the past years. Typically, small RNAs act via specific basepairing with target mRNAs, leading to modulation of translation initiation and mRNA stability. Quantitative studies suggest that small RNA regulation is characterized by unique features, which allow it to complement regulation at the transcriptional level. In particular, small RNAs are shown to establish a threshold for the expression of their target, providing safety mechanism against random fluctuations and transient signals. The threshold level is set by the transcription rate of the small RNA and can thus be modulated dynamically to reflect changing environmental conditions.


Predictors of pacing-induced cardiomyopathy detection and outcomes demonstration after conduction system pacing upgrade on patients with long-term persistent atrial fibrillation.
To identify the predictors of pacing-induced cardiomyopathy (PICM) and illustrate the safety and feasibility of conduction system pacing (CSP) upgrade on patients with long-term persistent atrial fibrillation (AF). All patients with long-term persistent AF and normal left ventricular ejection fraction (LVEF) ≥50% were consecutively enrolled from January 2008 to December 2017, and all the patients with atrioventricular block (AVB) and high right ventricular pacing (RVP) percentage of at least 40%. The predictors of PICM were identified, and patients with PICM were followed up for at least 1 year regardless of CSP upgrade. Cardiac performances and lead outcomes were investigated in all patients before and after CSP upgrade. The present study included 139 patients, out of which 37 (26.62%) developed PICM, resulting in a significant decrease in the left ventricular ejection fraction (LVEF) from 56.11 ± 2.56% to 38.10 ± 5.81% (p< .01). The median duration for the development of PICM was 5.43 years. Lower LVEF (≤52.50%), longer paced QRS duration (≥175 ms), and higher RVP percentage (≥96.80%) were identified as independent predictors of PICM. Furthermore, the morbidity of PICM progressively increased with an increased number of predictors. The paced QRS duration (183.90 ± 22.34 ms vs. 136.57 ± 20.71 ms, p < .01), LVEF (39.35 ± 2.71% vs. 47.50 ± 7.43%, p < .01), and left ventricular end-diastolic diameter (LVEDD) (55.53 ± 5.67 mm vs. 53.20 ± 5.78 mm, p = .03) improved significantly on patients accepting CSP upgrade. CSP responses and complete reverse remodeling (LVEF ≥50% and LVEDD < 50 mm) were detected in 80.95% (17/21) and 42.9% (9/21) of patients. The pacing threshold (1.52 ± 0.78 V/0.4 ms vs. 1.27 ± 0.59 V/0.4 ms, p = .16) was stable after follow-up. PICM is very common in patients with long-term persistent AF, and CSP upgrade was favorable for better cardiac performance in this patient population.


Shear stress induces changes in the morphology and cytoskeleton organisation of arterial endothelial cells.
The aim of this study was to determine the changes in the morphology and cytoskeleton organisation of endothelial cells (EC) determined by exposure to a laminar flow. Cultured EC were exposed to a wall shear stress of 6 dyne/cm2 for 24 hours. The morphology of EC was analysed by light and scanning electron microscopy. The organisation of the cytoskeleton was determined by double fluorescence labeling with antibody anti-vimentin, anti-vinculin, anti-tubulin, and with rhodamine-labeled phalloidin. EC exposed to laminar flow become round-shaped with decreased area of adhesion to the substrate. There was a clear reorganisation of the cytoskeleton after exposure to shear stress; the distribution of actin changed from a stress fibre pattern to a more diffuse membrane-associated distribution. These changes in shape and cytoskeleton organisation were reversible after a 48-hour resting period. EC respond to laminar flow in a predictable manner and these findings may be correlated to the functional changes of EC observed after exposure to shear stress.


Lgr5 Marks Adult Progenitor Cells Contributing to Skeletal Muscle Regeneration and Sarcoma Formation.
Regeneration of adult skeletal muscle is driven largely by resident satellite cells, a stem cell population increasingly considered to display a high degree of molecular heterogeneity. In this study, we find that Lgr5, a receptor for Rspo and a potent mediator of Wnt/β-catenin signaling, marks a subset of activated satellite cells that contribute to muscle regeneration. Lgr5 is found to be rapidly upregulated in purified myogenic progenitors following acute cardiotoxin-induced injury. In vivo lineage tracing using our Lgr5-2ACreERT2R26tdTomatoLSL reporter mouse model shows that Lgr5+ cells can reconstitute damaged muscle fibers following muscle injury, as well as replenish the quiescent satellite cell pool. Moreover, conditional mutation in Lgr52ACreERT2;KrasG12D;Trp53flox/flox mice drives undifferentiated pleomorphic sarcoma formation in adult mice, thereby substantiating Lgr5+ cells as a cell of origin of sarcomas. Our findings provide the groundwork for developing Rspo/Wnt-signaling-based therapeutics to potentially enhance regenerative outcomes of skeletal muscles in degenerative muscle diseases.


Adrenocortical tumors in childhood.
Adrenocortical tumors (ACT) are rare in childhood. Determination of malignant potential is difficult. To assess the presentation, clinical behaviour, and histology of these tumors in our center, the records of nine patients with ACTs between 1989 and 2000 were analyzed. The age, sex, clinical presentation, investigations, treatment, follow-up data, and current status were determined. The pathological features were reanalyzed by our pathologist. The endocrine profile of the tumors was also retrieved from the records. There were two males and seven females; the median age at referral was 2.5 years. Two patients (one male, one female) presented with clinical features of Cushing's syndrome with hypertension. Four girls had features of Cushing's syndrome with associated virilization. One 11-year-old girl presented with hypertension, hypokalemia, and pseudoparalysis due to an aldosterone-secreting tumor. One girl presented with precocious pubic hair and clitoromegaly. One male had evidence of true precocious puberty. The endocrine profile was available in eight cases: cortisol levels were raised in four, testosterone in four, and aldosterone in one. One boy had pubertal levels of follicle-stimulating hormone and testosterone. Surgery was the only modality of therapy used. Histopathology showed capsular invasion in four patients and vascular invasion in two. The median tumor weight was 80 g (15-550 g) and the size ranged from 1.5 x 1.5 to 12 x 12 cm. Five patients are alive without tumor recurrence at a median follow-up time of 2 years. Tumor recurrence was seen in two patients, one with capsular rupture during surgery and another with a tumor weight of 16 g with associated capsular and vascular invasion. Atypical modes of presentation like pseudoparalysis must be kept in mind. Histologic criteria for malignancy in ACT are unreliable. Tumor weight may not always be accurate in predicting tumor behaviour. Complete surgical excision remains the only effective and potentially curative treatment.


Predictors of readmission for complications of coronary artery bypass graft surgery.
Risk factors for perioperative mortality after coronary artery bypass graft (CABG) surgery have been extensively studied. However, which factors are associated with early readmissions following CABG surgery are less clear. To identify significant predictors of readmission within 30 days following CABG surgery. Causes for readmission within 30 days were investigated for all patients discharged after CABG surgery in the state of New York from January 1, 1999, through December 31, 1999. A variety of patient demographics, preoperative risk factors, complications, operative and postoperative factors, and provider characteristics were considered as potential predictors of readmissions. Hospital readmissions within 30 days of discharge following CABG surgery. Of 16 325 total patients, 2111 (12.9%) were readmitted within 30 days for reasons related to CABG surgery. The most common causes of readmission were postsurgical infection (n = 598 [28%]) and heart failure (n = 331 [16%]). Eleven risk factors were found to be independently associated with higher readmission rates: older age, female sex, African American race, greater body surface area, previous myocardial infarction within 1 week, and 6 comorbidities. After controlling for these preoperative patient-level risk factors, 2 provider characteristics (annual surgeon CABG volume <100, hospital risk-adjusted mortality rate in the highest decile) and 2 postoperative factors (discharge to nursing home or rehabilitation/acute care facility, length of stay during index CABG admission of > or =5 days) were also related to higher readmission rates. Readmission within 30 days following discharge is an important adverse outcome of CABG surgery. Continued attempts should be made to explore the potential of readmission as a supplement to mortality in assessing provider quality.


Renal function after autologous bone marrow transplantation in children: a long-term prospective study.
We measured glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and the concentrating capacity of the kidneys in children after autologous BMT. Twenty-six patients had received TBI in their conditioning regimen and 14 patients had received chemotherapy only. Median follow-up was 10 years. Mean GFR before BMT was close to normal in both groups. Mean GFR decreased from 124 [CI 114,134] ml/min/1.73 m(2) before BMT to 99 [CI 82,115] ml/min/1.73 m(2) 6 months after BMT in the + TBI group (P < 0.001). There was no significant change in the -TBI group. Mean ERPF before BMT was high: 1110 [95% CI 830,1390] ml/min/1.73 m(2) in the + TBI group and 910 [CI 570,1250] ml/min/1.73 m(2) in the - TBI group. Six months after BMT, there was a tendency to a decrease in ERPF in the +TBI group, to 760 [CI 580,940] ml/min/1.73 m(2) (P = 0.064). After this initial decrease, GFR and ERPF remained essentially unchanged in both groups. The mean concentrating capacity of the kidneys was normal before and after BMT. In seven patients chronic renal impairment developed after BMT (GFR <70 ml/min/1.73 m(2)). All had received TBI. They had also received more nephrotoxic antibiotics than the other patients. We conclude that TBI was the principal cause of deterioration of renal function after BMT, possibly by limiting compensatory hyperperfusion and resulting in a fall in GFR. Antibiotic treatment may have contributed.


Childhood CIDP: Study of 31 patients and comparison between slow and rapid-onset groups.
To describe 31 children presenting a CIDP; to compare patients with rapid-onset disease vs. patients with slow-onset disease, a rapid-onset disease being defined by a time to peak impairment of less than 8 weeks. A retrospective chart review identified 31 patients completing criteria for childhood CIDP, with 24 "confirmed CIDP" and 7 "possible CIDP". Data collected were time to peak impairment, clinical presentation, cerebrospinal fluid analysis, nerve conduction study, nerve biopsy, treatments. Evaluation at the end of follow-up was reported according to modified Rankin scale. Thirteen patients (42%) exhibited symptoms in less than 2 months with more often cranial nerve abnormalities (38% vs. 6%, p = 0.059), and sensitive symptoms (62% vs. 11%, p = 0.0057). They evolved predominantly in a relapsing way (69% vs. 22%, p = 0.0047). Length of the disease was also longer in the rapid-onset group (5.5 years vs. 3.83 years) but without statistical difference. The slow-onset group exhibited more frequently ataxia at onset (28% vs. 8%, p > 0.05), and evolved predominantly in a progressive manner (61% vs. 15%, p > 0.05). Outcome was similar and good in the two groups. At least 3 out of the 4 major electrophysiological criteria were positive for 27/31 children (87%). Axonal involvement could be present very early. Immunoglobulins were given in 29 cases and corticosteroids in 22. A partial or complete recovery 1 month after first treatment was reported in 30 cases. Among second-line treatments, only azathioprine seemed effective in two out of three intractable children. The differences noted between the two groups should be tested in wider populations. Electrophysiological criteria are restrictive and axonal involvement should be studied. Prospective trials are required to find out the best first and second line treatments.


Influence of environmental conditions on the interfacial organisation of fengycin, a bioactive lipopeptide produced by Bacillus subtilis.
The effect of the environmental conditions both on the behaviour of fengycin at the air-aqueous interface and on its interaction with DPPC was studied using surface pressure-area isotherms and AFM. The ionisation state of fengycin is at the origin of its monolayer interfacial properties. The most organised interfacial arrangement is obtained when fengycin behaves as if having zero net charge (pH 2). In a fully ionised state (pH 7.4), the organisation and the stability of fengycin monolayers depend on the ionic strength in the subphase. This can modulate the surface potential of fengycin and consequently the electrostatic repulsions inside the interfacial monolayer, as well as the lipopeptide interaction with the layer of water molecules forming the air-water interface. Intermolecular interactions of fengycin with DPPC are also strongly affected by the ionisation state of lipopeptide and the surface pressure (Pi) of the monolayer. A better miscibility between both interfacial components is observed at pH 2, while negatively charged lipopeptide molecules are segregated from the DPPC phase. A progressive desorption of fengycin from the interface is observed at pH 7.4 when Pi increases while at pH 2, fengycin desorption brutally occurs when Pi rises above Pi value of the intermediate plateau.


Activated forms of oxygen in the metabolism of xenobiotics catalyzed by cytochrome P-450.
The Cu(Lys)2 complex is shown to be an effective inhibitor of the oxidation of 3,4-benzpyrene and aniline in microsomes. Apparently, this is due to the dismutation of superoxide radicals involved in the metabolism of these compounds. Possible interactions between Cu(Lys)2 and model membranes have been studied using spin probes. A model has been suggested according to which Cu(Lys)2 "builds" in the membrane hydrocarbon regions.


Apparent transgenerational effects of host plant in the leaf beetle Ophraella notulata (Coleoptera: Chrysomelidae).
The natural host of Ophraella notulata is Iva frutescens (Asteraceae); its close relative feeds on a related plant, Ambrosia artemisiifolia. We reared beetles on both plants, obtained progeny from the four possible crosses (two sexes X two parental hosts), and reared the progeny on both plant species. Survival to the imaginal stage of progeny reared on Iva varied with both maternal and paternal host. Hatchling feeding response to both plants showed a maternal host X paternal host interaction. Consumption of Ambrosia by adult beetles was, counter to expectation, higher for progeny of Iva-reared males than Ambrosia-reared males. Oviposition response, although based on too few data to be definitive, was peculiar: parental host did not affect oviposition on Ambrosia; on Iva daughters of Iva-reared males laid significantly more eggs than did daughters of Ambrosia-reared males, but only if they had been reared on Iva; those reared on Ambrosia displayed the reverse pattern. We discuss the possibility that nongenetic paternal transmission of host plant effects may explain these results, but offer a somewhat uncomfortable hypothesis of selection as a preferable explanation. An important outcome of the experiment is that it provided no evidence of maternal effects of host plant on offspring feeding or oviposition.


Generation and characterization of a human induced pluripotent stem cell (iPSC) line from a patient with congenital heart disease (CHD).
Epstein-Barr virus (EBV) immortalized lymphoblastoid cell lines (LCLs) are widely used for banking. This bioresource could be leveraged for creating human iPSC lines to model diseases including CHD. We generated an LCL-derived iPSC line (NCHi001-A) from a patient with congenital aortic valve stenosis. NCHi001-A was EBV and transgenes free, exhibited stem cell-like morphology, expressed pluripotency markers, has a normal karyotype, and could be differentiated into cells of three germ layers in vitro. Relationship inference via a microarray-based analysis showed NCHi001-A is identical to the parental cell line. NCHi001-A can be used for disease modeling, drug discovery, and cell therapy development.


Acute stress impairs (or induces) synaptic long-term potentiation (LTP) but does not affect paired-pulse facilitation in the stratum radiatum of rat hippocampus.
Rats were exposed to restraint coupled with 60, 1-sec, 1-mA, 60-Hz tail shocks. One hippocampus was immediately dissected for in vitro measurement of paired-pulse facilitation and LTP of the excitatory postsynaptic potential (EPSP) recording from the stratum radiatum of field CA1. There was no change in paired-pulse facilitation, suggesting that acute exposure to the stressor does not result in a decrease in presynaptic neurotransmitter release. There was, however, a significant decrease in the percent LTP produced by theta burst stimulation relative to naive controls. These results are consistent with the hypothesis that the stress-induced impairment of LTP is a result of changes in the postsynaptic glutamate receptors, specifically the AMPA type.


Evaluation of an amplified enzyme-linked immunoassay of placental alkaline phosphatase in testicular cancer.
The levels of serum placental alkaline phosphatase (PLAP) have been examined in 81 male controls, 51 untreated testicular tumours (41 seminomas and ten non-seminomatous testicular tumours) and 34 patients in complete remission (11 seminoma and 23 non-seminoma). Smoking induced a significant rise of serum PLAP in the controls, with a median level of 0.055 U/1 in non-smokers compared to 0.25 U/l in smokers. The levels found in pre-treatment seminoma (median 1.7 U/1) were significantly higher than in untreated teratoma (median 0.7 U/1). Treatment produced a significant fall in seminomas in remission (median 0.07 U/1). The role of PLAP in routine monitoring of seminomas was evaluated in 17 patients studied for 1-4 yr. PLAP shows similar trends to beta HCG but is an independent variable. The main role of PLAP is to help determine that the response to treatment has been satisfactory and that there are no unexpected foci of tumour.


Presence of Fe(II) and nitrate shapes aquifer-originating communities leading to an autotrophic enrichment dominated by an Fe(II)-oxidizing Gallionellaceae sp.
Autotrophic nitrate reduction coupled to Fe(II) oxidation is an important nitrate removal process in anoxic aquifers. However, it remains unknown how changes of O2 and carbon availability influence the community structure of nitrate-reducing Fe(II)-oxidizing (NRFeOx) microbial assemblages and what the genomic traits of these NRFeOx key players are. We compared three metabolically distinct denitrifying assemblages, supplemented with acetate, acetate/Fe(II) or Fe(II), enriched from an organic-poor, pyrite-rich aquifer. The presence of Fe(II) promoted the growth of denitrifying Burkholderiaceae spp. and an unclassified Gallionellaceae sp. This Gallionellaceae sp. was related to microaerophilic Fe(II) oxidizers; however, it did not grow under microoxic conditions. Furthermore, we explored a metagenome and 15 metagenome-assembled genomes from an aquifer-originating, autotrophic NRFeOx culture. The dominant Gallionellaceae sp. revealed the potential to oxidize Fe(II) (e.g. cyc2), fix CO2 (e.g. rbcL) and perform near-complete denitrification leading to N2O formation (e.g. narGHJI,nirK/S and norBC). In addition, Curvibacter spp.,Methyloversatilis sp. and Thermomonas spp. were identified as novel putative NRFeOx taxa. Our findings provide first insights into the genetic traits of the so far only known autotrophic NRFeOx culture originating from an organic-poor aquifer, providing the genomic basis to study mechanisms of nitrate removal in organic-poor subsurface ecosystems.


The long noncoding RNA NRF regulates programmed necrosis and myocardial injury during ischemia and reperfusion by targeting miR-873.
Emerging evidences suggest that necrosis is programmed and is one of the main forms of cell death in the pathological process in cardiac diseases. Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation. However, it is not yet clear whether lncRNAs can regulate necrosis in cardiomyocytes. Here, we report that a long noncoding RNA, named necrosis-related factor (NRF), regulates cardiomyocytes necrosis by targeting miR-873 and RIPK1 (receptor-interacting serine/threonine-protein kinase 1)/RIPK3 (receptor-interacting serine/threonine-protein kinase 3). Our results show that RIPK1 and RIPK3 participate in H2O2-induced cardiomyocytes necrosis. miR-873 suppresses the translation of RIPK1/RIPK3 and inhibits RIPK1/RIPK3-mediated necrotic cell death in cardiomyocytes. miR-873 reduces myocardial infarct size upon ischemia/reperfusion (I/R) injury in the animal model. In exploring the molecular mechanism by which miR-873 expression is regulated, we identify NRF as an endogenous sponge RNA and repress miR-873 expression. NRF directly binds to miR-873 and regulates RIPK1/RIPK3 expression and necrosis. Knockdown of NRF antagonizes necrosis in cardiomyocytes and reduces necrosis and myocardial infarction upon I/R injury. Further, we identify that p53 transcriptionally activates NRF expression. P53 regulates cardiomyocytes necrosis and myocardial I/R injury through NRF and miR-873.Our results identify a novel mechanism involving NRF and miR-873 in regulating programmed necrosis in the heart and suggest a potential therapeutic avenue for cardiovascular diseases.


Association between obesity and education level among the elderly in Taipei, Taiwan between 2013 and 2015: a cross-sectional study.
The inverse association between obesity and education level has been demonstrated in many developed countries; however, few studies have investigated obesity in geriatric populations. This cross-sectional analysis explored the association between geriatric obesity and education level, along with other demographic characteristics in Taipei, Taiwan between 2013 and 2015. Taipei citizens ≥ 65 years (aborigines ≥ 55 years) were recruited to participate in the elderly health examination programme. Logistic regression was applied to analyse the relationship between obesity (defined as body mass index ≥ 27 kg/m2 in Taiwan) and education level among men and women after controlling for age, race, income status, and smoking status. A total of 28,092 men and 31,835 women were included in the final analysis. Compared to those with education years ≥ 16, older men and women with education years ≤ 12 had higher odds of being obese. The odds ratios increase as years of education decrease, and the trend is more pronounced among women. Aborigines had much higher chances of being obese among men and women, while there were no differences by income status. The results clarified the factors related to obesity in the elderly, and will be useful for authorities working to improve health outcomes among this population.


Improving the antidepressant efficacy of transcranial magnetic stimulation: maximizing the number of stimulations and treatment location in treatment-resistant depression.
To assess the efficacy of increasing the number of fast left repetitive transcranial magnetic stimulations (rTMS) (10 Hz @ 120% of motor threshold (MT) over the left dorsolateral prefrontal cortex (DLPFC)) needed to achieve remission in treatment-resistant depression (TRD). And, to determine if patients who do not remit to fast left will remit using slow right rTMS (1 Hz @ 120% MT over the right DLPFC). Patients were part of a multicenter sham-controlled trial investigating the efficacy of fast left rTMS. Patients who failed to meet minimal response criteria in the sham-controlled study could enroll in this open fast left rTMS study for an additional 3-6 weeks. Patients who failed to remit to fast left could switch to slow right rTMS for up to 4 additional weeks. The final outcome measure was remission, defined as a HAM-D score of <3 or 2 consecutive HAM-D scores less than 10. Forty-three of 141 (30.5%) patients who enrolled in the open phase study eventually met criteria for remission. Patients who remitted during fast left treatment received a mean of 26 active treatments (90,000 pulses). Twenty-six percent of patients who failed fast left remitted during slow right treatment. The total number of rTMS stimulations needed to achieve remission in TRD may be higher than is used in most studies. TRD patients who do not respond to fast left rTMS may remit to slow right rTMS or additional rTMS stimulations.


When Thoughts Have No Off Switch: The Cost of Telepressure and Message-based Communication behaviour within Boundary-crossing Contexts.
Communication technology enables employees to be constantly connected at the cost of potentially blurring the boundaries between work and private life, which can be detrimental to their well-being. The present study utilised a quantitative diary approach (N = 269 employees, N = 1256 data points) to provide further evidence on the association between telepressure and ruminative thoughts within boundary-crossing contexts (i.e., including work-related behaviour and cognitions during leisure time as well as private-related behaviour and cognitions at work). On a day-to-day level, we examined if context-incongruent telepressure had a positive effect on context-incongruent affective rumination through context-incongruent message-based communication behaviour. Multilevel analyses supported our hypothesised mediation models. Altogether, findings reveal that quickly replying towards messages or its related cognition (i.e., telepressure) may result in a resource-draining experience in terms of affective rumination within both boundary-crossing contexts. Theoretical and practical implications as well as future research avenues are discussed.


Topological sub-structural molecular design approach: radical scavenging activity.
In the last decades phenolic compounds have gained enormous interest because of their beneficial health effects such as anti-inflammatory, anticancer, or antiviral activities. The pharmacological effects of phenolic compounds are mainly due to their antioxidant activity and their inhibition of certain enzymes. This antoxidant activity is related to the structure and has been extensively reported throught SAR or QSAR models. These studies confirmed that the number and position of hydroxyl groups, the related glycosylation and other substitutions in the phenolic ring largely determined radical scavenging activity. Most of these models are based on certain families of chemicals (flavonoids, cinnamic acids, etc…) and the model by itself is not useful for other substances of a different family. In this study we developed a QSAR model for a heterogeneous group of substances with TOPS-MODE descriptors for an interpretation of the antioxidant activity of these compounds in the form of bond contributions. The model developed, able to describe more than 90% of the variance in the experimental activity, also has a good predictive ability and stability. The information extracted from the QSAR model revealed that the major driving forces for radical scavenging activity are hydrogen bond donation and polarity. With this work we have managed to unify the different families of antioxidants in a single model with sufficient capacity to make predictions of radical scavenging activity for unknown substances.


Association between antenatal corticosteroids use and perinatal mortality among preterm singletons and twins in Mwanza, Tanzania: an observational study.
To examine the association between antenatal corticosteroids (ACS) use and perinatal mortality in singletons and twins delivered before 35 weeks of gestation. Secondary analysis of data from an observational prospective chart review study that investigated if exposure to ACS was associated with lower rates of perinatal mortality in preterm infants. This study was conducted in four hospitals located in Mwanza region, Tanzania. The study population included all preterm singletons and twins delivered at these hospitals between 24 weeks 0 days and 34 weeks 6 days of gestation from July 2019 to February 2020. The primary outcome was perinatal mortality; the secondary outcome was respiratory distress syndrome (RDS). The study included 844 singletons and 210 twin infants. Three hundred and fourteen singletons (37.2%) and 52 twins (24.8%) were exposed to at least one dose of ACS. Adjusted multivariate analyses revealed that among singletons' exposure to ACS was significantly associated with a lower likelihood of perinatal mortality, adjusted relative risk (aRR) 0.30 (95% CI 0.22 to 0.40) and RDS, aRR 0.92 (95% CI 0.87 to 0.97). In twin infants, exposure to ACS was associated with a reduced risk of RDS only, aRR 0.87 (95% CI 0.78 to 0.98). The use of ACS between 24 weeks 0 days and 34 weeks 6 days of gestation in both singletons and twins in low-resource settings is associated with positive infant outcomes. No adverse effects were noted. Further research that examines the benefits of ACS for twin infants is needed.


Economic evaluation of endothelial keratoplasty techniques and penetrating keratoplasty in the Netherlands.
To evaluate cost-effectiveness of penetrating keratoplasty (PK), femtosecond laser-assisted Descemet stripping endothelial keratoplasty (FS-DSEK), and Descemet stripping automated endothelial keratoplasty (DSAEK). Cost-effectiveness analysis based on data from a randomized multicenter clinical trial and a noncomparative prospective study. Data of 118 patients with corneal endothelial dysfunction were analyzed in the economic evaluation. Forty patients were included in the PK group, 36 in the FS-DSEK group, and 42 in the DSAEK group. The primary incremental cost-effectiveness ratio (ICER) was the incremental costs per clinically improved patient, defined as a patient with a combined effectiveness of both a clinically improved BSCVA (defined as an improvement of at least 2 lines) and a clinically acceptable refractive astigmatism (defined as less than or equal to 3.0 diopters). Analysis was based on a 1-year follow-up period after transplantation. The percentage of treated patients who met the combined effectiveness measures was 52% for DSAEK, 44% for PK, and 43% for FS-DSEK. Mean total costs per patient were €6674 (US$7942), €12 443 (US$14 807), and €7072 (US$8416) in the PK group, FS-DSEK group, and DSAEK group, respectively. FS-DSEK was less effective and more costly compared to both DSAEK and PK. DSAEK was more costly but also more effective compared to PK, resulting in incremental costs of €4975 (US$5920) per additional clinically improved patient. The results of this study show that FS-DSEK was not cost-effective compared to PK and DSAEK. DSAEK, on the other hand, was more costly but also more effective compared to PK. Including societal costs, a longer follow-up period and preparation of the lamellar transplant buttons in a national cornea bank could improve the cost-effectiveness of DSAEK.