Laennec's approach for laparoscopic anatomic hepatectomy based on Laennec's capsule.
Although isolating Glissonean pedicles and hepatic veins are critical procedures during anatomical hepatectomy, there is no standardized approach. We propose the novel Laennec's approach for laparoscopic anatomic hepatectomy (LAH) based on Laennec's capsule, which serves as the anatomic landmark for LAH. The aim of this study was to elucidate that the natural gap between Laennec's capsule and the adjacent tissues contributes to standardization of the surgical technique for LAH. Eighty-four cases were enrolled in this observable clinical trial. They underwent LAH for liver diseases. Laennec's approach was proposed for LAH based on Laennec's capsule. The liver tissues close to Glissonean pedicle, hepatic veins, naked area, and inferior vena cava were collected for hematoxylin and eosin, resorcinol-fuchsin staining, and immunohistochemistry. The staining revealed capsule packaging of the whole liver independent of the adjacent tissues and intrahepatic vessels. A natural gap was found between Laennec's capsule and the adjacent tissues at different sites. Laennec's capsule served as the landmark for isolating Glissonean pedicle and hepatic veins, mobilizing the liver, and performing Hanging maneuver. Eighty-four cases underwent LAH for liver diseases using this strategy. The operation time was 277.23 min. The mean of hospital days was 9.8. Laennec's approach based on Laennec's capsule contributes to standardization of the surgical technique for LAH, and brings innovations that facilitates safe and effective liver resection under laparoscopy.


Fungal Infections of the Central Nervous System in Small Animals: Clinical Features, Diagnosis, and Management.
Small animal mycoses vary geographically. Different clinical presentations are seen in animals with infection of the central nervous system (CNS), including multifocal meningoencephalomyelitis, intracranial lesions that accompany sinonasal lesions, rapidly progressive ventriculitis, or solitary granuloma of the brain or spinal cord. Systemic, nasal, or extraneural clinical signs are common but, especially in granuloma cases, do not always occur. Surgery may have a diagnostic and therapeutic role in CNS granuloma. There have been recent advancements in serology. Fluconazole, voriconazole, and posaconazole cross the blood-brain barrier, but voriconazole is neurotoxic to cats. Liposomal and lipid-encapsulated formulations of amphotericin B are preferred.


Characterization of the copper-thiolate cluster in yeast metallothionein and two truncated mutants.
Cu-metallothionein was purified from Saccharomyces cerevisiae harboring plasmids containing mutated CUP1 metallothionein genes resulting in deletions at the carboxy-terminal end of the polypeptide. The truncated polypeptides are recovered as polypeptides of 35 and 48 residues in length. The Cu-S cluster in the wild-type metallothionein and the two truncates were characterized. The truncated proteins, designated T35 and T48, contain 4 and 2 fewer cysteinyl residues, respectively, compared to the 12 cysteines in wild-type metallothionein; yet the mutant molecules bind Cu(I) ions in a stoichiometry comparable to the wild-type protein, i.e. 7-8 mol eq. The Cu(I) ions bound to T48 are as tenaciously bound as those bound to the wild-type molecule. The electronic transitions in the ultraviolet are similar for Cu-T48 and the wild-type protein. Both mutants and wild-type Cu-protein exhibit luminescence. The corrected emission maxima occurs at 609 nm with a corrected excitation peak near 277 nm. The luminescence quantum yield and lifetime of fluorescence decay of Cu-T48 and wild-type Cu-metallothionein are similar. The absolute quantum yield of the wild-type Cu-protein luminescence is 0.0058 and has a 440-ns lifetime. The similar fluorescence rate constant in the two molecules suggests they possess a similar chromophore. The Cu-T35 protein is more labile than Cu-T48 or the wild-type protein in the association of Cu(I) ions and the air sensitivity of the electronic transitions and luminescence. Although T48 lacks 2 of the 12 cysteines in the wild-type protein, we are unable to detect any differences in the properties of the native metal clusters in the two molecules; T35 lacking 4 cysteinyl residues forms a Cu(I) cluster with properties significantly different from the wild-type molecule. Properties of the Cu-thiolate cluster were also studied in Cu(I)-reconstituted samples. The cluster in wild-type metallothionein forms in all-or-nothing fashion. This conclusion is based on copper binding stoichiometry and luminescence studies. The relative quantum yield of samples with intermediate Cu(I) levels was constant, consistent with all-or-none cluster formation.


Ammonium and nitrate uptake in gap, generalist and understory species of the genus Piper.
We studied root net uptake of ammonium (NH 4+ ) and nitrate (NO 3- ) in species of the genus Piper (Piperaceae) under high, intermediate and low photosynthetically active photon flux densities (PFD). Plants were grown hydroponically, and then transferred to temperature controlled (25° C) root cuvettes for nutrient uptake determinations. Uptake solutions provided NH 4+ and NO 3- simultaneously (both) or separately (single). In the first experiment, seven species of Piper, from a broad range of rainforest light habitats ranging from gap to understory, were screened for mineral nitrogen preference (100 μM NH 4+ and/or 100 μM NO 3- ) at intermediate PFD (100 μmol m-2 s-1). Preference for NH 4+ relative to NO 3- , defined as the ratio of NH 4+ (both):NO 3- (both) net uptake, was higher in understory species than in gap species. Ammonium repression of NO 3- uptake, defined as the ratio of NO 3- (single): NO 3- (both) net uptake, was also higher in understory species as compared to gap species. In a second set of experiments, we examined the effect of nitrogen concentration (equimolar, 10 to 1000 μM) on NH 4+ preference and NH 4+ repression of NO 3- net uptake at high (500 μmol m-2 s-1) and low (50 μmol m-2 s-1) PFD in a gap (P. auritum), generalist (P. hispidum) and understory species (P. aequale). All species exhibited negligible NH 4+ repression of NO 3- net uptake at high PFD. At low PFD, NH 4+ preference and repression of NO 3- net uptake occurred in all species (understory > generalist > gap), but only at intermediate nitrogen concentrations, i.e. between 10 and 200 μM. Ammonium repression of net NO 3- uptake decreased or increased rapidly (in < 48 h) after transitions from low to high or from high to low PFD respectively. No significant diurnal patterns in NO 3- or NH 4+ net uptake were observed.


Integrated care programs for patients with psychological comorbidity: A systematic review and meta-analysis.
Presently, little is known about the characteristics and impact of integrated care programs for patients with psychological comorbidity. The aim was to provide an overview of these integrated care programs and their effectiveness. Systematic literature review including papers published between 1995 and 2014. An integrated care program had to consist of interventions related to at least two out of the six components of the Chronic Care Model. Programs had to address patients with psychological comorbidity, which is a psychological disease next to a somatic chronic disease. A meta-analysis was performed on depression treatment response and a best evidence synthesis was performed on other outcomes. Ten programs were identified, which mostly addressed comorbid depression and consisted of interventions related to three to five components of the Chronic Care Model. Meta-analysis showed significantly higher odds for depression treatment response for patients receiving integrated care (OR: 2.49, 95%CI [1.66-3.75]). Best evidence synthesis suggested moderate evidence for cost-effectiveness and for a beneficial effect on patient satisfaction and emotional well-being. Insufficient evidence was found for a beneficial effect on health-related quality of life, medication adherence, Hb1Ac levels and mortality. There are few studies evaluating integrated care programs for patients with psychological comorbidity. Although these studies suggest that integrated care programs could positively affect several patient outcomes and could be cost-effective, additional studies are recommended to further assess the value of integrated care for this patient group. This is especially important since the number of people with psychological comorbidity is rising.


Prevalence of obstructive sleep apnea in patients with peripheral arterial diseases.
The presence of obstructive sleep apnea (OSA), a novel cardiovascular risk factor, contributes to the development of peripheral arterial diseases (PAD). There is a lack of data showing how often these diseases coexist. The aim of the study was to determine the prevalence of OSA in the population of patients with PAD. Patients previously qualified for the first revascularization due to PAD were included in the study. All patients underwent an overnight sleep study to detect OSA. Diagnosis of OSA was made when the apnea-hypopnea index (AHI) was ≥5 per hour. From 141 patients (60% men, age 69.6 ± 9.5 years), OSA was diagnosed in 68 patients (48%). OSA occurred in mild form (5 ≤ AHI < 15/h) in 39 cases (28%), in moderate form (15 ≤ AHI < 30/h) in 21 cases (15%), and in severe form (AHI ≥ 30/h) in 8 cases (6%). Patients without OSA had significantly lower body mass index (BMI; 26.9 ± 5.5 vs. 27.7 ± 5.3 kg/m2, p = 0.01) and lower hip circumference (97.4 ± 11.7 vs. 98.7 ± 7.4, p = 0.04). There were no differences in the distribution of other investigated cardiovascular risk factors and diseases between these groups. There were no significant differences in OSA distribution or its severity between patients with lower extremity artery disease and carotid artery disease. The prevalence of OSA in patients with PAD is very high, affecting nearly half of the studied population.


Simple, Transparent, and Flexible Automated Quality Assessment Procedures for Ambulatory Electrodermal Activity Data.
Electrodermal activity (EDA) is a noninvasive measure of sympathetic activation often used to study emotions, decision making, and health. The use of "ambulatory" EDA in everyday life presents novel challenges-frequent artifacts and long recordings-with inconsistent methods available for efficiently and accurately assessing data quality. We developed and validated a simple, transparent, flexible, and automated quality assessment procedure for ambulatory EDA data. A total of 20 individuals with autism (5 females, 5-13 years) provided a combined 181 h of EDA data in their home using the Affectiva Q Sensor across 8 weeks. Our procedure identified invalid data using four rules: First, EDA out of range; second, EDA changes too quickly; third, temperature suggests the sensor is not being worn; and fourth, transitional data surrounding segments identified as invalid via the preceding rules. We identified invalid portions of a pseudorandom subset of our data (32.8 h, 18%) using our automated procedure and independent visual inspection by five EDA experts. Our automated procedure identified 420 min (21%) of invalid data. The five experts agreed strongly with each other (agreement: 98%, Cohen's κ: 0.87) and, thus, were averaged into a "consensus" rating. Our procedure exhibited excellent agreement with the consensus rating (sensitivity: 91%, specificity: 99%, accuracy: 92%, κ: 0.739 [95% CI = 0.738, 0.740]). We developed a simple, transparent, flexible, and automated quality assessment procedure for ambulatory EDA data. Our procedure can be used beyond this study to enhance efficiency, transparency, and reproducibility of EDA analyses, with free software available at http://www.cbslab.org/EDAQA.


The effects of a specific prompting sign on speed reduction.
The purpose of this experiment was to determine whether a specifically worded prompting sign ("BEGIN SLOWING HERE") could reduce speeding where a highway entered an urban area with a residential speed limit. Speed measurements were obtained on vehicles at the start of the residential speed limit zone. Following a baseline period the prompting sign was introduced, removed and reintroduced. The results indicated that the prompting sign produced clear reductions in the percentage of motorists travelling 10, 15 and 20 km or more over the speed limit. These results suggest the importance of more specific road signs in influencing the behavior of motorists.


When neurons split the load.
Various aspects of olfactory memory are represented as modulated responses across different classes of neurons in C. elegans.


Fat Embolism Syndrome With Cerebral Involvement: An Underrecognized Complication of Long Bone Fractures.
Fat embolism syndrome (FES) occurs when fat particles are aberrantly distributed into the microcirculation, and it often manifests as either hypoxemia, neurological deficit, or petechial rash. Although cases have been reported in the literature since the twentieth century, no formal diagnostic criteria have been universally adopted, and FES remains a diagnostic challenge. We present a unique case of FES from a long bone fracture, leading to pulmonary embolism with paradoxical arterial embolization and cerebral infarction, and provide a review of the related literature.


Operative treatment of alveolar echinococcosis of the liver.
This study is based on the experience with 51 cases of hepatic alveolar echinococcosis underwent operative treatment up to the end of 1976. Hepatic resection was carried out in 28 cases with overall operative mortality of 25 per cent, but no death occurred in the last 10 years period during which 12 cases were subjected to the procedure. This apparent improvement of the result is ascribed to the establishment of the strict criteria for operative intervention, i.e., when less than three segments are involved, the hepatic hilum is not highly involved, and the inferior vena cava is not invaded. Marsupialization is employed when hepatic resection is not indicated and the lesion shows liquefaction. Ten cases underwent the procedure with one operative death. Biliary tract reconstruction was carried out in two cases with hilar involvement, but the prognosis was poor. Eleven cases were only with celiotomy. The follow-up studies indicated that the hepatic resection offers the best hope for cure followed by marsupialization. Unlike unilocular echinococcosis in which a cyst grows expansively, the alveolar echinococcosis should be considered clinically malignant, in that it grows invasively and often shows metastatic lesions. Surgical intervention at its early developmental stage is the only definitive way of the treatment. Only recent advances in diagnostic procedures and development of type specific serological studies made it possible to bring the disease under control.


Is Repetitive Transcranial Magnetic Stimulation (RTMS) a Promising Therapeutic Intervention for Eating Disorders and Obesity? Clinical Considerations Based on a Meta-Analytic Review.
Repetitive Transcranial Magnetic Stimulation (rTMS) has been introduced to treat eating disorders (EDs), especially Anorexia, Bulimia Nervosa (AN and BN) and other EDs not otherwise specified (NOS). Provisional rTMS single-case studies and clinical trials have been carried out for the treatment of binge eating disorder (BED) and obesity. However, it is still unclear whether and to what extent rTMS might be considered an effective intervention for these conditions. This meta-analysis includes 15 independent studies examining the clinical effects of rTMS among different EDs and obesity (N = 402 patients). Several primary and secondary treatment outcomes have been considered. Cohen's d was used as an effect size measure. The analyses estimate heterogeneity across findings, sources of variability and publication bias together with an assessment of the quality of the studies. The analyses show that rTMS induced large improvements in body mass index (BMI) among obese individuals. Null clinical effects have been detected for primary outcomes (i.e., BMI, binge eating and compensatory behaviors; urge to binge and to eat; severity of EDs symptoms) among individuals with AN, BN and other EDs-NOS. rTMS shows moderate therapeutic effects on the affective functioning (i.e., negative affectivity, depressive and anxious symptoms) of individuals with EDs. rTMS should be considered a promising intervention for the treatment of obesity. This evidence might provisionally support the hypothesis on the implementation of rTMS for BED. Furthermore, rTMS could be included as an ancillary intervention for the other EDs, especially considering secondary treatment outcomes. Future controlled trials are needed to clarify the clinical effects of rTMS for EDs.


Trifarotene for the Treatment of Facial and Truncal Acne.
This article reviews clinical trials to assess the efficacy, safety, and clinical application of trifarotene 0.005% cream (Aklief). A systematic review of the literature was performed using the terms trifarotene OR Aklief OR CD5789 in MEDLINE (PubMed) and EMBASE databases. Articles prior to May 2020 were considered for inclusion. Bibliographies and ClinicalTrials.gov were also searched to identify further studies. Relevant English language and human studies related to pharmacology, clinical trials, and safety were considered. In the 52-week phase III trial, treatment success rates for facial acne (Investigator Global Assessment [IGA] rating of no or almost no acne) and truncal acne (Physician's Global Assessment [PGA] rating of no or almost no acne) were 65.1% and 66.9%, respectively. Overall success rates (IGA and PGA success in the same patient) were 57.9%; 52.8% of patients had a Dermatology Quality of Life Index score of 0 or 1, compared with 22.6% at baseline. Trifarotene was well tolerated, with pruritus, irritation, and sunburn as the most common adverse effects. Trifarotene is a newly Food and Drug Administration-labeled fourth-generation topical retinoid that shows particular promise in the treatment of facial and truncal acne vulgaris. It is an effective and safe addition to currently available retinoids. Trifarotene is effective and safe for treatment of facial and truncal acne. Future trials should compare its efficacy and tolerability with that of the older, clinically established retinoids. Despite efficacy, cost may be a prohibitive factor.


Towards hospital-on-chip supported by 2D MXenes-based 5th generation intelligent biosensors.
Existing public health emergencies due to fatal/infectious diseases such as coronavirus disease (COVID-19) and monkeypox have raised the paradigm of 5th generation portable intelligent and multifunctional biosensors embedded on a single chip. The state-of-the-art 5th generation biosensors are concerned with integrating advanced functional materials with controllable physicochemical attributes and optimal machine processability. In this direction, 2D metal carbides and nitrides (MXenes), owing to their enhanced effective surface area, tunable physicochemical properties, and rich surface functionalities, have shown promising performances in biosensing flatlands. Moreover, their hybridization with diversified nanomaterials caters to their associated challenges for the commercialization of stability due to restacking and oxidation. MXenes and its hybrid biosensors have demonstrated intelligent and lab-on-chip prospects for determining diverse biomarkers/pathogens related to fatal and infectious diseases. Recently, on-site detection has been clubbed with solution-on-chip MXenes by interfacing biosensors with modern-age technologies, including 5G communication, internet-of-medical-things (IoMT), artificial intelligence (AI), and data clouding to progress toward hospital-on-chip (HOC) modules. This review comprehensively summarizes the state-of-the-art MXene fabrication, advancements in physicochemical properties to architect biosensors, and the progress of MXene-based lab-on-chip biosensors toward HOC solutions. Besides, it discusses sustainable aspects, practical challenges and alternative solutions associated with these modules to develop personalized and remote healthcare solutions for every individual in the world.


Expression of cell cycle control proteins in normal epithelium, premalignant and malignant lesions of oral cavity.
In this study, we examined the expression of cyclins, cyclin dependent kinase (CDKs) and CDK inhibitors by immunohistochemical analysis in 20 normal mucosa, 42 epithelial dysplasia (ED), and 117 oral squamous cell carcinoma. Neither Cyclin D1 nor CDK2 were detectable in normal tissue and ED. Their presence, however, was detectable in squamous cell carcinoma (SCCs) (Cyclin D1, 35.9%; CDK2, 66.7%). Cyclin E was detectable in 57.1% of severe ED and 62.8% of SCCs. For the CDK inhibitors, these proteins were detectable in all normal mucosa and most of the mild and moderate ED. For severe ED, expression of these proteins was not observed in some cases (p12(DOC-1), 14.3%; p16(INK4A), 28.6%; p27(KIP1), 7.1%). For SCCs, the expression of p12(DOC-1) was lost in 71.8%, p16(INK4A) in 69.2% and p27(KIP1) in 35.9%. These results suggest that elevated expression of cyclin D1, cyclin E, CDK2 and loss of p12(DOC-1), p16(INK4A) and p27(KIP1) may contribute to the multistep nature of oral carcinogenesis.


Lanthanide chelates as a tool in nucleic Acid chemistry.
The potentiality of lanthanide chelates as photoluminescent markers and cleaving agents of nucleic acids is discussed, the main emphasis being on the chelates derived from aromatic nitrogen bases.


Heisenberg Ising-Kondo necklace model with transverse field for the heavy fermion compound URu2Si2.
In this work, we introduce the Heisenberg Ising-Kondo necklace with transverse field as a possible model to describe the heavy-fermion compound URu2Si2. The physics of this compound presents many open questions, like the transition to the hidden order (HO) phase at T 0 = 17.5 K. Our Hamiltonian includes elements that come from crystal field processes and Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction. The main idea is to allow the transverse field, that a priori acts only in the localized moments, to influence the conduction-electrons via the RKKY interaction. Our results, obtained using a spin-wave approach for a one-dimensional lattice system, reveal a re-entrance behavior on the zero temperature phase diagram. This is an interesting result since combined with the magnetization values of the canted AF phase allow to link this phase with the mixed hidden order/large moment antiferromagnetic (HO/LMAF) phase observed in URu2Si2.


Comparing the marginal leakage and retention of implant-supported restorations cemented by four different dental cements.
Despite the wide use of implants in dentistry, there is insufficient information about the ideal cement for retention. To determine the cement bond strength and marginal leakage of crown and partial denture cemented to implant abutments by four different types of cement. Eighty-four direct abutments were divided into eight groups (n = 7). Fifty-six crown and bridge restorations were cemented using zinc phosphate (ZM), temporary cement (TM), resin-modified glass-ionomer cement (GM), and self-adhesive resin cement (RM). After cementation, thermal cycling and incubation in basic fuchsin dye was applied. The maximum load to failure, marginal leakage, and fracture modes were evaluated. The mean of retention strength for the bridges (874 N) was higher than the crown samples (705 N) (P = .005). The mean of retention strength for each cement group was ZM = 1298, RM = 1027, GM = 646, and TM = 187 N (P ≤ .0001). Marginal leakage was recorded in majority of the samples; the highest incidence was detected for ZM samples. The cement fracture was mostly adhesive in nature. Self-adhesive resin and resin-modified glass ionomer cement had better mechanical properties to retain implant supported restorations.


Aripiprazole.
Aripiprazole is a new chemical entity with a unique pharmacological profile. It has strong affinities for certain dopamine receptors, and intermediate affinity for serotonin, adrenergic and histamine receptors. Partial agonism of the D2 dopamine and 5HT1A serotonin receptors, and antagonism of the 5HT2 serotonin receptor are believed to be the functional basis of its therapeutic efficacy. Its clinical effects are best documented in patients suffering from schizophrenia and bipolar disorder, in which it has been demonstrated to have antipsychotic and antimanic properties superior to placebo in dose ranges of 10-30 mg/day. Two published longer term trials document maintenance of antipsychotic effects and relapse prevention in schizophrenia patients. In general, aripiprazole seems to be a well-tolerated drug, especially with regard to metabolic side effects. The most commonly reported side effects include restlessness/akathisia, somnolence and nausea. These may be dose-dependent and usually occur early on during treatment, with many patients developing tolerance. Aripiprazole is an interesting and important addition to the currently available spectrum of antipsychotic drugs. Further studies in other indications and clinical trials that confirm results from the Phase II and III clinical development programme are eagerly awaited.


Intraoperative blood pressure and cerebral perfusion: strategies to clarify hemodynamic goals.
Blood pressure can vary considerably during anesthesia. If blood pressure falls outside the limits of cerebrovascular autoregulation, children can become at risk of cerebral ischemic or hyperemic injury. However, the blood pressure limits of autoregulation are unclear in infants and children, and these limits can shift after brain injury. This article will review autoregulation, considerations for the hemodynamic management of children with brain injuries, and research on autoregulation monitoring techniques.


Optimal control of a black-box system based on surrogate models by spatial adaptive partitioning method.
When the dynamic model of a classical optimal control problem is explicit, we can transform this problem into a nonlinear programming problem and solve it by employing a traditional method. However, in some cases, no mathematical model of state equations is provided explicitly except for input-output data obtained from a simulation model. The hybrid model composed of functional mockup unit blocks generated in multiple platforms is a typical example. In this work, we regard these blocks as black-box models and use hierarchical neural network model to surrogate right-hand-side derivative functions of state equations. Specifically, to obtain highly accurate hierarchical neural network model, we explore a spatial adaptive partitioning criterion combining global sensitivity indices and interval length of local spaces based on the input-output data. Compared with models trained by several other partition criteria, numerical results verify that surrogate models obtained by the spatial adaptive partitioning method have higher accuracy. A mathematical example and a trajectory optimization problem of the black-box industrial robot Manutec r3 indicate the effectiveness of our proposed strategy.


Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis.
Hepatopulmonary syndrome affects 10-30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation. The Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >64 years), positive contrast-enhanced transthoracic echocardiography and absence of lung disease. We included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-Stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median (interquartile range) 15 (12-19) versus 14 (10-17), p=0.006). Hepatopulmonary syndrome patients had significantly lower 6-min walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin 2, Tie2, tenascin C, tyrosine protein kinase Kit (c-Kit), vascular cell adhesion molecule 1 and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80, 95% CI 1.03-3.16, p=0.04), which persisted despite adjustment for covariates (hazard ratio 1.79, 95% CI 1.02-3.15, p=0.04). This association did not vary based on levels of oxygenation, reflecting the severity of hepatopulmonary syndrome. Hepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.


Anesthetic binding in a pentameric ligand-gated ion channel: GLIC.
Cys-loop receptors are molecular targets of general anesthetics, but the knowledge of anesthetic binding to these proteins remains limited. Here we investigate anesthetic binding to the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel (GLIC), a structural homolog of cys-loop receptors, using an experimental and computational hybrid approach. Tryptophan fluorescence quenching experiments showed halothane and thiopental binding at three tryptophan-associated sites in the extracellular (EC) domain, transmembrane (TM) domain, and EC-TM interface of GLIC. An additional binding site at the EC-TM interface was predicted by docking analysis and validated by quenching experiments on the N200W GLIC mutant. The binding affinities (K(D)) of 2.3 ± 0.1 mM and 0.10 ± 0.01 mM were derived from the fluorescence quenching data of halothane and thiopental, respectively. Docking these anesthetics to the original GLIC crystal structure and the structures relaxed by molecular dynamics simulations revealed intrasubunit sites for most halothane binding and intersubunit sites for thiopental binding. Tryptophans were within reach of both intra- and intersubunit binding sites. Multiple molecular dynamics simulations on GLIC in the presence of halothane at different sites suggested that anesthetic binding at the EC-TM interface disrupted the critical interactions for channel gating, altered motion of the TM23 linker, and destabilized the open-channel conformation that can lead to inhibition of GLIC channel current. The study has not only provided insights into anesthetic binding in GLIC, but also demonstrated a successful fusion of experiments and computations for understanding anesthetic actions in complex proteins.


A novel hybrid drug between two potent anti-tubulin agents as a potential prolonged anticancer approach.
We report the design, synthesis and biological characterisation of a novel hybrid drug by conjugation of two tubulin inhibitors, a hemiasterlin derivative A (H-Mpa-Tle-Aha-OH), obtained by condensation of three non-natural amino acids, and cis-3,4',5-trimethoxy-3'aminostilbene (B). As we have previously demonstrated synergy between A and B, we used a monocarbonyl derivative of triethylene glycol as linker (L) to synthesise compounds A-L and A-L-B; via HPLC we analysed the release of its potential hydrolysis products A, A-L, B and B-L in physiological fluids: the hybrid A-L-B undergo hydrolysis in rat whole blood of the ester bond between A and L (half-life=118.2±9.5min) but not the carbamate bond between B and L; the hydrolysis product B-L was further hydrolyzed, but with a slower rate (half-life=288±12min). The compound A-L was the faster hydrolyzed conjugate (half-life=25.4±1.1min). The inhibitory activity of the compounds against SKOV3 ovarian cancer cell growth was analysed. The IC50 values were 7.48±1.27nM for A, 40.3±6.28nM for B, 738±38.5nM for A-L and 37.9±2.11nM for A-L-B. The anticancer effect of A-L-B was evidenced to be obtained via microtubule dynamics suppression. Finally, we stated the expression of the active efflux transporters P-gp (ABCB1) and MRP1 (ABCC1) in the human normal colon epithelial NCM460 cell line by reverse-transcription PCR. Via permeation studies across NCM460 monolayers we demonstrate the poor aptitude of A to interact with active efflux transporters (AET): indeed, the ratio between its permeability coefficients for the basolateral (B)→apical (A) and B→A transport was 1.5±0.1, near to the ratio of taltobulin (1.12±0.06), an hemiasterlin derivative able to elude AETs, and significantly different form the ratio of celiprolol (3.4±0.2), an AET substrate.


Outcomes after Lower Extremity Revascularization for Treatment of Critical Limb Ischemia with Tissue Loss in Patients with Chronic Immune-Mediated Inflammatory Disease.
To evaluate outcomes after lower extremity revascularization for critical limb ischemia with tissue loss in patients with chronic immune-mediated inflammatory disease. A retrospective medical record review of all lower extremity revascularization for critical limb ischemia with tissue loss at a university-affiliated hospital over a 3-year period was completed for demographics, comorbidities, lower extremity revascularization indication, angiogram results, complications, mortality, limb salvage, and reintervention. Chronic immune-mediated inflammatory disease (CIID) and control (no autoimmune disease) were compared by chi-squared test, Student's t-test, Kaplan-Meier, and Cox Regression. There were 349 procedures performed (297 patients): (1) 44 (13%) primary amputations and (2) 305 (87%) lower extremity revascularizations, in which 83% were endovascular interventions; 12% was bypass; and 5% was hybrid, in which 40% was infrainguinal and 60% was infrageniculate, 72% Wounds Ischemia Infection Score System (WIFi) tissue loss class 2-3, 35% CIID. No differences were noted between CIID and control for primary amputation (P = 0.11), lower extremity revascularization type (P = 0.50), or lower extremity revascularization anatomic level (P = 0.43). Mean age was 71 + 13 years, and 56% of the patients were of male gender. Those with CIID were of similar age as controls (71 ± 14 vs. 71 ± 13; P = 0.87) and presented with comparable runoff: (1) ≤1 vessel (52% vs. 47%; P = 0.67), (2) WIFi tissue loss classification class 2-3 (66% vs. 76%; P = 0.09), and (3) WIFi infection classification class 2-3 (29% vs. 30%; P = 0.9). They were also less likely to be male (47% vs. 61%; P = 0.022) or current smokers (13% vs. 27%; P = 0.008). Postoperative mortality (P = 0.70) morbidity and reoperation (0.31) were comparable. Twenty-four-month survival was similar for CIID and control (83% ± 5% vs. 86% + 3%; P = 0.78), as was the amputation-free interval (69% ± 5% vs. 61% ± 4%; P = 0.18) and need for target extremity revascularization (40% vs. 53%; P = 0.04). Use of steroids and other anti-inflammatory medications was associated with improved 24-month amputation-free interval (87% ± 9% vs. 63% ± 3%; P = 0. 05). Dialysis (odds ratio: 2.6; 1.5-4.7; P = 0.001), WIFi infection class 2-3 (odds ratio: 2.8; 1.6-4.9; P < 0.001), prerunoff vessel (0-1 vs. 2-3) to the foot (odds ratio: 0.52; 0.37-0.73; P < 0.001), steroids/other anti-inflammatory agents (0.29; 0.06-0.96; P = 0.04), and statins (0.44; 0.25-0.77; P = 0.005) were independent predictors of 24-month amputation-free interval (Cox proportional hazard ratio). Patients with critical limb ischemia, tissue loss, and concomitant CIID can be successfully treated with lower extremity revascularization with similar limb salvage and need for reintervention. Steroid/anti-inflammatory use appears beneficial.


Value of serum inorganic phosphate in the diagnosis of ischemic bowel disease.
To clarify the value of the serum inorganic phosphate concentration in the diagnosis of ischemic bowel disease, a retrospective study of 24 patients with various causes of intestinal ischemia was carried out. Only 25 percent of the patients had elevations of their serum phosphate concentrations. These patients had the combination of extensive bowel injury, acute renal insufficiency, and acidosis. Mortality was significantly increased in these patients. Thus, the serum phosphate concentration was not a sensitive indicator of ischemic bowel disease, but elevations did predict extensive injury and poor prognosis.


Crocin Alleviates Intracerebral Hemorrhage-Induced Neuronal Ferroptosis by Facilitating Nrf2 Nuclear Translocation.
Intracerebral hemorrhage (ICH) is the deadliest type of stroke. Oxidative stress was considered to play an important role in ICH-induced secondary injury. Crocin, the main compound isolated from Crocus sativus L., possesses a potential anti-oxidative function in many types of diseases including ICH. In the current study, the protective role of crocin in ICH-induced brain injury was investigated in the ICH model. The ICH-induced brain edema and neurological deficits were analyzed by brain edema measurement and neurological testing. The superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activity and the content of malondialdehyde (MDA) were assessed by a total superoxide dismutase assay kit. The expressions of ferroptosis-related genes were verified by quantitative real-time PCR (qPCR) and western blotting. The ICH-induced brain edema and neurological deficits were significantly decreased after treatment with crocin. Moreover, the SOD and GSH-px activities were obviously increased in the ICH with crocin-treated group compared with the ICH group, while the content of MDA was markedly decreased after treatment with crocin. Crocin inhibited ferroptosis of neuron cells, as evidenced by increased Fe2+ concentration and the expression of GPX4, FTH1, and SLC7A11. Mechanistically, crocin treatment increased the expression and nuclear translocation of Nrf2. Our data suggest that crocin alleviates intracerebral hemorrhage-induced neuronal ferroptosis by facilitating Nrf2 nuclear translocation.


Evidence-based individual psychotherapy for complex posttraumatic stress disorder and at-risk groups for complex traumatization: A meta-review.
The current meta-review of meta-analyses on psychotherapy research for complex post-traumatic stress disorder (CPTSD) and samples at risk of complex traumatization has three aims: first, to provide an overview of efficacy of individual psychotherapies; second, to compare the quality of the meta-analyses; and third, to assess statistical power. The literature search was conducted until August 2020. Meta-analyses providing individual treatment effect estimates focusing on CPTSD or samples at risk of complex traumatization (i.e., victims of childhood sexual abuse (CSA), war or torture, refugees, and veterans with PTSD) were eligible for inclusion. The effect sizes were classified according to Cohen as small, medium, or large. The "A MeaSurement Tool to Assess systematic Reviews" (AMSTAR) was applied to assess the quality of the meta-analyses, and power was assessed post-hoc. Twenty-four meta-analyses were suitable for inclusion. The efficacy of the interventions varied (g = -0.04 (CI -0.39; 0.48), controlled, to d = 2.73 (1.69; 3.76), uncontrolled). Overall, 16 effect estimates were large. On average, the quality of the meta-analyses was good (average AMSTAR total score 7.71 points (range 3-11). Considering quality assessments and power together, nine meta-analyses were evaluated as high quality. No meta-analysis for CPTSD was eligible and the number of individuals with complex traumatization was not directly assessed in the at-risk groups. For at-risk groups for complex traumatization, on average, good-quality empirical evidence exists. Given the limited research on CPTSD, future studies are needed to further investigate the efficacy of interventions.


Effectiveness of fosfomycin combined with other antimicrobial agents against multidrug-resistant Pseudomonas aeruginosa isolates using the efficacy time index assay.
We investigated the effectiveness of fosfomycin combined with other antibiotics, such as piperacillin, cefepime, ceftazidime, imipenem, meropenem, aztreonam, gentamicin, or levofloxacin, against 30 Pseudomonas aeruginosa strains, including multidrug-resistant strains, isolated from clinical specimens, using the efficacy time index (ETI) assay. The assay refers to the result of pharmacokinetics obtained from adult men volunteers, and yields an ETI to evaluate the effect of a combination of antimicrobial agents. With the ETI, based on serum concentration 3 h after the administration of two antimicrobial agents, the effectiveness of antimicrobial combinations was evaluated as follows: poor, ETI < 0.5; fair, 0.5 < or = ETI < 1; good, 1 < or = ETI < 8; and excellent, ETI > or = 8. The combination of fosfomycin and cefepime (efficacy rate [excellent plus good], 76.7%) and fosfomycin/aztreonam (efficacy rate, 76.7%) appeared to be the most effective, followed by fosfomycin/meropenem (efficacy rate, 76.6%), fosfomycin/imipenem (efficacy rate, 73.3%), fosfomycin/ceftazidime (efficacy rate, 70%), fosfomycin/gentamicin (efficacy rate, 70%), fosfomycin/piperacillin (efficacy rate, 66.7%), and fosfomycin/levofloxacin (efficacy rate, 66.7%). Fosfomycin/cefepime, fosfomycin/aztreonam, and fosfomycin/meropenem may be clinically useful in selected patients, particularly for P. aeruginosa. The ETI assay provided information on the minimum inhibitory concentration (MIC) of many pairs of combined antimicrobial agents simultaneously. The ETI assay may be a useful technique with which to investigate the effect of combinations of antimicrobial agents against P. aeruginosa, including multidrug-resistant strains.


A randomized trial of the effects of pharmacist intervention on the cost of antiemetic therapy with ondansetron.
Ondansetron has had a major impact on the prevention of emesis in patients receiving chemotherapy. However, the high cost and potential for inappropriate prescribing of this agent warranted a closer examination of its utilization. Hospital guidelines regarding the use of ondansetron were prepared by the Pharmacy and Therapeutics Committee and approved by the Medical Advisory Committee. The guidelines were then distributed to all physicians. Physicians were randomized into an intervention or non-intervention group. A prospective drug use evaluation was then conducted for a 10-week period where pharmacists monitored ondansetron prescribing and compared each order against hospital guidelines. For orders deemed inappropriate, only the intervention-group physicians were contacted for therapy modification. The control of nausea and vomiting was then assessed for all patients 24 h and 72 h after chemotherapy via a simple patient questionnaire. There were no significant differences with respect to the control of nausea and vomiting between patients who received ondansetron according to guidelines and those who did not. A total of 76% (48/63) of the prescriptions met hospital guidelines in the intervention group compared to 51.6% (33/64) in the control (P = 0.007). During the study period, physicians in the intervention group prescribed $Can 757 worth of ondansetron inappropriately compared to $1814 in the control. Drug use evaluation with pharmacist intervention was an effective method of controlling unnecessary hospital costs and contributed towards the appropriate use of ondansetron without compromising patient care.


Combination of psoas muscle mass index and neutrophil/lymphocyte ratio as a prognostic predictor for patients undergoing nonsurgical hepatocellular carcinoma therapy.
Reliable predictors for hepatocellular carcinoma (HCC) are urgently needed. The psoas muscle index (PMI) is a simple and rapid method for evaluating muscle atrophy. Furthermore, the neutrophil/lymphocyte ratio (NLR) is a prognostic factor that is easy to calculate in everyday clinical practice. We aimed to investigate the value of the PMI and NLR as prognostic factors for patients receiving nonsurgical HCC therapy, hepatic arterial infusion chemotherapy (HAIC), transcatheter arterial chemoembolization (TACE), or molecular targeted drugs such as sorafenib (SOR) and lenvatinib (LEN). We enrolled 87 patients with HCC who were treated with HAIC, TACE, SOR, or LEN. The primary endpoint was overall survival (OS) with variable PMI or NLR status. For Barcelona Clinic Liver Cancer (BCLC)-B patients, useful prognostic factors were examined by comparing the OS between stratified groups. Prognostic factors including PMI and NLR were evaluated by univariate and multivariate analysis. Analysis of HAIC or TACE (HAIC/TACE) and SOR or LEN (SOR/LEN) patients showed significant differences in OS between low and high PMI. In patients treated with TACE, there was a significant difference in OS between low and high NLR. For BCLC-B and low PMI, the prognosis was significantly worse for SOR/LEN than for TACE, although there was no difference for high PMI, suggesting that PMI may be useful for treatment selection. In addition, the prognostic formula composed of PMI, NLR, and up-to-seven criteria developed in the present study may be useful. PMI and NLR are considered to be independent prognostic factors for HCC.


Recombinational repair of alkylation lesions in phage T4. II. Ethyl methanesulfonate.
Treatment of bacteriophage T4 by ethyl methanesulfonate (EMS) caused more than a doubling in recombination between two rII markers. The functions of genes 47, 46, 32, 30, uvsX and y are known to be required for genetic recombination, and mutants defective in these genes were found to be more sensitive to inactivation by EMS than wild-type phage. This suggests that a recombinational pathway involving the products of these genes may be employed in repairing EMS induced lethal lesions. Genes 45 and denV are apparently not involved in recombination, and mutants defective in these genes were not EMS-sensitive. Gene 47, 46 and y mutants which were defective in the repair of EMS induced lethal lesions had no detectable deficiency in their ability to undergo EMS-induced mutation. This implies that recombinational repair of EMS lesions does not contribute substantially to EMS mutagenesis. The results obtained here with EMS are general similar to the results reported in the preceding paper with MNNG, suggesting that the lesions caused by both of these monofunctional alkylating agents may be eliminated by similar recombinational repair processes.


Case of bullous pemphigoid refractory to corticosteroids by antiepileptic drug-induced CYP3A4.
The most common treatment option for patients with bullous pemphigoid is systemic corticosteroids. CYP3A4, a drug-metabolizing enzyme in the liver, metabolizes synthetic steroids to a varying degree. Although there are many CYP3A4-inducing drugs, several antiepileptic drugs, such as phenytoin and phenobarbital, strongly induce CYP3A4, thereby reducing the effects of corticosteroids. Here, we report a case of refractory bullous pemphigoid that rapidly improved after the discontinuation of phenytoin and phenobarbital. To achieve adequate pharmacological effects of corticosteroids, we must always ensure that patients who require corticosteroids for treatment are not medicated with CYP3A4-inducing agents.


Ultrastructural morphometric analysis of lesional skin: mast cells from patients with systemic and nonsystemic mastocytosis.
Lesional skin mast cells from some patients with mastocytosis appear morphologically atypical; however, these subjective differences have not been quantified. Herein we describe an objective method for analyzing cutaneous mastocytosis mast cells by a combination of morphometric analysis and electron microscopy. By this technique, lesional mast cells from patients with adult systemic mastocytosis had a significantly larger mean cytoplasmic area (53.3 microns2), nuclear size (20.4 microns2), and granule diameter (0.81 micron) when compared with mast cells from adults with nonsystemic mastocytosis (36.3 micron 2, 15.4 microns2, and 0.67 micron, respectively) and normal age-matched control subjects (34.4 microns2, 14.1 microns2, and 0.67 micron, respectively). Lesional skin mast cells from infants with nonsytemic mastocytosis were very similar to adult nonsystemic mastocytosis mast cells but differed by several parameters from mast cells in adults with systemic involvement. This study demonstrates that there are quantitative differences between lesional skin mast cells from patients with systemic mastocytosis and those with nonsystemic disease.


Intragastric balloon in association with lifestyle and/or pharmacotherapy in the long-term management of obesity.
Intragastric balloon (BioEnterics Intragastric Balloon, BIB®) or pharmacotherapy are possible options for the treatment of obese patients when traditional approaches have failed. The aim of our study was to compare in obese patients the effect on weight loss and metabolic changes of lifestyle modifications associated with either BIB or pharmacotherapy or the two treatments in sequence as a maintenance strategy for weight loss. Fifty obese patients were recruited and randomly assigned to lifestyle modifications combined with either BIB for 6 months (n = 30) or sibutramine (pharmacotherapy group) for 1 year (n = 20). After BIB removal, patients were randomly assigned to either correct lifestyle (BIB/lifestyle) or lifestyle plus pharmacotherapy (BIB/pharmacotherapy). At 6 months, patients treated with BIB lost significantly (P < 0.05) more weight (percent of initial weight lost, %IWL = 14.5 ± 1.2; percent of excess BMI lost, %EBL = 37.7 ± 3.2) than patients who received pharmacological treatment (%IWL = 9.1 ± 1.5, %EBL = 25.3 ± 4.1). At 1 year, the weight lost was significantly (P < 0.05) greater in patients treated with either BIB/pharmacotherapy (%IWL = 15.8 ± 2.3%, %EBL = 41.3 ± 6.7%) or BIB/lifestyle (%IWL = 14.3 ± 2.7, %EBL = 34.9 ± 6.5%) in respect to pharmacotherapy group (%IWL = 8.0 ± 1.4%, %EBL = 22.1 ± 3.9%). Moreover, patients treated sequentially with BIB/lifestyle or BIB/pharmacotherapy showed a significant (P < 0.05) improvement in insulin sensitivity and triglycerides levels. BIB represents an efficacious long-term obesity treatment when supplemental strategies, as lifestyle modifications or pharmacotherapy, are established for weight maintenance after its removal.


Guided internet-based cognitive-behavioral therapy for patients with chronic pain: A meta-analytic review.
Chronic pain has a large individual and societal burden. Previous reviews have shown that internet-based cognitive-behavioral therapy (iCBT) can support patients' pain coping. However, factors related to participant experience of iCBT and effective and safe iCBT delivery for chronic pain have not recently been summarized. The aim of this review was to give an overview of the efficacy of guided iCBT for chronic pain on psychological, physical, and impact on daily life outcomes, including factors that inform optimal delivery. Cochrane, Emcare, Web of Science, PubMed, PsycINFO, and Embase were systematically searched from inception to 11 February 2022. Randomized controlled trials on guided iCBTs for adults with chronic pain were included with a broad range of outcomes. The search yielded 7406 studies of which 33 studies were included totaling 5133 participants. ICBT was more effective than passive control conditions for psychological (ES = 0.34-0.47), physical (ES = 0.26-0.29), and impact outcomes (ES = 0.38-0.41). ICBT was more effective than active control conditions for distress (ES = 0.40), pain acceptance (ES = 0.15), and pain interference after outlier removal (ES = 0.30). Longer treatments were associated with larger effects for anxiety and quality of life than shorter treatments. Mode of therapist contact (synchronous, asynchronous or a mix of both) was not related to differences in effect sizes in most outcomes. However, studies with mixed and synchronous contact modes had higher effects on pain self-efficacy than studies with asynchronous contact modes. Treatment satisfaction was high and adverse events were minor. Dropout was related to time, health, technical issues, and lack of computer skills. Guided iCBT is an effective and potentially safe treatment for chronic pain. Future research should more consistently report on iCBT safety and detail the effectiveness of individual treatment components to optimize iCBT in clinical practice.


Determination of the mechanical and physical properties of cartilage by coupling poroelastic-based finite element models of indentation with artificial neural networks.
One of the most widely used techniques to determine the mechanical properties of cartilage is based on indentation tests and interpretation of the obtained force-time or displacement-time data. In the current computational approaches, one needs to simulate the indentation test with finite element models and use an optimization algorithm to estimate the mechanical properties of cartilage. The modeling procedure is cumbersome, and the simulations need to be repeated for every new experiment. For the first time, we propose a method for fast and accurate estimation of the mechanical and physical properties of cartilage as a poroelastic material with the aid of artificial neural networks. In our study, we used finite element models to simulate the indentation for poroelastic materials with wide combinations of mechanical and physical properties. The obtained force-time curves are then divided into three parts: the first two parts of the data is used for training and validation of an artificial neural network, while the third part is used for testing the trained network. The trained neural network receives the force-time curves as the input and provides the properties of cartilage as the output. We observed that the trained network could accurately predict the properties of cartilage within the range of properties for which it was trained. The mechanical and physical properties of cartilage could therefore be estimated very fast, since no additional finite element modeling is required once the neural network is trained. The robustness of the trained artificial neural network in determining the properties of cartilage based on noisy force-time data was assessed by introducing noise to the simulated force-time data. We found that the training procedure could be optimized so as to maximize the robustness of the neural network against noisy force-time data.


The incidence of eosinophilic oesophagitis in 2007-2017 among children in North Denmark Region is lower than expected.
In North Denmark Region (NDR), the incidence of Eosinophilic Oesophagitis (EoE) among adults has increased following a new biopsy protocol in 2011, whereas data on the incidence of EoE among children is lacking. To describe the incidence of EoE in children aged 0-17 in NDR as well as diagnostic delay, clinical manifestations, treatment and complications. This retrospective, register-based DanEoE cohort study included 18 children diagnosed with EoE between 2007-2017 in NDR. Medical files were reviewed with attention to symptoms, reason for referral, disease progress, treatment, symptomatic and histological remission as well as diagnostic delay. The median incidence per year (2007-2017) was 0.86/100,000 children in NDR aged 0-17 years. The median diagnostic delay among children was four years and six months. Sixty percent presented with food impaction at first hospital visit. After initial treatment, only one of 18 children achieved symptomatic and histologic remission and had a long-term treatment plan. The calculated incidence among children was lower compared to similar studies. Combined with poor remission rates and lack of follow-up, it is likely that EoE is an underdiagnosed and insufficiently treated disease among children in NDR. Our findings suggest that more knowledge concerning EoE in children could lead to a higher incidence, shorter diagnostic delay and more effective treatment.


Prediction of margin-negative resection of pancreatic ductal adenocarcinoma following neoadjuvant therapy: Diagnostic performance of NCCN criteria for resection vs CT-determined resectability.
Accurate assessment of pancreatic ductal adenocarcinoma (PDAC) resectability after neoadjuvant therapy (NAT) is crucial. Recently, the NCCN introduced criteria for resection of PDAC following NAT. We analyzed 127 patients who underwent NAT and pancreatectomy for PDAC between January 2010 and March 2020. CT-determined resectability according to the NCCN guideline and CA 19-9 level was evaluated before and after NAT. Diagnostic performance of the NCCN criteria for margin-negative (R0) resection was investigated and compared with CT alone. R0 resection was achieved in 104 (81.9%) patients. After NAT, there were 30 (23.6%) resectable, 90 (70.9%) borderline resectable, and seven (5.5%) locally advanced tumors. Significantly decreased or stable CA 19-9 levels were noted in 114 (89.8%) patients. The sensitivity and specificity of the NCCN criteria were 87.5% (91/104) and 21.7% (5/23), respectively, which were significantly different from CT including only resectable PDAC (26.9% [28/104] and 91.3% [21/23]; P < .001), but less prominently different from CT including resectable and borderline resectable PDAC (95.2% [99/104]; P = .022 and 8.7% [2/23]; P = .375). The NCCN criteria for resection following NAT showed high sensitivity and low specificity for predicting R0 resection. It had supplementary benefit over CT alone, mainly in preventing underestimation of R0 resection.


The origin of sheep settlement in Western Mediterranean.
The arrival of Neolithic culture in North Africa, especially domestic animals has been essentially documented from archaeological records. As the data relative to sheep are scarce, we studied the genetic relationship between Moroccan sheep breeds and Mediterranean ones using the sequencing of 628 bp of the mitochondrial DNA control region in 193 Moroccan individuals, belonging to six breeds, and 652 sequences from other breeds in Europe and Middle East. Through Network analysis and an original phylogenetically derived method, the connection proportions of each Moroccan breed to foreign ones were estimated, highlighting the strong links between Moroccan and Iberian breeds. The first founders of Moroccan sheep population were issued at 79% from Iberia and 21% from a territory between Middle East and Africa. Their calculated expansion times were respectively 7,100 and 8,600 years B.P. This suggests that Neolithization was introduced by a double influence, from Iberia and from another route, maybe Oriental or Sub-Saharan. The consequence of the environmental changes encountered by founders from Iberia was tested using different neutrality tests. There are significant selection signatures at the level of Moroccan and European breeds settled in elevated altitudes, and an erosion of nucleotide diversity in Moroccan breeds living in arid areas.


The voltage-dependent block of ATP-sensitive potassium channels of frog skeletal muscle by caesium and barium ions.
1. Patch clamp techniques were used to study the action of external Cs+ and Ba2+ on adenosine 5'-triphosphate (ATP)-dependent K+ channels in sarcolemmal vesicles from frog skeletal muscle. Both ions block channels in a voltage-dependent fashion, block increasing with hyperpolarization. 2. The Cs+ block is flickery, mean unitary current being reduced and open-level noise increased. The concentration dependence is consistent with 1:1 binding, with a dissociation constant (Kd) of 4.1 mM at -62 mV. The Kd increases e-fold for a 20 mV depolarization. 3. The kinetics of Cs+ block were analysed by amplitude distribution analysis, and by measurement of the excess open-level variance. Both methods gave similar rate constants for blocking and unblocking; about 20 mM-1 ms-1 and 75 ms-1 at -62 mV. 4. All the voltage dependence of the Cs+ block appears to lie in the blocking reaction; unblocking is independent of voltage. 5. Ba2+ blocks with slower kinetics, so that blocking events can be resolved in single-channel records. Ba2+ reduces mean open time and causes long closings. 6. The blocking rate constant for Ba2+ was measured from the open times. It was about 1.7 mM-1 ms-1 at -62 mV and increased e-fold for a 40 mV hyperpolarization. The unblocking rate, measured from closed times, yielded a Kd of about 0.1 mM at -62 mV, in agreement with that measured from the reduction in open-state probability. 7. Our results suggest that Cs+ and Ba2+ block at sites within the channel, and provide evidence that the channel is a multi-ion pore.


Evaluation of A plasma for incompatible patients.
Plasma transfusion is a critical treatment in managing bleeding patients. In an effort to make plasma immediately available in spite of the limited amount of AB plasma, providers have begun using A plasma in life-threatening emergencies. As this practice becomes widely adopted it is important to evaluate safety. Hemolytic transfusions reactions are underreported, and hemolysis may be subclinical. A retrospective study was performed at the University of Florida/Shands Hospital of B and AB patients who received 1 unit or more of A plasma. Patient charts were reviewed and data collected included age; sex; mortality; intensive care unit (ICU) length of stay; and laboratory tests used in identifying hemolysis including direct antiglobulin test, lactate dehydrogenase, haptoglobin, indirect bilirubin, aspartate aminotransferase, urinalysis, hemoglobin, and hematocrit. The primary end points of the study were immune mediated hemolysis, mortality, and length of ICU stay. Ninety-three patients were identified as eligible for the study. One patient suffered a delayed hemolytic transfusion reaction determined to be due to an anti-Jka . No evidence of hemolysis due to ABO-incompatible plasma transfusion was identified. The volume of A plasma transfused was found to be weakly related to mortality and ICU stay. No evidence of ABO immune-mediated hemolysis was observed in the patient population. The results of the study support the safety of A plasma transfusion in B and AB patients. We hypothesize the relationship observed between A plasma volume and mortality/ICU stay may be from collinearity with disease severity.


On the importance of dissolved organic matter in the nutrition of zooplankton in some lake waters.
A steady state, radiotracer technique was used to study the original source of the carbon in zooplankton. The experiments were started in filtered lake water with added inorganic radiocarbon. At the beginning of the experiments, a proportionally insignificant volume of unfiltered water was introduced into the culture, together with some ovigerous zooplankton individuals. Since the radioactivity: carbon ratio in the dissolved inorganic carbon was kept constant, a similar ratio would be expected to develop in the autotrophic phytoplankton. The same ratio would then be expected to develop in the zooplankton, if its sole carbon source was autotrophic phytoplankton.According to the results of this approach dissolved organic matter seems to be an important food resource for zooplankton, particularly in highly humic lakes. This conclusion was confirmed by the finding that zooplankton from these lakes was able to grow and reproduce in experiments started with filtered lake water and conducted in complete darkness.The development of algae was followed over the course of one experiment in highly humic water. The same micro-flagellates reproduced equally well in both light and darkness, which indicates the importance of heterotrophic metabolism in their nutrition. Although there are no direct observations about the food of zooplankton in our experiments, it appears likely that heterotrophic flagellates play an important role as a food of zooplankton in humic waters.The importance of dissolved organic matter in the nutrition of aquatic organisms would seem to be much greater than has generally been recognized. Consequently the prevailing concepts of the structure and functioning of planktonic ecosystem should be thoroughly re-evaluated.


The Impact of Religious Participation and Religious Upbringing on the Sexual Behavior of Emerging Adults in the Southern United States.
Emerging adults face a disproportionate burden of unintended pregnancies and sexually transmitted diseases, especially in the southern United States. This study investigates how multiple dimensions of current religiosity as well as religious upbringing influence the sexual behaviors, including contraceptive usage, of individuals 18-25 years old (n=211) in the South. Based on regression analyses, results suggest that emerging adults with higher levels of current religiosity are more likely to remain abstinent, but less likely to use pregnancy prevention methods, such as birth controls pills and long-acting reversible contraceptives. Having a religious upbringing is also associated with lower contraceptive usage. Through the assessment of multiple dimensions of religiosity and various sexual behaviors, this study presents a nuanced picture of the complex associations between religion and sexual health, specifically among emerging adults in the southern United States.


Freezing degradation of the anticonvulsant oxcarbazepine by bromate in water ice under sunlight irradiation.
Ice plays a crucial role in contaminant transformation in seasonally ice-covered waters. In this study, the characteristics and mechanisms of an emerging contaminant oxcarbazepine (OXC) degradation by a disinfection by-product bromate ( [Formula: see text] ) in ice were explored via combined experiments and theoretical calculations. Results showed that 74.0 % and 86.4 % of OXC was degraded by [Formula: see text] in ice after 140 min in dark and 120 min under solar irradiation, respectively, while the reaction was negligible in water. The oxidation-reduction potential of [Formula: see text] solution at 1000 μmol L-1 was 56.9 % higher than that at 50 μmol L-1. The oxidation-reduction potential of [Formula: see text] solution at pH 2 was 14.8 %-109.5 % higher than those at other pH values. Enhanced OXC degradation by [Formula: see text] in ice could be attributed to increased [Formula: see text] oxidation capacity resulting from locally elevated [Formula: see text] and H+ concentrations. Hypobromous acid (HOBr), •OH, and Br• generated by direct photolysis under solar irradiation further promoted the OXC degradation in ice. Br• formed by the direct photolysis of accumulated HOBr under solar irradiation caused the generation of bromine-containing degradation products. Bromine-containing degradation products possessed higher potential toxicities, which could contribute to increase the secondary pollution of water environment.


The allometry of the weight of fruit on trees and shrubs in Barbados.
Branch sampling of branch diameter and fruit crop on 22 species of Barbadian trees and shrubs provided sufficient data to build regressions between plant size and fruit crop weight. Orchard plants bear much more fruit than wild, feral or garden plants of similar size, but this difference disappears in multiple regression of fruit crop weight (F in g, fresh mass) on branch or stem diameter (D in cm) and individual fruit weight (W in g): F=22D1.2 W0.57. This explains 89% of the variation in F and successfully predicts crop weight for wild tropical and temperate trees and shrubs, but underestimated the crops on commercial, temperate, fruit trees by an order of magnitude. Comparisons of crop weight for feral, wild, and garden plants (Ff) using a simple regression Ff=47D1.9 show that crop weight is a minor load relative to branch weight for larger branches. Although fruit crops represent a declining proportion of total plant weight as plants become larger, the crops become larger relative to leaf and twig weight and in this sense, reproductive investment increases in larger plants. Finally, our equations, combined with the self-thinning rule, suggest that stands of large species of fruit plants produce more fruit per unit of land area than stands of small ones.


Rat cathepsin K: Enzymatic specificity and regulation of its collagenolytic activity.
Human cathepsin K (hCatK), which is highly expressed in osteoclasts, has the noteworthy ability to cleave type I and II collagens in their helical domain. Its collagenase potency depends strictly on the formation of an oligomeric complex with chondroitin 4-sulfate (C4-S). Accordingly, hCatK is a pivotal protease involved in bone resorption and is an attractive target for the treatment of osteoporosis. As rat is a common animal model for the evaluation of hCatK inhibitors, we conducted a comparative analysis of rat CatK (rCatK) and hCatK, which share a high degree of identity (88%) and similarity (93%). The pH activity profile of both enzymes displayed a similar bell-shaped curve (optimal pH: 6.4). Presence of Ser134 and Val160 in the S2 pocket of rCatK instead of Ala and Leu residues, respectively, in hCatK, led to a weaker peptidase activity, as observed for mouse CatK. Also, regardless of the presence of C4-S, rCatK cleaved in the nonhelical telopeptide regions of both type I (tail) and type II (articular joint) rat collagens. Structure-based computational analyses (electrostatic potential, molecular docking, molecular dynamics, free energy calculations) sustained that the C4-S mediated collagenolytic activity of rCatK obeys distinct molecular interactions from those of hCatK. Additionally, T-kininogen (a.k.a. thiostatin), a unique rat serum acute phase molecule, acted as a tight-binding inhibitor of hCatK (Ki = 0.11 ± 0.05 nM). Taken into account the increase of T-Kininogen level in inflamed rat sera, this may raise the question of the appropriateness to evaluate pharmacological hCatK inhibitors in this peculiar animal model.


Effect of histamine on the length-tension properties of guinea pig trachealis muscle.
The isotonic length-tension properties of excised live guinea pig trachealis muscle have been determined as a function of histamine concentration. Over the range of histamine concentrations studied, a family of curves corresponding to the total and active tensions were obtained. Reciprocal plots of the tension-concentration data revealed a length dependence of the affinity constant of histamine for its receptor The tensions and lengths below resting were considered to be of special importance because of the role of muscle contraction in airway closure. A mechanochemical model for shortening and reelongation of the trachealis muscle during anaphylaxis has been proposed on the basis of this data. By comparing the force-length properties of the muscle at the lowest histamine concentration, it was suggested that the formation of a histamine-Ca++ receptor complex causes an increase in the rigidity of the muscle membrane. The complete range of lengths, tensions, and concentrations must be employed in order to propose a mechanism of action from mechanical data alone.


Time and place of death from automobile crashes: Research endpoint implications.
Vehicle crashes are a leading cause of US injury and death. Early death, however, has almost entirely been studied in-hospital. The US Department of Transportation Fatality Analysis Reporting System (FARS) database captures both prehospital and in-hospital mortality. FARS location (prehospital, in-hospital) and time of death were reviewed (1978-2013), and a 2003-2005 subgroup of 55,537 early deaths (i.e., between 5 minutes and 4 hours after injury) was analyzed to quantify risk of death over time. There has been an overall decrease in 1978-2013 US vehicle-related deaths (from 3.3 deaths per 100 million vehicle miles traveled to 1.1 and from 22.6 per 100,000 population to 10.4). Snapshots of the death data reveal an overall downward trend of total in-hospital and prehospital deaths. The proportion of hospital deaths decreased by 58%, whereas the proportion of deaths in the prehospital period increased to 56%. Subgroup analysis revealed a rate of mortality risk of 0.4% per minute for the first 30 minutes, 1% per minute for the next 60 minutes, and 0.2% per minute and plateauing thereafter. Analysis of census FARS data of motor vehicle crash-related deaths showed an overall 35% decrease in mortality over a period of 36 years. The disproportionate reduction in in-hospital deaths is perhaps a testament to the effectiveness of trauma centers. However, there is a demonstrable need to focus on prehospital deaths with resuscitative and adjuvant therapy research and trauma system design. Quantifying risk of death over time should help focus emergency medical services, trauma system, and resuscitation goals. Epidemiologic study, level III.


Clinical and pathological response to neoadjuvant chemotherapy with different chemotherapy regimens predicts the outcome of locally advanced breast cancer.
This retrospective analysis was designed to research whether clinical response partial response (PR)/complete response (CR) and pathological response (PCR) to neoadjuvant chemotherapy can translate into prognosis benefit pathological response in patients with locally advanced breast cancer and whether different chemotherapy regimens will influence the outcomes. One hundred and thirty-five patients with breast cancer patients who received neoadjuvant chemotherapy were included in the retrospective analysis. Patients were followed up strictly. Overall survival (OS) was evaluated by the Kaplan-Meier analysis. The comparison of the clinical and pathological characteristics and recurrence was performed using the carried out by chi-squared and Fisher's exact tests. Univariate and multivariate analyses were performed by the Cox regression analysis. Clinical response was strongly correlated with lymph nodes status (P=0.032). The OS comparison of pathological response between the pCR group and non-pCR groups did not exhibit statistically significant differences (P=0.400). A similar non-significant response result was observed in the comparison of clinical response between the PR/CR and SD/PD groups group (P=0.108). Univariate and multivariate analyses did not support clinical response (P=0.156 P=0.095 respectively) or pathological response (P=0.600 P=0.144 respectively) as the predictors of prognosis. There were no significant differences in either the comparison of the clinical response group it seems no statistically significance (P=0.496) or the comparison of the pathological response group (P=0.460). OS analyses across different neoadjuvant chemotherapy regimens demonstrated no significant differences (P=0.307). In the PR/CR and PD/SD comparison of every single regimen, there were no significant differences. However, for patients with PR/CR patients from the comparison of five regimens, namely, TAC, FAC, AC-T, AT and TCBP demonstrated a significant difference (P=0.022). In the group of patients with luminal A breast cancer, the result of the Fisher's exact test approached significant (P=0.059). Neither PR/CR nor pCR can translate into long-term outcome benefit. PR/CR and PCR are not independent predictors in patients with advanced breast cancer. Patients who received a taxane + anthracycline regimen exhibited a higher recurrence rate than any other regimens, especially those patients with luminal A breast cancer.


Adaptation of siblings to childhood malignancy.
To explore the impact of childhood cancer, school-aged patients and their healthy siblings from 71 families were given one or more of the following psychologic tests: the Piers-Harris Children's Self-Concept Scale, the Bene-Anthony Family Relations Test, and the Thematic Apperception Test. The siblings showed even more distress than the patients in the areas of perceived social isolation, perception of their parents as overindulgent and overprotective of the sick child, fear of confronting family members with negative feelings, and concern with failure (older siblings only). In other areas, such as anxiety and vulnerability to illness and injury, the patients' and siblings' experience appeared very similar. These results indicate that siblings, like patients, experience severe stress when confronted with a chronic, life-threatening illness such as cancer. In recognizing and attending to their needs, one can practice primary prevention in pediatrics by facilitating their healthy adaptation to a very difficult situation.


Deficits in adolescent social functioning, dysfunctional family processes and genetic risk for schizophrenia spectrum disorders as risk factors for later psychiatric morbidity of adoptees.
Social functioning deficits during adolescence are associated with later psychiatric morbidity, particularly in offspring at high genetic risk for schizophrenia spectrum disorders. However, a shortcoming of earlier study findings is the lack of control of the impact of the family rearing environment. The study was aimed to examine the association of adoptees' social functioning during adolescence, adoptive family functioning, and adoptees' high (HR) or low (LR) genetic risk for schizophrenia spectrum disorders with adoptees' later psychiatric morbidity. The present subsample from the nationwide Finnish Adoptive Family Study of Schizophrenia included 57 HR and 60 LR adoptees. Adolescent social functioning was assessed using UCLA Social Attainment Survey (UCLA SAS). Adoptive family functioning was based on Global Family Ratings (GFRs) and psychiatric disorders on DSM-III-R criteria. The results indicated that, after controlling for adoptive family functioning and genetic risk for schizophrenia spectrum disorders, deficits in peer relationships during adolescence were associated with an increased likelihood of psychiatric morbidity of adoptees. Our findings highlight social functioning deficits during adolescence, specifically in peer relationships, as plausible independent risk factors for later psychiatric disorders. These results can be utilized in identifying possible at-risk groups and targets for prevention and in developing preventive strategies.


Tobramycin pharmacokinetics in morbidly obese patients.
Tobramycin kinetics were examined in 9 morbidly obese women following a single intravenous (120 mg) bolus. After the injection, serum elimination conformed to a 2-compartment open model with alpha and beta t1/2s of 0.285 and 2.1 hr. The volume of distribution (Varea) was determined to be 0.44 1/kg ideal body weight (IBW) and 0.20 1/kg total body weight (TBW). To normalize Varea to 0.26 1/kg, 58% of the patients' adipose weight (TBW -- IBW) must also be taken into account.


The stimulation of Escherichia coli stringent factor-dependent synthesis of guanosine 3',5'-polyphosphate [(p)ppGpp] by rat liver ribosomal proteins.
The effect of groups of proteins from rat liver ribosomes on the Escherichia coli stringent factor-catalyzed synthesis of (p)ppGpp was tested. Most groups were capable of supporting (p)ppGpp synthesis; the exceptions were A40, B140, B240 and B160 which contain proteins which are relatively less basic than those in the active groups. The capacity of 30 individual rat liver ribosomal proteins to activate stringent factor was assessed; most sustained the synthesis of (p)ppGpp. Proteins S12, S21, L12, P1, and P2 (which are acidic or relatively acid) had no activity; proteins S6, S8, and L3 were the most active: the others had moderate activity.


Cardiac tamponade and acute renal failure following Salmonella agona pericarditis.
A 19-year-old female presented with cardiac tamponade complicated by acute renal failure. Salmonella agona was cultured from pericardial aspirate after repeated pericardiocentesis in several sites. Treatment with ampicillin and intermittent haemodialysis led to complete recovery.


Analysis of 16S rRNA environmental sequences using MEGAN.
Metagenomics is a rapidly growing field of research aimed at studying assemblages of uncultured organisms using various sequencing technologies, with the hope of understanding the true diversity of microbes, their functions, cooperation and evolution. There are two main approaches to metagenomics: amplicon sequencing, which involves PCR-targeted sequencing of a specific locus, often 16S rRNA, and random shotgun sequencing. Several tools or packages have been developed for analyzing communities using 16S rRNA sequences. Similarly, a number of tools exist for analyzing randomly sequenced DNA reads. We describe an extension of the metagenome analysis tool MEGAN, which allows one to analyze 16S sequences. For the analysis all 16S sequences are blasted against the SILVA database. The result output is imported into MEGAN, using a synonym file that maps the SILVA accession numbers onto the NCBI taxonomy. Environmental samples are often studied using both targeted 16S rRNA sequencing and random shotgun sequencing. Hence tools are needed that allow one to analyze both types of data together, and one such tool is MEGAN. The ideas presented in this paper are implemented in MEGAN 4, which is available from: http://www-ab.informatik.uni-tuebingen.de/software/megan.


Isocyanate crosslinked reactive starch nanoparticles for thermo-responsive conducting applications.
Hydrophobic nanoparticles and nanocomposite films of 1,4-hexamethylene diisocyanate (HMDI)-modified starch nanoparticles (SNPs) have been synthesized at ambient temperatures. The platelet-like starch nanocrystals become pseudospherical after modification with HMDI and the size increases or decreases depending on diisocyanate concentration compared to the ungrafted particles as revealed by transmission electron microscopy (TEM) results. The obtained nanocrystals were characterized by means of the FT-IR and X-ray diffraction (XRD) techniques. When compared with the hydrophobic performance of the unmodified starch nanocrystals, that of crosslinked starch nanocrystals significantly increased. X-ray diffraction reveals that the crystalline structure of modified starch nanocrystals was preserved. The resulting hydrophobic starch nanoparticles are versatile precursors to the development of nanocomposites. The polyether-polyurethane crosslinked with SNPs nanocomposite film exhibited thermo-responsive electrical conductivity.


Drug-Induced Sexual Dysfunction: An Analysis of Reports to a National Pharmacovigilance Database.
Sexual dysfunction (SD) is a problem that can affect any phase of the sexual response cycle (such as sexual desire, arousal and orgasm) and individuals of any age. SD can be caused by physical reasons, such as medical conditions, alcoholism or drug abuse; psychological factors, such as stress and anxiety; and different medicines, such as selective serotonin reuptake inhibitors (SSRIs), and their associated adverse effects. The aim of this study was to characterise drugs suspected to have caused SD adverse drug reactions (ADRs) in patients, by conducting a descriptive study based on pharmacovigilance reports. Reports submitted to the Netherlands Pharmacovigilance Centre Lareb from January 2003 to December 2019 were used to investigate drug-induced sexual disorders. Selected reports had at least one ADR reported in the Medical Dictionary for Regulatory Activities (MedDRA®) System Organ Class (SOC) 'Reproductive system and breast disorders' and the SOC 'Psychiatric disorders' relating to sexual disorders and corrected for drug utilisation (expenditure) for the Dutch population. A total of 2815 SD ADRs were reported in the observed period. Data were divided according to three variables: pharmacotherapeutic group, the drug itself, and sex. A total of 722 different SD/pharmacotherapeutic group pairs were observed. The pharmacotherapeutic groups with the highest frequency of SD reports were SSRIs (n = 488, 17.58%), other antidepressants (n = 172, 6.20%) and HMG-CoA reductase inhibitors (n = 149, 5.37%). Distinguishing ADRs by sex, men suffered more from erectile dysfunction, decreased libido and ejaculation disorders, while among women, libido disorders, dyspareunia and SD were the most common ADRs. Different reactions and disproportionality of reactions were detected between the sexes. Antidepressants, antihypertensives, oral contraceptives, α-blockers, and anti-androgens were the pharmacotherapeutic groups with the highest number of SD reports and corresponding high odds ratios.


Occurrence of an atypical alkaline phosphatase fraction ("biliary") in primary liver cancer.
The appearance and clinical significance of an atypical fraction of serum alkaline phosphatase called "biliary" have been evaluated in patients with primary liver cancer (PLC) and control subjects. The "biliary" fraction was present in all 42 PLC patients and proved to be the most sensitive of the biochemical parameters utilized. The association with alpha-fetoprotein determination allowed us to identify patients affected by hepatic pathology of neoplastic type, with a diagnostic efficiency of 92%.


Patterns of long-term use of non-vitamin K antagonist oral anticoagulants for non-valvular atrial fibrillation: Quebec observational study.
Studies on long-term utilization of non-vitamin K antagonist oral anticoagulants (NOACs) in non-valvular atrial fibrillation (NVAF) are scarce. We evaluated predictors of use and long-term persistence of NOACs in a real-world setting. This population-based cohort study used the computerized databases of the Canadian Province of Quebec's health insurance. Patients with a first NVAF diagnosis from 2011 until 2014 were included. A logistic regression model yielded adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for predictors of treatment initiation with NOACs versus VKAs. Cox proportional hazards models yielded adjusted hazard ratios (HRs) and 95% CIs for predictors of switching from VKAs to NOACs versus remaining on VKAs, and for predictors of discontinuation of anticoagulation treatment. Of the 62 867 newly diagnosed NVAF patients, 14 646 initiated NOACs and 17 685 VKAs. Initiation with NOACs was less likely for patients ≥ 80 years old (OR 0.55, 95% CI 0.41-0.73) or with CHA2 DS2 -VASc ≥ 2 (OR 0.49, 95% CI 0.42-0.57). Switching from VKAs to NOACs was less likely for patients with chronic kidney disease (HR 0.53, 95% CI 0.48-0.59). After 3 years, persistence was 54% with NOACs and 25% with VKAs. Discontinuation of anticoagulation treatment was less likely for patients ≥ 80 years old (HR 0.47, 95% CI 0.40-0.55) or with CHA2 DS2 -VASc ≥ 2 (HR 0.64, 95% CI 0.57-0.70). Older, high-risk patients are less likely to initiate NOACs than VKAs. NOAC users show a higher long-term persistence than VKA users, and older, high-risk patients are less likely to discontinue anticoagulation treatment.


Small hydrocarbons formed by the peroxidation of squalene.
Experiments were undertaken to determine whether peroxidized squalene forms isoprene in a manner such that peroxidation could be considered as a possible route for the formation of in vivo human breath isoprene. Small hydrocarbons derived from peroxidation of positions 1-6 of squalene were identified in the head space. The most unusual product, proposed to arise from peroxidation of carbon 1 and intramolecular cyclization, was a mixture of dimethylcyclopentadiene isomers. Sonication of an aqueous mixture or low O2 partial pressure favored isoprene formation.


Mechanism of action of the nitrosoureas--V. Formation of O6-(2-fluoroethyl)guanine and its probable role in the crosslinking of deoxyribonucleic acid.
DNA which has been exposed to 2-haloethylnitrosoureas has been shown to contain the chemical crosslink 1-(N3-deoxycytidyl), 2-(N1-deoxyguanosinyl)-ethane [W. P. Tong, M. C. Kirk and D. B. Ludlum, Cancer Res. 43, 3102 (1982)]. We have hypothesized that this structure is formed by an initial attack of a 2-haloethyl group on the 6 position of guanine followed by an intramolecular rearrangement and secondary crosslinking reaction with cytosine. We have now shown that DNA which had been reacted with N-(2-fluoroethyl)-N'-cyclohexyl-N-nitrosourea contained O6-(2-fluoroethyl)guanine and have thus demonstrated that the first step in the proposed mechanism occurs. Furthermore, O6-(2-fluoroethyl)guanosine hydrolyzed to N1-(2-hydroxyethyl)guanosine, showing that the necessary intramolecular rearrangement occurs. These two observations greatly strengthen the proposed route to DNA crosslinking by the 2-haloethylnitrosoureas.


A 62-dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis. A twice-weekly, directly observed, and cost-effective regimen.
To evaluate the efficacy and toxicity of a 62-dose, four-drug, 6-month, and directly observed regimen for treatment of pulmonary and extrapulmonary tuberculosis. An open, nonblinded clinical trial, with intended follow-up of patients for 36 months after the completion of therapy. A metropolitan tuberculosis clinic in a public health department. From March 1981 through April 1989, we enrolled 160 patients with suspected or known tuberculosis; 35 of these patients were excluded from the analysis. Isoniazid, rifampin, pyrazinamide, and streptomycin were administered daily for 2 weeks; these drugs were then given in higher doses twice weekly for 6 weeks, followed by isoniazid and rifampin twice weekly for 6 weeks, followed by isoniazid and rifampin twice weekly for 18 weeks. A total of 62 doses were administered, and all therapy was directly observed by a nurse or an outreach worker. Of the 125 evaluable patients, 101 (81%) had pulmonary tuberculosis, 7 (6%) had both pulmonary and extrapulmonary involvement, and 17 (13%) had extrapulmonary disease only. Seventy-one (57%) patients had a history of recent alcoholism. There were two relapses (1.6% +/- 2.2%), occurring 6 and 56 months after the completion of therapy. The time at which sputum samples became culture negative in pulmonary patients ranged from 1 to 19 weeks (median, 4.6 weeks); 40% +/- 9.6% of patients were culture-negative after 4 weeks of therapy, 75% +/- 8.5% after 8 weeks, 94% +/- 4.7% after 12 weeks, 97% +/- 3.3% after 16 weeks, and 100% after 20 weeks. Adverse drug reactions included hyperuricemia (greater than 178 mumol/L [3 mg/dL] above normal) secondary to pyrazinamide in 80 patients (64%), twofold or greater elevations of aspartate aminotransferase in 21 patients (17%), 1.5-fold or greater elevations of alkaline phosphatase in 33 patients (27%), cutaneous abnormalities in 8 patients (6%), nausea in five patients (4%), and dizziness in 1 patient (1%). This 62-dose, largely twice-weekly tuberculosis treatment regimen is efficacious and relatively nontoxic and is especially useful for patients in whom directly observed therapy is indicated.


A public health approach to addressing arthritis in older adults: the most common cause of disability.
Arthritis is highly prevalent and is the leading cause of disability among older adults in the United States owing to the aging of the population and increases in the prevalence of risk factors (e.g., obesity). Arthritis will play a large role in the health-related quality of life, functional independence, and disability of older adults in the upcoming decades. We have emphasized the role of the public health system in reducing the impact of this large and growing public health problem, and we have presented priority public health actions.


Rh-Catalyzed Direct Amination of Unactivated C(sp(3) )-H bond with Anthranils Under Mild Conditions.
C-N Bond formation is of great significance due to the ubiquity of nitrogen-containing compounds. Here, a mild and efficient Rh(III) -catalyzed C(sp(3) )-H aryl amination reaction is reported. Anthranil is employed as the nitrogen source with 100 % atom efficiency. This C-H amination reaction exhibits broad substrate scope without using any external oxidants. Mechanistic studies including rhodacycle intermediates, H-D exchange, kinetic isotope effect (KIE) experiments, and in situ IR are presented.


Fabrication of carboxyl and amino functionalized carbonaceous microspheres and their enhanced adsorption behaviors of U(VI).
Design and fabrication of materials with abundant functional groups represent an important and promising direction in the remediation of aqueous contaminants. In recent years, carbon-based materials have drawn widespread concern on account of their low cost, large specific surface area, good chemical stability as well as controllable porosity. The U(VI) binding onto raw carbon-based materials is still confronted with the problem of limited adsorption capacity, which severely hinders the practical applications of materials. Herein, amino- and carboxyl-functionalized carbonaceous spheres (denoted as ACSs and CCSs) were fabricated by in-situ polymerization and simply annealing methods, respectively. The highest adsorption amounts of ACSs and CCSs towards U(VI) were calculated to be 73.83 and 401.61 mg·g-1 from Langmuir model at pH = 4.0 and 298 K, which were higher to that of raw carbonaceous material (19.31 mg·g-1). Interestingly, the Freundlich model could well simulate U(VI) sorption isotherms on ACSs at these temperatures (T = 298, 313 and 328 K), while U(VI) sorption isotherms on CCSs were able to significantly conform to the Langmuir model. According to FT-IR and XPS analysis, U(VI) was enriched on both materials on account of the ample functional groups on ACSs (e.g. CNOH/CNH2) and CCSs (e.g. OH/COOH). In addition, effect of ionic strength manifested that U(VI) elimination on ACSs and CCSs were greatly caused by the formation of outer-sphere and inner-sphere surface complexes, respectively. This work promises to provide two facile approaches for engineering diverse functionalized materials towards a highly rapid and efficient sequestering U(VI) from contaminated water.


The Effect of Single-Anastomosis Sleeve Ileal (SASI) Bypass on Patients with Severe Obesity in Three Consecutive Years.
Sparse data are available regarding the efficacy and safety of single anastomosis sleeve ileal (SASI) bypass surgery, where most available studies utilized short-term follow-ups. Therefore, this study was conducted to evaluate the safety and outcomes of this procedure in three consecutive years after the surgery. This retrospective study was carried out with 116 patients who underwent SASI from October 2016 to September 2021. Anthropometric, clinical, and biochemical data were recorded before, 1, 2, and 3 years after surgery. The 1, 2, and 3-year percentage of excess weight loss (%EWL) were 87.37%, 90.7%, and 80.6%, respectively. Remission or improvement was recorded for diabetes mellitus in 90.9%, hypertension in 80.0%, hyperlipidemia in 100%, sleep apnea in 100%, and irregular menstruation in 58.06 at 3 years after surgery. No mortality and 5.1% early major postoperative complications were recorded. Eight patients (6.8%) had reversal surgery due to EWL > 100%. The SASI bypass is an effective bariatric surgery that achieved sequential weight loss and improvement in medical comorbidities three years after the surgery; however, standardization of SASI procedure technique is needed to ameliorate nutritional deficiencies.


Analysis of Pseudomonas aeruginosa PAO1 lipid A changes during the interaction with model organism, Caenorhabditis elegans.
Lipopolysaccharide (LPS) is the main surface constituent of Gram-negative bacteria. Lipid A, the hydrophobic moiety, outer monolayer of the outer cell membrane forms the major component of LPS. Immunogenic Lipid A is recognized by the innate immune system through the TLR 4/MD-2 complex. Pseudomonas aeruginosa PAO1, a Gram-negative bacterium is known to cause nosocomial infection and known for its adaptation to adverse environmental conditions. Pseudomonas aeruginosa can infect a broad host spectrum including Caenorhabditis elegans, a simple free living soil nematode. Here, we reveal that PAO1 modifies its Lipid A during the host interaction with C. elegans. The penta-acylated form of Lipid A was identified by using matrix assisted laser desorption ionization-time of flight analysis and the β-(1,6)-linked disaccharide of glucosamine with phosphate groups, 2 and 2' amide linked fatty acid chain and 3 and 3' ester linked fatty acids were investigated for the modification using the non destructive (1)H NMR, spin-lattice (T₁) relaxation measurement, differential scanning calorimetry. T₁ relaxation measurements showed that the 2 and 2' amide linked fatty acid chain, -CH in the glucosamine disaccharide of PAO1 lipid A, in an exposed host had a different spin lattice relaxation time compared to an unexposed host and the findings were reconfirmed using in vitro human corneal epithelial cells cell lines. Furthermore, scanning electron microscope and confocal laser scanning microscopy analysis revealed that the P. aeruginosa PAO1 biofilm formation was disturbed in the exposed host condition. The daf-12, daf-16, tol-1, pmk-1, ins-7 and ilys3 immune genes of C. elegans were examined with live bacterial and isolated lipid moiety infection and the expression was found to be highly specific. Overall, the present study revealed that PAO1 modified its 2 and 2' amide linked fatty acid chain in the lipid A of PAO1 LPS during the exposed host condition.


A high performance liquid chromatographic system for the analysis of tetracycline drug standards, analogs, degradation products and other impurities.
This paper describes the high performance liquid chromatographic (HPLC) analysis of eight parent tetracycline standards: tetracycline, chlortetracycline, rolitetracycline, oxitetracycline, minocycline, doxycycline, democlocycline, methacycline; and three tetracycline epimers: epitetracycline, epianhydrotetracycline, and anhydrotetracycline. The HPLC system employs an octadecylsilane reverse phase column and an isopropanol-diethanolamine-phosphate-ammonium EDTA-water mobile phase. This system produced at least partial resolution of all eight parent compounds and many of their degradation products.