Corrosion-resistant cobalt phosphide electrocatalysts for salinity tolerance hydrogen evolution.
Seawater electrolysis is a viable method for producing hydrogen on a large scale and low-cost. However, the catalyst activity during the seawater splitting process will dramatically degrade as salt concentrations increasing. Herein, CoP is discovered that could reject chloride ions far from catalyst in electrolyte based on molecular dynamic simulation. Thus, a binder-free electrode is designed and constructed by in-situ growth of homogeneous CoP on rGO nanosheets wrapped around the surface of Ti fiber felt for seawater splitting. As expected, the as-obtained CoP/rGO@Ti electrode exhibits good catalytic activity and stability in alkaline electrolyte. Especially, benefitting from the highly effective repulsive Cl- intrinsic characteristic of CoP, the catalyst maintains good catalytic performance with saturated salt concentration, and the overpotential increasing is less than 28 mV at 10 mA cm-2 from 0 M to saturated NaCl in electrolyte. Furthermore, the catalyst for seawater splitting performs superior corrosion-resistance with a low solubility of 0.04%. This work sheds fresh light into the development of efficient HER catalysts for salinity tolerance hydrogen evolution.


Automatic functions in cardiac pacing: optimization of device and patient therapy.
An overview of advances is presented. The focus is on automatic functions that have been developed to monitor the patient continuously and readjust the postventricular atrial refractory period, the atrioventricular (AV) delay, the ventricular refractory period, and the pacemaker stimulus intensity. The advent of automatic algorithms for the postventricular atrial refractory period may have broadened considerably the clinical application of dual chamber pacemakers. Automatic adjustment of the ventricular refractory period has been demonstrated in an implantable pacemaker and may eliminate the rhythm disturbance associated with inappropriate T-wave sensing. Automatic adjustment of the AV delay has been implemented, and there is evidence suggesting that improved hemodynamics may result. Automatic output regulation has emerged in an implantable pacemaker and promises to increase device longevity while providing important patient safety benefits.


[Operative treatment of tumors of ventricles I-III following experiences 1953-1983].
A report is given on the experience gained in 254 patients presenting processes of the ventricles I-III at the Leipzig Hospital within a period of thirty years. The rate of radical operations rose from 29% to 60%. At present, however, inoperability is restricted almost exclusively to general surgical aspects. Palliative operations are carried out in the form of the V-A shunts. Of decisive importance is the use of microtechniques in conjunction with an optimum anesthesia and intensive care. The accesses used are shown in pictures. Special surgical aspects are benignity of many intraventricular tumours, pronounced vascularisation, localisation below functionally important corticocerebral regions as well as exact considerations with respect to the planning of the operation pathway.


Association Between Previous Injury and Risk Factors for Future Injury in Preprofessional Ballet and Contemporary Dancers.
To determine the prevalence of self-reported 1-year injury history and examine its association with preparticipation evaluation components aimed at predicting future injury risk (PPE-IP) among preprofessional ballet and contemporary dancers. Cross-sectional study. Preprofessional ballet school, university contemporary dance program. Full-time preprofessional ballet and contemporary dancers. Preparticipation evaluation consisted of the Athletic Coping Skills Inventory-28, body mass index, total bone mineral density, ankle range of motion, active standing turnout, lumbopelvic control, unipedal dynamic balance, and Y-Balance test. Self-reported 1-year history of dance-related medical attention and/or time-loss injury. A total of 155 ballet [n = 90, 80 females, median age 15 years (range 11-19)] and contemporary [n = 65, 63 females, median age 20 years (range 17-30)] dancers participated. Forty-six percent (95% confidence interval (CI), 38.4-54.6) reported a 1-year injury history. Self-reported injury history was not associated with any PPE-IP, however, an influence of age and psychological coping skills on the relationship between 1-year injury history and PPE-IP was identified. Multivariable analyses revealed that prevalence of 1-year injury history did not differ by age [referent group <15 years; 15-18 years: odds ratio (OR) 0.80 (95% CI, 0.35-1.79); >18 years: OR 0.69 (95% CI, 0.30-1.56)], or level of psychological coping skills [OR 1.35 (95% CI, 0.61-2.94)]. The prevalence of self-reported 1-year injury history among preprofessional ballet and contemporary dancers is high. Although measures of PPE-IP did not differ based on injury history, it is important that age and psychological coping skills are considered in future dance injury prevention and prediction research. Level 3 evidence.


[Anorectal diseases in HIV-positive patients. A prospective study].
The acquired immunodeficiency syndrome (AIDS) has transformed in a illness pandemic and it is thought that 120 million of people will be infected by the year 2000. About thirty five percent of HIV positive patients will have rectal manifestations during their illness, and from these the most important anorectal manifestation are perianal sepsis, anal condyloma, hemorrhoidal disease, chronic diarrhea syndrome, anal ulcer and anorectal tumors. To determinate in our medical environment which anorectal manifestation have the most frequency in HIV positive patients. We developed a linear prospective, comparative and observational trial between December 1993 and December 1994, which included 83 patients distributed in 4 groups: 1) HIV homosexual patients with AIDS, 2) positive HIV homosexual patients without AIDS, 3) negative HIV homosexual patients, 4) negative HIV heterosexual patients. The statistical analysis was done through a chi 2 (Chi square) test. In homosexual HIV patients with the disease, the most common lesion was the anal ulcer (55%). In positive HIV homosexual patients without disease and negative HIV homosexual patients the most frequent lesion is Condyloma acuminata (48 y 84%). In negative HIV heterosexual patients the most frequent disease was anal fistula (40%) and hemorrhoidal disease (36%). In negative HIV patients and positive HIV patients without disease the most frequent anorectal lesion is condyloma acuminata; when immunosuppression begins by AIDS, anal ulcer appears and is transformed in the most frequent anorectal disease in AIDS patients.


Feasibility of Dual-Energy Computed Tomography Imaging of Gadolinium-Based Contrast Agents and Its Application in Computed Tomography Cystography: An Exploratory Study to Assess an Alternative Option When Iodinated Contrast Agents Are Contraindicated.
The aim of this study was to compare the contrast enhancement differences between gadolinium-based and iodine-based contrast agents at different single-energy tube potentials and dual-energy-based virtual monochromatic energies. In addition, we describe the application of a gadolinium-based contrast agent in computed tomography (CT) cystography for a patient with contraindications to iodine. A phantom study was performed using 3 iodine samples (concentrations: 5, 10, and 15 mgI/mL) and 3 gadolinium samples (concentrations: 3.3, 6.6, and 9.9 mgGd/mL). The prepared phantom was scanned by a dual-energy CT (DECT) at 80, 100, 120, and 140 kV in the single-energy mode and at 100/Sn140 kV in the dual-energy mode. Virtual monoenergetic images (VMIs) at 50 keV were generated from the DECT scan. In addition, a DECT cystogram was performed using a gadolinium-based contrast agent in a patient with contraindications to iodinated contrast. Strong linear correlations between mean signal of contrast enhancement and mass concentration were found for both iodine and gadolinium samples across all single-energy CT (SECT) and DECT scan conditions. The VMI at 50 keV provided the highest contrast enhancement for both types of contrast samples at each concentration level, and single-energy CT scans at low-energy beams showed higher contrast enhancement than higher beam energies. In addition, the contrast enhancement for pure gadolinium solution was constantly higher than pure iodine solution at an identical mass concentration level. The DECT cystogram was performed with excellent technical success. The urinary bladder was appropriately distended with intravesical contrast measuring 606 Hounsfield units and no evidence of bladder leak or fistula. Imaging of gadolinium-based contrast agents is improved using a DECT technique, with VMI at 50 keV providing the highest contrast enhancement among our tested parameters. Dual-energy CT cystography using a gadolinium-based agent can be a safe and effective alternative when iodinated agents are contraindicated.


Choosing what to protect.
We study a strategic model in which a defender must allocate defensive resources to a collection of locations, and an attacker must choose a location to attack. The defender does not know the attacker's preferences, while the attacker observes the defender's resource allocation. The defender's problem gives rise to negative externalities, in the sense that increasing the resources allocated to one location increases the likelihood of an attack at other locations. In equilibrium, the defender exploits these externalities to manipulate the attacker's behavior, sometimes optimally leaving a location undefended, and sometimes preferring a higher vulnerability at a particular location even if a lower risk could be achieved at zero cost. Key results of our model are as follows: (1) the defender prefers to allocate resources in a centralized (rather than decentralized) manner; (2) as the number of locations to be defended grows, the defender can cost effectively reduce the probability of a successful attack only if the number of valuable targets is bounded; (3) the optimal allocation of resources can be nonmonotonic in the relative value of the attacker's outside option; and (4) the defender prefers his or her defensive allocation to be public rather than secret.


Employment of an algorithm of care including chest physiotherapy results in reduced hospitalizations and stability of lung function in bronchiectasis.
There is a paucity of data on long term clinical effects of high frequency chest wall oscillation (HFCWO) in the Bronchiectasis population. Other therapies such as nebulized mucolytics and long term antibiotics have proven benefit on quality of life and exacerbation rate. In this study a treatment algorithm that included HFCWO as a component was initiated to see what the long term effects of the proposed algorithm were on lung function, antibiotic use, and exacerbation rates. This was an observational comparative retrospective cohort study from database of patients with Bronchiectasis. Patients with > 2 exacerbations and significant symptom burden were enrolled to receive a treatment algorithm. The algorithm included: nebulized bronchodilators, mucolytics (hypertonic saline (3-7%) or n-acetylcysteine) inhaled daily or twice daily, thrice weekly macrolide therapy when appropriate, and high frequency chest wall oscillation (HFCWO) therapy (daily to twice daily per issued protocol) Outcomes from the cohort were analyzed for the subsequent twelve months after initiation to observe longitudinal lung function and clinical outcomes. Chart review was then done to obtain data the year prior to the start of the algorithm in this same cohort of patients. Sixty-five patients received the Smart Vest® HFCWO system and were enrolled into the algorithm for treatment during the study period. Of the sixty-five patients, forty-three were eligible due to adequate 1-year baseline and follow up data at the time of the study initiation. The mean FEV1 remained stable at 1-year post enrollment (1.85 ± 0.60 L pre vs 1.89 ± 0.60 L post, p = NS) and the number of exacerbations requiring hospitalization was reduced (1.3 ± 1.0 pre vs. 0.46 ± 0.81 hospitalizations, post initiation, p < 0.0001). Antibiotic use overall was also reduced (2.5 ± 0.86 courses/year pre vs 2.1 ± 0.92 courses per year post initiation, p < 0.0001). Standardized care for Bronchiectasis involving an algorithm for Mucociliary clearance that centers on initiation of HFCWO may help to reduce lung function decline, need for oral antibiotics, and reduced hospitalization rate.


Absence of Mycobacterium tuberculosis in arterial lesions from patients with Takayasu's arteritis.
Previous studies have suggested that Mycobacterium tuberculosis (MT) could be involved in the pathogenesis of Takayasu's arteritis (TA). The search for MT in arterial lesions of TA has never been assessed directly by sensitive methods. Our aim was to assess the presence of MT in arterial samples obtained in patients with TA. Fresh arterial samples were collected from 10 consecutive patients (9 women and 1 man, median age 42 yrs, range 19-67 yrs) with a diagnosis of TA according to the American College of Rheumatology criteria who underwent vascular surgical procedures for their disease. Three patients had recent onset of TA and 7 had longstanding disease. No patient had evidence of active tuberculosis. Arterial biopsies were collected during vascular surgical procedures, and were systematically studied by a pathologist specializing in vascular diseases. Presence of MT was assessed in the biopsies by acid-fast and auramine-fluorochrome stainings, mycobacterial cultures, and direct amplification test (DAT) for MT. Histological examination showed active (n = 5) and inactive (n = 5) arterial lesions. MT was not detected in arterial lesions of either active or inactive TA, by acid-fast and auramine-fluorochrome staining, mycobacterial cultures, or DAT. No DAT inhibitors were found. Our study does not support a direct role of MT in the pathogenesis of arterial lesions in either recent or longstanding TA, but does not exclude the possibility of a cross-reaction between mycobacterial and arterial antigens.


A study of the regional distribution of bone formed around hydroxyapatite implants in the tibiae of streptozotocin-induced diabetic rats using multiple fluorescent labeling and confocal laser scanning microscopy.
The present study was designed to compare the amount and regional distribution of bone formation around hydroxyapatite (HA) implants in normal (control) rats with that of animals with diabetes mellitus (DM), induced by streptozotocin 2 weeks prior to implant placement. Calcein (CAL), alizarin complexone (AL), and tetracycline (TC) were injected on the 7th, 14th, and 21st days after implantation, respectively, and the rats were sacrificed on the 28th day after implantation. Seventy-microns undecalcified sections of the HA-bone interface in both groups were then prepared for confocal laser scanning microscopy (CLSM) observation. In both groups, bone formation developed from the HA surface to the endosteum, periosteum, or bone marrow. In the control group, around the HA close to the endosteum and periosteum, the new bone showed an extensive lamination pattern of three color layers (CAL, AL, and TC), but in the DM group the labeling density of TC on the 21st day was low. In contrast, on the lateral part of the HA surface (away from the endosteum and periosteum), there was considerably less bone formation in the control group, and in the DM group it was almost completely suppressed. These findings indicate that bone formation around the HA was initiated from the HA surface in the control group, while in the DM group, bone formation along the lateral part of the HA away from the endosteum and periosteum was almost completely suppressed. Furthermore, it is also suggested that in the new bone along the HA close to the endosteum and periosteum, only calcification on the 21st day was depressed.


A high throughput, whole cell screen for small molecule inhibitors of the mitotic spindle checkpoint identifies OM137, a novel Aurora kinase inhibitor.
In mitosis, the kinetochores of chromosomes that lack full microtubule attachments and/or mechanical tension activate a signaling pathway called the mitotic spindle checkpoint that blocks progression into anaphase and prevents premature segregation of the chromatids until chromosomes become aligned at the metaphase plate. The spindle checkpoint is responsible for arresting cells in mitosis in response to chemotherapeutic spindle poisons such as paclitaxel or vinblastine. Some cancer cells show a weakened checkpoint signaling system that may contribute to chromosome instability in tumors. Because complete absence of the spindle checkpoint leads to catastrophic cell division, we reasoned that drugs targeting the checkpoint might provide a therapeutic window in which the checkpoint would be eliminated in cancer cells but sufficiently preserved in normal cells. We developed an assay to identify lead compounds that inhibit the spindle checkpoint. Most cells respond to microtubule drugs by activating the spindle checkpoint and arresting in mitosis with a rounded morphology. Our assay depended on the ability of checkpoint inhibitor compounds to drive mitotic exit and cause cells to flatten onto the substrate in the continuous presence of microtubule drugs. In this study, we characterize one of the compounds, OM137, as an inhibitor of Aurora kinases. We find that this compound is growth inhibitory to cultured cells when applied at high concentration and potentiates the growth inhibitory effects of subnanomolar concentrations of paclitaxel.


Salting out the polar polymorph: analysis by alchemical solvent transformation.
We computationally examine how adding NaCl to an aqueous solution with α- and γ-glycine nuclei alters the structure and interfacial energy of the nuclei. The polar γ-glycine nucleus in pure aqueous solution develops a melted layer of amorphous glycine around the nucleus. When NaCl is added, a double layer is formed that stabilizes the polar glycine polymorph and eliminates the surface melted layer. In contrast, the non-polar α-glycine nucleus is largely unaffected by the addition of NaCl. To quantify the stabilizing effect of NaCl on γ-glycine nuclei, we alchemically transform the aqueous glycine solution into a brine solution of glycine. The alchemical transformation is performed both with and without a nucleus in solution and for nuclei of α-glycine and γ-glycine polymorphs. The calculations show that adding 80 mg/ml NaCl reduces the interfacial free energy of a γ-glycine nucleus by 7.7 mJ/m(2) and increases the interfacial free energy of an α-glycine nucleus by 3.1 mJ/m(2). Both results are consistent with experimental reports on nucleation rates which suggest: J(α, brine) < J(γ, brine) < J(α, water). For γ-glycine nuclei, Debye-Hückel theory qualitatively, but not quantitatively, captures the effect of salt addition. Only the alchemical solvent transformation approach can predict the results for both polar and non-polar polymorphs. The results suggest a general "salting out" strategy for obtaining polar polymorphs and also a general approach to computationally estimate the effects of solvent additives on interfacial free energies for nucleation.


Targeting Cancer Stem Cells with Repurposed Drugs to Improve Current Therapies.
Cancer is a multistep process involving genetic and epigenetic changes in the somatic genome. Genetic mutations as well as environmental factors lead to the initiation, promotion, and progression of cancer. Metastasis allows cancer cells to spread via circulatory and lymphatic systems; secondary tumorigenesis typically leads to a fatal outcome. Recent experimental evidence suggests that Cancer Stem Cells (CSCs) play a pivotal role in tumor progression. A tumor is heterogeneous and composed of different cell types. CSCs are a subpopulation of tumor cells possessing abilities to self-renew and differentiate. The aim of this study was to present repurposed drugs, and potential candidates, that can serve as anticancer medications intended to target resistant cancer cells, i.e. CSCs. Research publications, FDA filings, and patents have been reviewed for repurposed drugs or drug combinations that can act to improve cancer treatment and care. Drugs that act against CSCs include ones approved for treatment of diabetes (metformin & thiazolidinediones), parasitic diseases (chloroquine, niclosamide, mebendazole & pyrvinium), psychotic disorders (thioridazine, clomipramine & phenothiazines), alcoholism (disulfiram), lipid disorder (statins), inflammatory diseases (tranilast, auranofin, acetaminophen & celecoxib), antibiotics (azithromycin), and other disorders. Current research findings advocate the existence of beneficial effects by combining these repurposed drugs, and also through their complementary use with conventional cancer therapies. Repurposing FDA-approved medications towards cancer care, by targeting the resistant CSCs, will allow for a quicker, cheaper development and approval process. A larger drug library available to physicians will allow for increased efficacy during both first-line and recurrent cancer treatments.


Opto4E-BP, an optogenetic tool for inducible, reversible, and cell type-specific inhibition of translation initiation.
The protein kinase mechanistic target of rapamycin complex 1 (mTORC1) is one of the primary triggers for initiating cap-dependent translation. Amongst its functions, mTORC1 phosphorylates eIF4E-binding proteins (4E-BPs), which prevents them from binding to eIF4E and thereby enables translation initiation. mTORC1 signaling is required for multiple forms of protein synthesis-dependent synaptic plasticity and various forms of long-term memory (LTM), including associative threat memory. However, the approaches used thus far to target mTORC1 and its effectors, such as pharmacological inhibitors or genetic knockouts, lack fine spatial and temporal control. The development of a conditional and inducible eIF4E knockdown mouse line partially solved the issue of spatial control, but still lacked optimal temporal control to study memory consolidation. Here, we have designed a novel optogenetic tool (Opto4E-BP) for cell type-specific, light-dependent regulation of eIF4E in the brain. We show that light-activation of Opto4E-BP decreases protein synthesis in HEK cells and primary mouse neurons. In situ , light-activation of Opto4E-BP in excitatory neurons decreased protein synthesis in acute amygdala slices. Finally, light activation of Opto4E-BP in principal excitatory neurons in the lateral amygdala (LA) of mice after training blocked the consolidation of LTM. The development of this novel optogenetic tool to modulate eIF4E-dependent translation with spatiotemporal precision will permit future studies to unravel the complex relationship between protein synthesis and the consolidation of LTM.


Preoperative onyx embolization of vascular head and neck tumors by direct puncture.
Preoperative embolization of hypervascular head and neck tumors is frequently performed to reduce operative times and blood loss. While traditional transarterial embolization is commonly used, direct tumoral puncture has also been advocated as an alternative. We report our series of head and neck tumors embolized with onyx via direct tumoral puncture to ascertain the safety and efficacy of embolization using this technique. We prospectively collected data on all head and neck tumors embolized with onyx at our institution during a 24-month period. A total of 18 patients underwent preoperative embolization via direct tumoral puncture. Tumors included nine carotid body tumors, three glomus vagale tumors, five juvenile nasopharyngeal angiofibromas (JNAs), and one intracranial frontal parasagittal meningioma. All embolizations were completed in a single session. Mean fluoroscopy time was 40 minutes. The overall mean percent tumor devascularization was 87%. Inadvertent transtumoral migration of onyx into the superior sagittal sinus occurred during intraoperative embolization of the meningioma using single-plane fluoroscopy and resulted in a large postoperative hemorrhagic venous infarct. There were no other endovascular-related complications in the remaining patients embolized using biplanar fluoroscopy. Embolization of hypervascular head and neck tumors with onyx via direct tumoral puncture can be performed safely and efficiently. Tumor embolization by direct puncture may theoretically lower the risk of inadvertent migration of onyx through nontarget arterial vessels, but may increase the risk of inadvertent transtumoral embolization of venous structures. Caution should be exercised when using this technique for intracranial pathologies, and the importance of biplanar fluoroscopy to allow better visualization of the onyx migration cannot be overemphasized.


[Torsion of gonadal hydatids in childhood].
On the basis of 34 cases of the torsion of the appendix testis, the authors describe the clinical symptoms and the differential diagnosis compared with other cases of the acute scrotum. The diagnostic value of the "button symptom", of Doppler sonography, scintigraphy, as well as the indication of early surgical intervention is discussed.


Fractal conical lenses.
A conical lens is an optical element that produces a continuous focal segment along the optical axis. In this paper we introduce a more general optical device: the fractal conical lens (FCL). As the profile of a FCL is generated using the Cantor function, we show that a classical conical lens is a particular case of these fractal lenses. FCLs are distinguished by the fractal focal segments they produce along the optical axis. The influence of the Fresnel number on the axial irradiance generated by these lenses is investigated.


Integrated in silico - in vitro strategy for the discovery of potential xanthine oxidase inhibitors from Egyptian propolis and their synergistic effect with allopurinol and febuxostat.
Xanthine oxidase (XO) has been well-recognized as a validated target for the treatment of hyperuricemia and gout. Currently, there are two drugs in clinical use that shut down XO overactivity, allopurinol and febuxostat; however, detrimental side effects restrict their applications. Propolis is a unique natural adhesive biomass of structurally variable and biologically active metabolites that exert remarkable health benefits. Moreover, combination drug therapy has become a promising pharmacotherapeutic strategy directed for reformulating existing drugs into new combination entities with potentiating therapeutic impacts. In this study, computer-aided molecular docking and MD simulations accompanied by biochemical testing were used for mining novel pharmacologically active chemical entities from Egyptian propolis to combat hyperuricemia. Further, with a view to decrease the potential toxicity of synthetic drugs and enhance efficacy, propolis hits were subjected to combination analysis with each of allopurinol and febuxostat. More specifically, Glide docking was utilized for a structure-based virtual screening of in-house datasets comprising various Egyptian propolis metabolites. Rosmarinic acid, luteolin, techtochrysin and isoferulic acid were the most promising virtual hits. In vitro XO inhibitory assays demonstrated the ability of these hits to significantly inhibit XO in a dose-dependent manner. Molecular docking and MD simulations revealed a cooperative binding mode between the discovered hits and standard XO inhibitors within the active site. Subsequently, the most promising hits were tested in a fixed-ratio combination setting with allopurinol and febuxostat separately to assess their combined effects on XO catalytic inhibition. The binary combination of each techtochrysin and rosmarinic acid with febuxostat displayed maximal synergy at lower effect levels. In contrast, individually, techtochrysin and rosmarinic acid with allopurinol cooperated synergistically at high dose levels. Taken together, the suggested strategy seems imperative to ensure a steady supply of new therapeutic options sourced from Egyptian propolis to regress the development of hyperuricemia.


Identification and partial purification of human tumor nucleolar antigen 54/6.3.
The present study was designed to characterize the human tumor nucleolar antigens found first in the HeLa cells and subsequently in a broad range of human cancers. For visualization of the antigens, HeLa cell nucleolar or nuclear protein fractions were analyzed on 4% polyacrylamide isoelectric focusing gels. The gels were incubated with rabbit antisera to HeLa cell nucleoli and then with fluorescein- or peroxidase-conjugated goat anti-rabbit immunoglobulin G. With this technique, two major nucleolar antigens (focusing at pH 6.3 and pH 6.1) were identified. These antigens were also found in the Namalwa cell, but not in human liver cells. Purification of the antigen(s) was achieved by selective extraction of Namalwa cell nuclei with 10 mM Tris-HCl (pH 8), 40 to 100% ammonium sulfate precipitation, diethylaminoethyl cellulose chromatography in which the antigen was eluted with 0.15 M NaCl buffer (DE-0.15M fraction), and use of isoelectric focusing gels. The immunostained bands (HuAg 6.3 and HuAg 6.1) and the bright nucleolar immunofluorescence of the HeLa cells were not observed after the antisera were preabsorbed with the DE-0.15M fraction. The immunostained bands (HuAg 6.3 and HuAg 6.1) and the nucleolar immunofluorescence of the HeLa cells were also observed when isoelectric focusing gels were incubated with antiserum from rabbits immunized with the DE-0.15M fraction. On the sodium dodecyl sulfate second dimension of the two-dimensional polyacrylamide gel electrophoresis, the antigen(s) migrated as single spots with appraent molecular weights of 54,000.


Discovery of hCES2A inhibitors from Glycyrrhiza inflata via combination of docking-based virtual screening and fluorescence-based inhibition assays.
Human carboxylesterase 2 (hCES2A) is a key target to ameliorate the intestinal toxicity triggered by irinotecan that causes severe diarrhea in 50%-80% of patients receiving this anticancer agent. Herbal medicines are frequently used for the prevention and treatment of the intestinal toxicity of irinotecan, but it is very hard to find strong hCES2A inhibitors from herbal medicines in an efficient way. Herein, an integrated strategy via combination of chemical profiling, docking-based virtual screening and fluorescence-based high-throughput inhibitor screening assays was utilized. Following the screening of a total of 73 herbal products, licorice (the dried root of Glycyrrhiza species) was found with the most potent hCES2A inhibition activity. Further investigation revealed that the chalcones and several flavonols in licorice displayed strong hCES2A inhibition activities, while isoliquiritigenin, echinatin, naringenin, gancaonin I and glycycoumarin exhibited moderate inhibition of hCES2A. Inhibition kinetic analysis demonstrated that licochalcone A, licochalcone C, licochalcone D and isolicoflavonol potently inhibited hCES2A-mediated fluorescein diacetate hydrolysis in a reversible and mixed inhibition manner, with Ki values less than 1.0 μM. Further investigations demonstrated that licochalcone C, the most potent hCES2A inhibitor identified from licorice, dose-dependently inhibited intracellular hCES2A in living HepG2 cells. In summary, this study proposed an integrated strategy to find hCES2A inhibitors from herbal medicines, and our findings suggested that the chalcones and isolicoflavonol in licorice were the key ingredients responsible for hCES2A inhibition, which would be very helpful to develop new herbal remedies or drugs for ameliorating hCES2A-associated drug toxicity.


Profile and outcomes of hospitalized patients with COVID-19 at a tertiary institution hospital in Ghana.
In high-income countries, mortality related to hospitalized patients with the Coronavirus disease 2019 (COVID-19) is approximately 4-5%. However, data on COVID-19 admissions from sub-Saharan Africa are scanty. To describe the clinical profile and determinants of outcomes of patients with confirmed COVID-19 admitted at a hospital in Ghana. A prospective study involving 25 patients with real time polymerase chain reaction confirmed COVID-19 admitted to the treatment centre of the University Hospital, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana from 1st June to 27th July, 2020. They were managed and followed up for outcomes. Data were analysed descriptively, and predictors of mortality assessed using a multivariate logistic regression modelling. The mean age of the patients was 59.3 ± 20.6 years, and 14 (56%) were males. The main symptoms at presentation were breathlessness (68%) followed by fever (56%). The cases were categorized as mild (6), moderate (6), severe (10) and critical (3). Hypertension was the commonest comorbidity present in 72% of patients. Medications used in patient management included dexamethasone (68%), azithromycin (96%), and hydroxychloroquine (4%). Five of 25 cases died (Case fatality ratio 20%). Increasing age and high systolic blood pressure were associated with mortality. Case fatality in this sample of hospitalized COVID-19 patients was high. Thorough clinical assessment, severity stratification, aggressive management of underlying co-morbidities and standardized protocols incountry might improve outcomes. None declared.


Symposium on microbiology update: old friends and new enemies. Staphylococcus aureus.
The analytical methods for the detection of the staphylococcal enterotoxins can be divided into 2 categories: (1) methods for detection of enterotoxin-producing staphylococcal strains; (2) methods for detection of enterotoxin in foods. Gel diffusion methods (Ouchterlony, microslide), in which the enterotoxin produced by any given strain is compared to one of the identified enterotoxins, are used most frequently for strain testing. The sensitivity of these methods is from 0.1 to 0.5 micrograms enterotoxin/mL, which is normally adequate to determine the enterotoxigenicity of strains. The methods for the detection of enterotoxin in foods need to be much more sensitive to detect less than 1 ng of enterotoxin/g of food that may be present. The radioimmunoassay (RIA), the enzyme-linked immunosorbent assay (ELISA), and the reversed passive latex agglutination (RPLA) method have the necessary sensitivity to detect 1 ng/g of enterotoxin in foods without the use of complicated extraction-concentration procedures. Kits based on the ELISA and RPLA methods are now available commercially for the detection of enterotoxins in foods. Tests have shown that the ELISA methods are somewhat more sensitive than the RPLA method.


Increasing diversity of functional genetics studies to advance biological discovery and human health.
In this perspective we discuss the current lack of genetic and environmental diversity in functional genomics datasets. There is a well-described Eurocentric bias in genetic and functional genomic research that has a clear impact on the benefit this research can bring to underrepresented populations. Current research focused on genetic variant-to-function experiments aims to identify molecular QTLs, but the lack of data from genetically diverse individuals has limited analyses to mostly populations of European ancestry. Although some efforts have been established to increase diversity in functional genomic studies, much remains to be done to consistently generate data for underrepresented populations from now on. We discuss the major barriers for this continuity and suggest actionable insights, aiming to empower research and researchers from underserved populations.


Amusia and protolanguage impairments in schizophrenia.
Both language and music are thought to have evolved from a musical protolanguage that communicated social information, including emotion. Individuals with perceptual music disorders (amusia) show deficits in auditory emotion recognition (AER). Although auditory perceptual deficits have been studied in schizophrenia, their relationship with musical/protolinguistic competence has not previously been assessed. Musical ability was assessed in 31 schizophrenia/schizo-affective patients and 44 healthy controls using the Montreal Battery for Evaluation of Amusia (MBEA). AER was assessed using a novel battery in which actors provided portrayals of five separate emotions. The Disorganization factor of the Positive and Negative Syndrome Scale (PANSS) was used as a proxy for language/thought disorder and the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognition. Highly significant deficits were seen between patients and controls across auditory tasks (p < 0.001). Moreover, significant differences were seen in AER between the amusia and intact music-perceiving groups, which remained significant after controlling for group status and education. Correlations with AER were specific to the melody domain, and correlations between protolanguage (melody domain) and language were independent of overall cognition. This is the first study to document a specific relationship between amusia, AER and thought disorder, suggesting a shared linguistic/protolinguistic impairment. Once amusia was considered, other cognitive factors were no longer significant predictors of AER, suggesting that musical ability in general and melodic discrimination ability in particular may be crucial targets for treatment development and cognitive remediation in schizophrenia.


Choice and value flexibility jointly contribute to the capacity of a subsampled quadratic classifier
Biophysical modeling studies have suggested that neurons with active dendrites can be viewed as linear units augmented by product terms that arise from interactions between synaptic inputs within the same dendritic subregions. However, the degree to which local nonlinear synaptic interactions could augment the memory capacity of a neuron is not known in a quantitative sense. To approach this question, we have studied the family of subsampled quadratic classifiers: linear classifiers augmented by the best k terms from the set of K = (d2 + d)/2 second-order product terms available in d dimensions. We developed an expression for the total parameter entropy, whose form shows that the capacity of an SQ classifier does not reside solely in its conventional weight values-the explicit memory used to store constant, linear, and higher-order coefficients. Rather, we identify a second type of parameter flexibility that jointly contributes to an SQ classifier's capacity: the choice as to which product terms are included in the model and which are not. We validate the form of the entropy expression using empirical studies of relative capacity within families of geometrically isomorphic SQ classifiers. Our results have direct implications for neurobiological (and other hardware) learning systems, where in the limit of high-dimensional input spaces and low-resolution synaptic weight values, this relatively little explored form of choice flexibility could constitute a major source of trainable model capacity.


Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa.
Cyclooxygenase enzymes (COX-1 and COX-2) catalyse the production of prostaglandins from arachidonic acid. Prostaglandins are important mediators in the inflammatory process and their production can be reduced by COX-inhibitors. Endocannabinoids, endogenous analogues of the plant derived cannabinoids, occur normally in the human body. The Endocannabinoids are structurally similar to arachidonic acid and have been suggested to interfere with the inflammatory process. They have also been shown to inhibit cancer cell proliferation. Anti-inflammatory effects of cannabinoids and endocannabinoids have been observed, however the mode of action is not yet clarified. Anti-inflammatory activity (i.e., inhibition of COX-2) is proposed to play an important role in the development of colon cancer, which makes this subject interesting to study further. In the present work, the six cannabinoids tetrahydrocannabinol (Δ⁹-THC), tetrahydrocannabinolic acid (Δ⁹-THC-A), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG) and cannabigerolic acid (CBGA), isolated from Cannabis sativa, were evaluated for their effects on prostaglandin production. For this purpose an in vitro enzyme based COX-1/COX-2 inhibition assay and a cell based prostaglandin production radioimmunoassay were used. Cannabinoids inhibited cyclooxygenase enzyme activity with IC₅₀ values ranging from 1.7·10⁻³ to 2.0·10⁻⁴ M.


Transformational and transactional leadership skills for mental health teams.
Many treatments for persons with severe mental illness are provided by mental health teams. Team members work better when led by effective leaders. Research conducted by organizational psychologists, and validated on mental health teams, have identified a variety of skills that are useful for these leaders. Bass (1990, 1997) identified two sets of especially important skills related to transformational and transactional leadership. Leaders using transformational skills help team members to view their work from more elevated perspectives and develop innovative ways to deal with work-related problems. Skills related to transformational leadership promote inspiration, intellectual stimulation, individual consideration, participative decision making, and elective delegation. Mental health and rehabilitation teams must not only develop creative and innovative programs, they must maintain them over time as a series of leader-team member transactions. Transactional leadership skills include goal-setting, feedback, and reinforcement strategies which help team members maintain effective programs.


Immune Modulation in Lung Cancer: Current Concepts and Future Strategies.
Cancer immunotherapy represents the most dynamic field of biomedical research currently, with thoracic immuno-oncology as a forerunner. PD-(L)1 inhibitors are already part of standard first-line treatment for both non-small-cell and small-cell lung cancer, while unprecedented 5-year survival rates of 15-25% have been achieved in pretreated patients with metastatic disease. Evolving strategies are mainly aiming for improvement of T-cell function, increase of immune activation in the tumor microenvironment (TME), and supply of tumor-reactive lymphocytes. Several novel therapeutics have demonstrated preclinical efficacy and are increasingly used in rational combinations within clinical trials. Two overarching trends dominate: extension of immunotherapy to earlier disease stages, mainly as neoadjuvant treatment, and a shift of focus towards multivalent, individualized, mutatome-based antigen-specific modalities, mainly adoptive cell therapies and cancer vaccines. The former ensures ample availability of treated and untreated patient samples, the latter facilitates deeper mechanistic insights, and both in combination build an overwhelming force that is accelerating progress and driving the greatest revolution cancer medicine has seen so far. Today, immune modulation represents the most potent therapeutic modality in oncology, the most important topic in clinical and translational cancer research, and arguably our greatest, meanwhile justified hope for achieving cure of pulmonary neoplasms and other malignancies in the next future.


"Not Taking it Will Just be Like a Sin": Young People Living with HIV and the Stigmatization of Less-Than-Perfect Adherence to Antiretroviral Therapy.
Global health priorities are being set to address questions on adherence to HIV antiretroviral therapy in adolescence. Few studies have explored young people's perspectives on the complex host of social and relational challenges they face in dealing with their treatment in secret and their condition in silence. In redressing this, we present findings from a longitudinal qualitative study with young people living with HIV in the UK, Ireland, US, and Uganda, embedded within the BREATHER international clinical trial. Drawing from Goffman's notion of stigma, we analyze relational dynamics in HIV clinics, as rare spaces where HIV is "known," and how young people's relationships may be threatened by non-adherence to treatment. Young people's reflections on and strategies for maintaining their reputation as patients raise questions about particular forms of medicalization of HIV and the moralization of treatment adherence that affect them, and how these may restrict opportunities for care across the epidemic.


Aerobic capacity in persons with multiple sclerosis: a systematic review and meta-analysis.
Aerobic capacity (VO2max) is a strong health and performance predictor and is regarded as a key physiological measure in the healthy population and in persons with multiple sclerosis (PwMS). However, no studies have tried to synthesize the existing knowledge regarding VO2max in PwMS. The objectives of this study were to (1) systematically review the psychometric properties of the VO2max test; (2) systematically review the literature on VO2max compared with healthy populations; (3) summarize correlates of VO2max; and (4) to review and conduct a meta-analysis of longitudinal exercise studies evaluating training-induced effects on VO2max in PwMS. A systematic literature search of six databases (PubMed, EMBASE, Cochrane Library, PEDro, CINAHL and SPORTDiscus) was performed. To be included, the study had to (1) enrol participants with definite MS according to defined criteria; (2) assess aerobic capacity (VO2max) by means of a graded exercise test to voluntary exhaustion; (3) had undergone peer review; and (4) be available in English, Danish or Dutch. The psychometric properties of the VO2max test in PwMS were reviewed with respect to reliability, validity and responsiveness. Simple Pearson correlation analysis was used to assess the relation between key study characteristics and the reported mean VO2max. The methodological quality of the intervention studies was evaluated using the original 11-item Physiotherapy Evidence Database (PEDro) scale. A random coefficient model was used to summarize individual, weighted, standardized effects of studies that assessed the effects of exercise on aerobic capacity in PwMS. A total of 40 studies, covering 165 healthy controls and 1,137 PwMS, fulfilled the inclusion criteria. VO2max testing in PwMS can be considered a valid measure of aerobic capacity, at least in PwMS having low-to-mild disability, and an ∼10% change between two tests performed on separate days can be considered the smallest reliable change (with 95% certainty) in VO2max in PwMS. The average body-weight-adjusted VO2max was significantly lower in PwMS (25.5 ± 5.2 mL·kg(-1)·min(-1)) compared with healthy controls (30.9 ± 5.4 mL·kg(-1)·min(-1)). The analysis of VO2max correlates revealed associations with a variety of outcomes covering all levels of the International Classification of Functioning, Disability and Health (ICF) model. The meta-analysis showed that aerobic training in PwMS may improve VO2max by as much as 3.5 mL·kg(-1)·min(-1). A valid and reliable test can be performed, in at least ambulant PwMS, by the gold standard whole-body maximal exercise test. Aerobic capacity in PwMS is impaired compared with healthy people, and is significantly associated with factors on all levels of the ICF model, including disease severity. Aerobic training can improve aerobic capacity in PwMS to a degree that is associated with secondary health benefits.


Transcatheter Vacuum-Assisted Mass Extraction Versus Surgical Debridement for Vegetations in Tricuspid Valve Infective Endocarditis: A Meta-Analysis of Observational Studies.
Tricuspid valve infective endocarditis (TVIE), often associated with vegetation in people who inject drugs, has introduced a less invasive option for vegetation removal: transcatheter vacuum-assisted mass extraction (TVME). This technique is emerging as an alternative to standard surgical debridement (SD) and valve repair. However, the comparative effectiveness of TVME versus SD in treating TVIE has yet to be investigated. A comprehensive systematic literature search was performed on PubMed, Embase, and Cochrane to identify all relevant studies comparing TVME with SD in patients with TVIE. The search covered studies from inception up to August 15, 2023. For data analysis, Review Manager (RevMan) 5.4 software was employed, using a random-effects model to calculate risk ratios (RRs), mean differences, and 95% confidence intervals (CIs). Five studies included a total of 431 patients (244 in the TVME arm and 187 in the SD arm). In-hospital mortality (p = 0.72), procedural mortality (p = 0.77), 30-day mortality (p = 0.25), and 1-year mortality (p = 0.44) insignificantly favored SD over TVME. Overall mortality across the 5 studies insignificantly favored TVME over SD (RR = 0.66, 95% CI 0.31 to 1.39, p = 0.27, I2 = 57%). When addressing heterogeneity by excluding 1 study, no statistical significance in the difference between the 2 arms regarding overall mortality was observed (RR 0.99, 95% CI 0.60 to 1.63, p = 0.97, I2 = 0%). This meta-analysis of the 5 observational studies found no significant difference in overall mortality between TVME and SD for the treatment of TVIE. However, prospective randomized controlled trials are necessary to further understand and compare the outcomes of these 2 approaches.


Synergistic Activity of Berberine with Azithromycin against Pseudomonas Aeruginosa Isolated from Patients with Cystic Fibrosis of Lung In Vitro and In Vivo.
Pseudomonas aeruginosa (PA) is one of the major opportunistic pathogens which can cause chronic lung infection of cystic fibrosis (CF). The formation of PA biofilm promotes CF development and restricts the antimicrobial efficacies of current antibiotics. The antimicrobial effects of azithromycin (AZM) and berberine (BER) alone and in combination were evaluated using microdilution method, checkerboard assay, time-kill test, qRT-PCR analysis and absorption method. The treatments of AZM and/or BER were further evaluated in an animal lung infection model via observing survival rate, bacterial burden and histopathology of lung, the levels of pro-/anti-inflammatory cytokines. AZM-BER were demonstrated to be synergistic against ten clinical PA isolates as well as the standard reference PA ATCC27853, in which PA03 was the most susceptible isolate to AZM-BER with FICI of 0.13 and chosen for subsequent experiments. The synergism of AZM-BER was further confirmed against PA03 in time-kill test and scanning electron microscope (SEM) at their concentrations showing synergism. In PA03, we found that AZM-BER could significantly attenuate productions of a series of virulence factors including alginate, LasA protease, LasB protease, pyoverdin, pyocyanin, chitinase as well as extracellular DNA, and remarkably inhibit the levels of quorum sensing (QS) molecules and the expressions of lasI, lasR, rhlI, rhlR at 1/2×MIC, 1×MIC and 2×MIC. In the infection model, the mice survival were increased markedly, the inflammations of infected lungs were improved greatly along with reduced IL-6, IL-8 and ascended IL-10 at 0.8 mg/kg of AZM combined with 3.2 mg/kg of BER. BER might be a promising synergist to enhance the antimicrobial activity of AZM in vitro and in vivo.


The Role of Excipients in the Stability of Triamcinolone Acetonide in Ointments.
Degradation of triamcinolone acetonide (TCA) in an ointment was investigated. TCA appeared to be concentrated in propylene glycol (PG) which in turn is dispersed in a lanolin-petrolatum mixture. Two predominant degradation products were identified: a 21-aldehyde and a 17-carboxylic acid. The 21-aldehyde is formed after TCA is oxidized by O2, a reaction that is catalyzed by trace metals. Logically, the content of trace metals has a profound effect on the degradation rate. It was shown that trace metals are extracted from lanolin and petrolatum by PG, increasing the concentration in PG. In accordance with these findings, TCA degrades faster in PG that is present in the ointment formulation than in regular PG. The 21-aldehyde was confirmed to be a primary degradation product, while the 17-carboxylic acid was identified as a secondary degradation product. Based on the mechanism of degradation, the ointment can be stabilized by the addition of sodium metabisulfite which was shown to reside also in the PG phase within the ointment.


[Evaluation of prostate cancer progression].
Prostate cancer occures in male, especially over 65 year old. It develops usually in the peripheral zone, less commonly in central or transitional ones. The neoplasm screening bases on clinical digital rectal examination and serum level of prostate-specific antigen (PSA). Among patients with increase PSA concentration, transrectal ultrasound usually with multiple core biopsies is performed. The obtained bioptates are histologically evaluated using Gleason's grading system. However, the method of choice to examine the entire pelvis is a magnetic resonance. According to current principles, the obtained images are evaluated using five-step PI-RADS classification based on T2-weithed, diffusion weighted and dynamic contrast enhancement images. Spectroscopy is also suggested especially in case of prostatic carcinoma. Such procedures allow precise evaluation of cancer progression, and is helpful in treatment planning and response monitoring.


Antimicrobial-induced endotoxaemia in patients with sepsis in the field of acute pyelonephritis.
In vitro results have shown that antimicrobial agents may induce the Gram-negative bacteria to release endotoxins (LPS), which in turn, could trigger the secretion of cytokines from monocytes. To compare the effect of cefuroxime, netilmicin or ciprofloxacin on serum levels of LPS and tumour necrosis factor-alpha (TNFalpha). Seventy-four patients with acute pyelonephritis caused by Gram-negative bacteria and signs of sepsis were randomly assigned to receive one of three intravenous regimens of cefuroxime, netilmicin or ciprofloxacin. Blood samples were collected before therapy and at specified time intervals for 96 hours after the initiation of treatment for the determination of serum levels of LPS and of TNFalpha. Patients treated with cefuroxime presented an early peak of LPS and of TNFalpha in serum two hours after the initiation of treatment compared to the other study groups. After that time interval, concentrations of LPS and TNFalpha were similar in all the study groups. Fever accompanied by endotoxaemia was still detected for 48 hours after the start of therapy in 36, 37.5 and 36% of patients treated with cefuroxime, netilmicin and ciprofloxacin respectively. The corresponding figures for these agents at 72 hours were 28, 12.5 and 24%, respective and 12, 4.2 and 4% at 96 hours (P value not significant). With the exception of an early peak in the serum levels of LPS and TNFalpha in patients treated with cefuroxime, no significant difference could be detected amongst the study groups as far as their effect on serum levels of LPS and TNFalpha were concerned. This suggests that these three antimicrobial agents may be administered safely at the early stages of sepsis.


PAUPAR and PAX6 sequentially regulate human embryonic stem cell cortical differentiation.
Long noncoding RNAs (lncRNAs) play a wide range of roles in the epigenetic regulation of crucial biological processes, but the functions of lncRNAs in cortical development are poorly understood. Using human embryonic stem cell (hESC)-based 2D neural differentiation approach and 3D cerebral organoid system, we identified that the lncRNA PAUPAR, which is adjacent to PAX6, plays essential roles in cortical differentiation by interacting with PAX6 to regulate the expression of a large number of neural genes. Mechanistic studies showed that PAUPAR confers PAX6 proper binding sites on the target neural genes by directly binding the genomic regions of these genes. Moreover, PAX6 recruits the histone methyltransferase NSD1 through its C-terminal PST enrichment domain, then regulate H3K36 methylation and the expression of target genes. Collectively, our data reveal that the PAUPAR/PAX6/NSD1 complex plays a critical role in the epigenetic regulation of hESC cortical differentiation and highlight the importance of PAUPAR as an intrinsic regulator of cortical differentiation.


EBV-associated mucocutaneous ulcer, a rare cause of a frequent problem.
This report presents a 74-year-old renal transplant patient suffering of polymorphic-post-transplant-associated lymphoproliferative disease (P-PTLD) within an Eppstein-Barr Virus (EBV) associated mucocutaneous rectal ulcer (MCU). He was initially treated by stapled hemorrhoidopexy for a symptomatic grade III hemorrhoidal prolapse refractory to conservative treatment and rubber band ligations. This leads to severe urge, frequency and stool fragmentation. The symptoms were investigated with a number of interventions until a proctoscopy with biopsies finally revealed the diagnosis. The patient had triple therapy of tacrolimus, mycophenolate mofetil and prednisone initially after transplant several years ago with recent reduction to mycophenolate. The MCU was successfully treated with Retuximab and there was no sign of relaps after 6 months. As EBV-associated PTLD is a well known complication after renal transplant, rectum-MCU seems a rare and only recently described subform of this disease that should be excluded in case of ulcerating lesions in immunosuppressed patients.


[Usefulness of percutaneous endoscopic gastrostomy (PEG) in home health care--investigation from the viewpoint of cost effectiveness].
The use of percutaneous endoscopic gastrostomy (PEG) has widely spread in recent years, even in Japan. In our hospital, we have performed this procedure in over 20 patients per year recently. In this study, we investigated the usefulness of PEG in home health care from the view point of cost effectiveness. We found that medical expenses decreased remarkably when patients underwent PEG because they could switch from hospital care to home health care, shortening there by the period of hospital care. The role of PEG in home health care will be more important also from cost effectiveness.


Prevalence and risk factors for long COVID and post-COVID-19 condition in Africa: a systematic review.
An improved estimation of the clinical sequelae of SARS-CoV-2 infection is crucial in African countries, where the subject has received little attention despite more than 12 million reported cases and evidence that many more people were infected. We reviewed the evidence on prevalence, associated risk factors for long COVID, and systemic or sociocultural determinants of reporting long COVID. We conducted a systematic review, searching PubMed, the Living OVerview of Evidence platform, and grey literature sources for publications from Dec 1, 2019, to Nov 23, 2022. We included articles published in English, French, Spanish, or Portuguese that reported on any study type in Africa with participants of any age who had symptoms for 4 weeks or more after an acute SARS-CoV-2 infection. We excluded secondary research, comments, and correspondence. Screening and data extraction were performed by two reviewers. Summary estimates were extracted, including sociodemographic factors, medical history, prevalence of persistent symptoms, and symptoms and associated factors. Results were analysed descriptively. The study was registered on the Open Science Framework platform. Our search yielded 294 articles, of which 24 peer-reviewed manuscripts were included, reporting on 9712 patients from eight African countries. Only one study exclusively recruited children, and one other study included children as part of their study population. Studies indicated moderate to low risk of bias. Prevalence of long COVID varied widely, from 2% in Ghana to 86% in Egypt. Long COVID was positively associated with female sex, older age, non-Black ethnicity, low level of education, and the severity of acute infection and underlying comorbidity. HIV and tuberculosis were not identified as risk factors. Factors influencing reporting included absence of awareness, inadequate clinical data and diagnostics, and little access to health-care services. In Africa, research on long COVID is scarce, particularly among children, who represent the majority of the population. However, existing studies show a substantial prevalence across settings, emphasising the importance of vaccination and other prevention strategies to avert the effects of long COVID on individual wellbeing, the increased strain on health systems, and the potential negative effects on economically vulnerable populations. At a global level, including African countries, tools for research on long COVID need to be harmonised to maximise the usefulness of the data collected. None.


Dynamical consequences of orthohydrogen-parahydrogen disequilibrium on jupiter and saturn.
The Voyager observation of high zonal flow speeds (about 400 meters per second) in the atmosphere of Saturn has raised fundamental questions about the flow on both Jupiter and Saturn. One possibility is that the flow is extremely deep, perhaps extending through the planet. Another is that the flow is confined near the cloud tops and is associated with very strong buoyancy contrasts. It is demonstrated that the heat of conversion from parahydrogen to orthohydrogen can provide buoyancy contrasts of the required magnitude, and a feedback mechanism is proposed to couple the heat of conversion to the flow dynamics.


Dietary patterns and 15-y risks of major coronary events, diabetes, and mortality.
Few studies have examined the long-term effect of habitual diet on risks of incident diabetes, coronary heart disease, and mortality. We analyzed the prospective relation of dietary patterns with incident chronic disease and mortality during 15 y of follow-up in the Whitehall II study. We conducted a prospective analysis (106,633 person-years at risk) among men and women (n = 7731) with a mean age of 50 y at the time of dietary assessment (127-item food-frequency questionnaire). Coronary death or nonfatal myocardial infarction and incident diabetes were verified by record tracing and oral-glucose-tolerance tests. Cluster analysis identified 4 dietary patterns at baseline. The patterns were termed unhealthy (white bread, processed meat, fries, and full-cream milk; n = 2665), sweet (white bread, biscuits, cakes, processed meat, and high-fat dairy products; n = 1042), Mediterranean-like (fruit, vegetables, rice, pasta, and wine; n = 1361), and healthy (fruit, vegetables, whole-meal bread, low-fat dairy, and little alcohol; n = 2663). Compared with the unhealthy pattern, the healthy pattern reduced the risk of coronary death or nonfatal myocardial infarction and diabetes; hazard ratios (95% CI) were 0.71 (0.51, 0.98) and 0.74 (0.58, 0.94), respectively, after adjustment for age, sex, ethnicity, dietary energy misreporting, social position, smoking status, and leisure-time physical activity. Dietary pattern was not associated with all-cause mortality. Residual confounding by socioeconomic factors was unlikely to account for the observed dietary effects. The healthy eating pattern reduced risks of diabetes and major coronary events. Such dietary patterns offer considerable health benefits to individuals and contribute to public health.


Use of an Ultrasonic Aspirator in Removal of an Orbital Rim Hemangioma.
Intraosseous hemangiomas are rare bony neoplasms that infrequently develop in the calvarium or facial bones. Due to their highly vascular nature, biopsy or resection of these tumors can present a surgical challenge, with reports of significant blood loss during tumor resection. Traditional surgical resection of intraosseous hemangiomas often includes the use of high speed oscillating or sagittal saws. Ultrasonic aspirators, which spare adjacent soft-tissue structures and minimize blood loss, have been successfully used in resection of firm soft tissue masses of the orbit; however, this technology has not been demonstrated in the treatment of a vascular tumor in the orbit. The authors present the case of a 37-year-old woman who presented with an intraosseous hemangioma at the left inferior orbital rim and maxilla; the mass was successfully resected with the aid of a Sonopet Ultrasonic Aspirator bone knife. The knife allowed for simultaneous emulsification and cautery of the bone encasing the mass with low risk to sensitive surrounding tissue.


Impact of levothyroxine therapy for maternal subclinical and overt hypothyroidism on early child neurodevelopment: A prospective cohort study.
Treatment indication of maternal subclinical hypothyroidism (SCH) is undetermined, despite the wide administration of levothyroxine for maternal overt hypothyroidism (OH). This study aimed to evaluate the therapeutic effect of levothyroxine for maternal SCH and OH in real-world practice, with a focus on early child neurodevelopment. Prospective cohort study. Pregnant women diagnosed with SCH at the first antenatal visit were enroled and compared to those diagnosed with OH. Thyroid follow-ups were conducted during pregnancy. Early child neurodevelopment was assessed using the Gesell Development Diagnosis Scale (GDDS) at 1, 3, 6, 12 and 24 months of age. From January 2012 to December 2013, a total of 442 pregnant women were included in final analysis, among whom 194 and 248 were assigned to the SCH and OH groups, respectively. The percentage of levothyroxine therapy at the first antenatal visit was significantly lower in the SCH group than that in the OH group (91.24% vs. 97.58%, p < .01), with a similar treatment rate at delivery (99.4% vs. 100%, p > .05). Notably, GDDS scores were lower in the SCH group than those in the OH group at 6 months to 2 years of age, which was confirmed by subgroup analyses and sensitivity analyses. Children born with maternal SCH demonstrated slightly lower neuropsychological scores at 6 months to 2 years of age compared to those with maternal OH in the clinical practice. The therapeutic effect of maternal SCH on the child neurodevelopment requires further exploration.


Cytokeratin No. 9, an epidermal type I keratin characteristic of a special program of keratinocyte differentiation displaying body site specificity.
Plantar epidermis of the bovine heel pad as well as human plantar and palmar epidermis contain large amounts of an acidic (type I) keratin polypeptide (No. 9) of Mr 64,000 which so far has not been found in epidermis of other sites of the body. We present evidence for the keratinous nature of this protein, including its ability to form cytokeratin complexes and intermediate-sized filaments in vitro. We have isolated RNA from plantar epidermis of both species and show, using translation in vitro, that these polypeptides are genuine products of distinct mRNAs. Using immunofluorescence microscopy with specific antibodies against this protein, we demonstrate its location in most cells of suprabasal layers of plantar epidermis as well as in sparse keratinocytes which occur, individually or in small clusters, in upper layers of epidermis of other body locations. We conclude that cytokeratin No. 9 is characteristic of a special program of keratinocyte differentiation which during morphogenesis is expressed in most epidermal keratinocytes of soles and palms but only in a few keratinocytes at other body sites. This example of cell type-specific expression of a member of a multigene family in relation to a body site-related program of tissue differentiation raises important biological questions concerning the regulation of keratinocyte differentiation and morphogenesis as well as the function of such topological heterogeneity within a given type of tissue.


Exploring the ethnic diversity of UK dentistry.
This article was migrated. The article was marked as recommended. It is widely acknowledged that there are many social benefits to having a multicultural health force, including ensuring that there is less of a barrier around access for underrepresented groups. Despite this, certain healthcare professions, including dentistry, have struggled with the historical legacy of being conceptualised as a "white" profession and whether it is ethnically representative of the public it serves. This article examines the role and place of ethnicity in the dental profession in the UK. It will describe the changing ethnic composition of UK dentistry and highlight some of the challenges faced by the profession from an equality and diversity perspective. The current qualitative work of the author exploring the barriers and facilitators faced by students from an ethnic background pursuing a career in dentistry will also be introduced. It concludes by encouraging more research on this topic.


Interleukin-4 regulates proteoglycan-induced arthritis by specifically suppressing the innate immune response.
Interleukin-4 (IL-4) is an antiinflammatory cytokine that inhibits the onset and severity of proteoglycan-induced arthritis (PGIA). To distinguish the role of IL-4 in the innate immune response versus the adaptive immune response, we generated mice with a specific deletion of the IL-4 receptor alpha-chain (IL-4Ralpha) in macrophages and neutrophils. To obtain mice in which IL-4Ralpha is deleted in macrophages and neutrophils, we intercrossed mice carrying a loxP-flanked (floxed) IL-4Ralpha allele and Cre recombinase expressed under control of the regulatory region for the lysozyme M gene (LysM(cre) mice) with conditional IL-4Ralpha(flox/flox) mice and then mated them to complete IL-4Ralpha(-/-) mice to obtain hemizygous LysM(cre)IL-4Ralpha(flox/-) mice. LysM(cre)-negative IL-4Ralpha(flox/-) mice (IL-4Ralpha(flox/-) mice) were used as control mice. PGIA was induced by immunization with human PG in adjuvant. The onset, incidence, and severity of arthritis were monitored over time. Levels of proinflammatory cytokines were measured in the sera of PG-immunized mice, and cytokine and chemokine transcripts were measured in joints. The severity of PGIA was exacerbated in IL-4Ralpha(-/-) and LysM(cre)IL-4Ralpha(flox/-) mice in comparison with control (IL-4Ralpha(flox/-)) mice. The increase in arthritis susceptibility in IL-4Ralpha(-/-) and LysM(cre)IL-4Ralpha(flox/-) mice correlated with elevated serum levels of the proinflammatory cytokines IL-1beta and IL-6 and with elevated cytokine (IL-1beta and IL-6) and chemokine (macrophage inflammatory protein 1alpha [MIP-1alpha] and MIP-2) transcripts from joints. However, arthritis susceptibility did not correlate with IL-2 or interferon-gamma (IFNgamma) concentrations or with PG-specific antibody IgG2a isotype, since levels of IL-2, IFNgamma, or PG-specific antibody IgG2a isotype in control (IL-4Ralpha(flox/-)) and LysM(cre)IL-4Ralpha(flox/-) mice were reduced in comparison with those in IL-4Ralpha(-/-) mice. These findings indicate that IL-4 functions as a major antiinflammatory cytokine in PGIA by governing the activity of macrophages/neutrophils and less so by controlling T cell activity and autoantibody isotype expression.


[Electroshock therapy in clinical practice].
Electroconvulsive therapy (ECT) has been recognized as an effective treatment for depressive disorders, with a reasonably low risk/benefit ratio. It is still disputed, however, and considered with suspicion by the public and by some nursing teams as well. Probably the feeling that the parameters used are not well controlled is responsible for this attitude. This paper presents a review of data allowing to optimize ECT. Currently, the best method seems to be the use of brief pulse stimuli applied in volleys, bilaterally.


Oxygen harvesting from carbon dioxide: simultaneous epoxidation and CO formation.
Due to increasing concentrations in the atmosphere, carbon dioxide has, in recent times, been targeted for utilisation (Carbon Capture Utilisation and Storage, CCUS). In particular, the production of CO from CO2 has been an area of intense interest, particularly since the CO can be utilized in Fischer-Tropsch synthesis. Herein we report that CO2 can also be used as a source of atomic oxygen that is efficiently harvested and used as a waste-free terminal oxidant for the oxidation of alkenes to epoxides. Simultaneously, the process yields CO. Utilization of the atomic oxygen does not only generate a valuable product, but also prevents the recombination of O and CO, thus increasing the yield of CO for possible application in the synthesis of higher-order hydrocarbons.


Emergence of vanA Enterococcus faecium in Denmark, 2005-15.
To describe the changing epidemiology of vancomycin-resistant Enterococcus faecium and Enterococcus faecalis in clinical samples in Denmark 2005-15 according to species and van type, and, furthermore, to investigate the genetic relatedness of the clinical E. faecium isolates from 2015. During 2005-14, all clinical VRE isolates were tested for the presence of vanA/B/C genes by PCR. In 2015, all clinical VRE isolates were whole-genome sequenced. From the WGS data, the presence of van genes and MLST STs were extracted in silico . Core-genome MLST (cgMLST) analysis was performed for the vancomycin-resistant E. faecium isolates. During 2005-15, 1043 vanA E. faecium , 25 vanB E. faecium , 4 vanA E. faecalis and 28 vanB E. faecalis were detected. The number of VRE was <50 isolates/year until 2012 to > 200 isolates/year in 2013-15. In 2015, 368 vanA E. faecium and 1 vanB E. faecium were detected along with 1 vanA E. faecalis and 1 vanB E. faecalis . cgMLST subdivided the 368 vanA E. faecium isolates into 33 cluster types (CTs), whereas the vanB E. faecium isolate belonged to a different CT. ST203-CT859 was most prevalent (51%), followed by ST80-CT14 (22%), ST117-CT24 (6%), ST80-CT866 (4%) and ST80-CT860 (2%). Comparison with the cgMLST.org database, previous studies and personal communications with neighbouring countries revealed that the novel cluster ST203-CT859 emerged in December 2014 and spread to the south of Sweden and the Faroe Islands during 2015. VRE increased in Denmark during 2005-15 due to the emergence of several vanA E. faecium clones.


Prevention of neonatal late-onset sepsis: a randomised controlled trial.
Late-onset sepsis (LOS), defined as sepsis occurring after 48 h of age causes substantial mortality and morbidity in very low birth weight infants. Risk factors for LOS include immaturity, intravascular catheters, mechanical ventilation, and prolonged parenteral nutrition (PN). Little attention has been paid to studying the effects of PN administration methods. The aim of the study was to compare a bundle of measures for PN line management incorporating a strict aseptic technique with standard line management on LOS in very low birth weight infants. Infants <1500 g birth weight who required PN were randomised to either a bundle of a strict aseptic technique for line management together with single use intravascular catheter for PN or a standard technique. The primary outcome was the incidence of LOS in the first 28 days of life. Secondary outcomes were mortality, neonatal morbidities and developmental outcome at 12 months of age. There were 126 infants in the aseptic technique group and 123 in the standard technique group. Forty (31.8%) infants in the aseptic technique group and 36 (29.3%) in the standard technique group had an episode of sepsis (p = 0.77). This corresponds to incidences of 15.8 and 14.2 episodes of sepsis per 1000 patient days respectively. Subgroup analyses for infants <1000 g also revealed no difference in the rate of sepsis between the intervention and control groups. (p = 0.43). There were no significant differences in secondary outcomes and development between the groups. A bundle of measures including strict aseptic technique for parenteral nutrition line management did not result in a reduction in LOS when compared to a standard technique. There is no evidence to recommend this as routine practice. Interdisciplinary Maternal Perinatal Australasian Collaborative Trials (IMPACT) Network, TRN registration number: PT0363. Date: 06/03/2001; Australian New Zealand Clinical Trials Registry (ANZCTR), TRN registration number: ACTRN12617000455369 . Date: 28/03/2017 (retrospectively registered).


Hantaan virus: identification of virion proteins.
SDS-PAGE and immunoprecipitation analyses were carried out on the virion and cell-associated proteins of Hantaan virus, the causative agent of haemorrhagic fever with renal syndrome (HFRS). Purified virions have a density of 1.17 g/ml in sucrose, and contain four proteins with molecular weights of 45 000 (45K), 56K, 72K and 200K, confirming recent evidence that the virus is a member of the family Bunyaviridae. Detergent treatment of virions indicates that the 45K protein is the virus nucleoprotein. Both the 72K and the 56K proteins were labelled with [3H]glucosamine and were removed from virions by bromelain treatment, indicating that they are envelope glycoproteins. The 200K protein was found only in [35S]methionine-labelled preparations. By analogy to prototype viruses of the family Bunyaviridae, these proteins were designated N, G1, G2, and L respectively. Three virus-specific proteins (N, G1, G2) were detected in virus-infected cells. These proteins were precipitable by human convalescent serum and by serum of a Rattus norvegicus trapped in the United States. No additional virus proteins were detected in infected cells. These results confirm recent morphological and RNA studies that Hantaan virus is a member of the family Bunyaviridae. Our results also support the suggestion that Hantaan virus be placed in a new genus of Bunyaviridae.


Detachment of giant liposomes - coupling of receptor mobility and membrane shape.
Cellular adhesion is an intricate physical process controlled by ligand-receptor affinity, density, mobility, and external forces transmitted through the elastic properties of the cell. As a model for cellular adhesion we study the detachment of cell-sized liposomes and membrane-coated silica beads from supported bilayers using atomic force microscopy. Adhesion between the two surfaces is mediated by the interaction between the adhesive lipid anchored saccharides lactosylceramide and the ganglioside GM3. We found that force-distance curves of liposome detachment have a very peculiar, partially concave shape, reminiscent of the nonlinear extension of polymers. By contrast, detachment of membrane coated beads led to force-distance curves similar to the detachment of living cells. Theoretical modelling of the enforced detachment suggests that the non-convex force curve shape arises from the mobility of ligands provoking a switch of shapes from spherical to unduloidal during detachment.


Epithelial transcytosis of monomeric IgA and IgG cross-linked through antigen to polymeric IgA. A role for monomeric antibodies in the mucosal immune system.
We recently demonstrated that the polymeric IgR (pIgR) mediates epithelial transcytosis of immune complexes (IC) containing dimeric IgA (dIgA). In vivo, this "excretory" pathway could allow direct elimination of IgA IC at the mucosal sites where they are likely to form. In contrast, IC containing only monomeric IgA (mIgA) were not transported, consistent with the specificity of pIgR for polymeric IgA. However, the potential exists in vivo that monomeric Ig like mIgA or IgG could become associated through binding to multivalent Ag with IC containing dIgA, and that such mixed IC could act as ligands for pIgR. In the present work, using Madin-Darby canine kidney epithelial cells that express pIgR, we showed that 125I-labeled anti-DNP mIgA or IgG in the same IC with unlabeled dIgA antibody and DNP-BSA Ag was vectorially transported from the basolateral to the apical surface and then released. However, 125I-mIgA IC or 125I-IgG IC (without dIgA) and 125I-mIgA or 125I-IgG in the presence of dIgA antibody (but without Ag) were not transported, demonstrating the necessity for monomeric Ig to be in an IC with dIgA to be transported. Transcytosis of mixed mIgA/dIgA or IgG/dIgA IC was mediated by pIgR because no transport was observed in untransfected, wild-type Madin-Darby canine kidney cells lacking pIgR. The data demonstrate that mIgA and IgG can participate along with dIgA in the "excretory" pathway for local elimination of IgA IC, thus providing a means by which monomeric antibodies have the potential to participate in the mucosal immune system.


Survival strategies for community nursing centers.
The development of innovations in any area presents a myriad of challenges. The establishment of a community nursing center in a competitive health care market place is not a role for the faint of heart or those with limited motivation or energy to devote to such an endeavor. Even so, many nurses are committed to the goal of establishing CNCs as demonstration sites for experimentation with alternative structures of health care delivery in spite of the challenges and the odds. Until reimbursement mechanisms are modified to allow nurses practicing in CNCs to generate client/service-based revenue, reliance on alternative sources of funding will continue. Several strategies have been presented here that have been identified as useful in the acquisition of financial resources for the support of a community nursing center. The strategies include: focusing on community need rather than the model of delivery when approaching potential donors; securing funds from multiple sources; centralizing the funding strategy and the preparation of grant applications; and adopting a policy of patience and persistence in seeking extramural funding. It is my hope that these strategies will assist those of you engaged in the struggle to develop community nursing centers to significantly improve the level of financial security in your center.


Occupational exposure to the risk of HIV infection among health care workers in Mwanza Region, United Republic of Tanzania.
During 1993, we collected data on knowledge of human immunodeficiency virus (HIV) transmission, availability of equipment, protective practices and the occurrence of prick and splash incidents in nine hospitals in the Mwanza Region in the north-west of the United Republic of Tanzania. Such incidents were common, with the average health worker being pricked five times and being splashed nine times per year. The annual occupational risk of HIV transmission was estimated at 0.27% for health workers. Among surgeons, the risk was 0.7% (i.e. more than twice as high) if no special protective measures were taken. Health workers' knowledge and personal protective practices must therefore be improved and the supply of protective equipment supported. Reduction of occupational risk of HIV infection among health workers should be an integral part of acquired immunodeficiency syndrome (AIDS) control strategies.


A comparison of clinical and structured interview diagnoses in a homeless mental health clinic.
This study compared psychiatric diagnoses ascertained by independent clinicians with structured research interviews of homeless psychiatric patients assessed in a mental health clinic and in the community. Problems of both overdiagnosis and underdiagnosis in structured research interviews compared to clinician assessment were predicted. Over a period of a year, 97 patients referred to a mental health clinic for homeless people were assessed with the Diagnostic Interview Schedule (DIS) administered by a clinical social worker who then completed a full clinical psychiatric social work assessment. These same patients received a thorough and systematic clinical psychiatric evaluation by a psychiatrist or psychologist, both experienced with this population. These clinicians gathered data from multiple sources, often with extended observation over time. The DIS and clinician diagnoses were made blind to one another and then compared; the clinician was often made aware of some of the symptoms that the social worker had elicited, but not whether the elicited material was from the DIS or from the clinical assessment. Diagnoses of 33 clinic patients previously assessed by trained nonclinician DIS interviews in an epidemiologic study of the homeless population in the community were also compared to clinician diagnoses, and no information from these patients' survey DIS interviews was made available to the clinicians. Compared to clinician assessment, structured interviews underdiagnosed antisocial personality disorder (ASPD) and overdiagnosed major depression. Alcohol use disorder and schizophrenia showed only small discrepancies by assessment method. Drug use disorder revealed no bias according to method of ascertainment, but showed very discrepant kappa levels comparing DIS to clinician assessment in the two different comparison contexts. If structured research methods assessing the homeless population actually overestimate depression, underestimate ASPD, and misclassify drug abuse, then policies stemming from structured interview research recommendations may call for levels and types of services not optimally suited to the reality of this population's needs. Because mental illness and substance abuse are thought to be critical factors in the generation and perpetuation of homelessness, the issue of accurate diagnosis is tantamount to understanding and providing workable solutions to the problem of homelessness. Further research is needed to untangle potential confounders of the homeless situation to psychiatric diagnosis.


Anasazi solar marker: the use of a natural rockfall.
The midday "sun dagger" solstice and equinox marker on Fajada Butte in Chaco Canyon, New Mexico, is formed by three sandstone slabs that collimate sunlight onto two spiral petroglyphs. The slabs appear to be the result of a natuiral rockfall and not a construct of the Chacoan Anasazi. Although neither the rockfall nor the petroglyphs can be dated accurately, it is likely that the petroglyphs were designed after the rockfall by people who observed the details of the light pattern for several annual cycles.


The structure of elongated viral capsids.
There are many viruses whose genetic material is protected by a closed elongated protein shell. Unlike spherical viruses, the structure and construction principles of these elongated capsids are not fully known. In this article, we have developed a general geometrical model to describe the structure of prolate or bacilliform capsids. We show that only a limited set of tubular architectures can be built closed by hemispherical icosahedral caps. In particular, the length and number of proteins adopt a very special set of discrete values dictated by the axial symmetry (fivefold, threefold, or twofold) and the triangulation number of the caps. The results are supported by experimental observations and simulations of simplified physical models. This work brings about a general classification of elongated viruses that will help to predict their structure, and to design viral cages with tailored geometrical properties for biomedical and nanotechnological applications.


Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways.
Clara cells of mammalian airways have multiple functions and are morphologically heterogeneous. Although Notch signaling is essential for the development of these cells, it is unclear how Notch influences Clara cell specification and if diversity is established among Clara cell precursors. Here we identify expression of the secretoglobin Scgb3a2 and Notch activation as early events in a program of secretory cell fate determination in developing murine airways. We show that Scgb3a2 expression in vivo is Notch-dependent at early stages and ectopically induced by constitutive Notch1 activation, and also that in vitro Notch signaling together with the pan-airway transcription factor Ttf1 (Nkx2.1) synergistically regulate secretoglobin gene transcription. Furthermore, we identified a subpopulation of secretory precursors juxtaposed to presumptive neuroepithelial bodies (NEBs), distinguished by their strong Scgb3a2 and uroplakin 3a (Upk3a) signals and reduced Ccsp (Scgb1a1) expression. Genetic ablation of Ascl1 prevented NEB formation and selectively interfered with the formation of this subpopulation of cells. Lineage labeling of Upk3a-expressing cells during development showed that these cells remain largely uncommitted during embryonic development and contribute to Clara and ciliated cells in the adult lung. Together, our findings suggest a role for Notch in the induction of a Clara cell-specific program of gene expression, and reveals that the NEB microenvironment in the developing airways is a niche for a distinct subset of Clara-like precursors.


Doubling the power of DP4 for computational structure elucidation.
A large-scale optimisation of density functional theory (DFT) conditions for computational NMR structure elucidation has been conducted by systematically screening the DFT functionals and statistical models. The extended PyDP4 workflow was tested on a diverse and challenging set of 42 biologically active and stereochemically rich compounds, including highly flexible molecules. MMFF/mPW1PW91/M06-2X in combination with a 2 Gaussian, 1 region statistical model was capable of identifying the correct diastereomer among up to an upper limit of 32 potential diastereomers. Overall a 2-fold reduction in structural uncertainty and a 7-fold reduction in model overconfidence have been achieved. Tools for rapid set-up and analysis of computational and experimental results, as well as for the statistical model generation, have been developed and are provided. All of this should facilitate rapid and reliable computational NMR structure elucidation, which has become a valuable tool to natural product chemists and synthetic chemists alike.


Comparison of buccal infiltration of 4% articaine with 1 : 100,000 and 1 : 200,000 epinephrine for extraction of maxillary third molars with pericoronitis: a pilot study.
We compared the buccal infiltration of 4% articaine with 1 : 100,000 or 1 : 200,000 epinephrine without a palatal injection for the extraction of impacted maxillary third molars with chronic pericoronitis. This prospective, double-blind, controlled clinical trial involved 30 patients between the ages of 15 and 46 years who desired extraction of a partially impacted upper third molar with pericoronitis. Group 1 (15 patients) received 4% articaine with 1 : 100,000 epinephrine and group 2 (15 patients) received 4% articaine with 1 : 200,000 epinephrine by buccal infiltration. None of the patients in group 1 reported pain, but 3 patients in group 2 reported pain, which indicated a need for a supplementary palatal injection. The palatal injections were all successful in eliminating the pain. Two additional patients in group 2 experienced pain when the suture needle penetrated their palatal mucosa. Based on these results, 4% articaine with 1 : 100,000 epinephrine was found to be more effective for the removal of upper third molars in the presence of pericoronitis than 4% articaine hydrochloride with 1 : 200,000 epinephrine when only a buccal infiltration was used.


Sodium and water handling after gastric bypass surgery in a rat model.
It was the aim to investigate the influence of gastric bypass on renal sodium and water handling. The relationship between sodium and water absorption along the gastrointestinal tract and their renal excretion is poorly understood. Beneficial effects on blood pressure have been seen after bariatric surgery before significant weight loss has occurred. Male Wistar rats (348 ± 19 g) underwent either gastric bypass (n = 14) or sham operation (n = 7) and were given a low-sodium diet with deionized water ad libitum. Before and after surgery, the rats received an oral sodium load (1.5 mmol/kg) as hyperosmolar saline (616 mM), and were then placed in individual metabolic cages so the urine volume, sodium content, and water intake for 8 hours could be recorded. The urine sodium concentration was also measured. The rats that had undergone gastric bypass had a significantly lower body weight than the sham-operated controls throughout the follow-up period (346 ± 21 g versus 501.3 ± 8.0 g at day 60; P = .0004). An oral sodium load after gastric bypass led to an increase in water intake (.07 ± .01 mL/g versus .03 ± .01 mL/g; P = .023), urine output (.03 ± .01 mL/g versus .02 ± .002 mL/g; P = .027), and sodium excretion (65.99 ± 10.7 mol versus 31.71 ± 8.7 mol; P = .020). No change was seen in water intake, urine output, or sodium excretion after sham surgery. Urine output, water intake, and sodium excretion are all increased after gastric bypass surgery in rats given an oral sodium load compared with sham-operated controls. More rapid excretion, and less retention, of a dietary sodium load could be a part of the mechanism underlying the beneficial effect of bariatric surgery on blood pressure.


Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23.
In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia. The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH. Two sequential open-label phase 1/2 studies were done. Six academic medical centers were used. Twenty-eight adults with XLH participated in a 4-month dose-escalation study (0.05-0.6 mg/kg); 22 entered a 12-month extension study (0.1-1 mg/kg). KRN23 was injected sc every 28 days. The main outcome measure was the proportion of subjects attaining normal serum Pi and safety. At baseline, mean TmP/GFR, serum Pi, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 1.6 ± 0.4 mg/dL, 1.9 ± 0.3 mg/dL, and 36.6 ± 14.3 pg/mL, respectively. During dose escalation, TmP/GFR, Pi, and 1,25(OH)2D increased, peaking at 7 days for TmP/GFR and Pi and at 3-7 days for 1,25(OH)2D, remaining above (TmP/GFR, Pi) or near [1,25(OH)2D] pre-dose levels at trough. After each of the four escalating doses, peak Pi was between 2.5 and 4.5 mg/dL in 14.8, 37.0, 74.1, and 88.5% of subjects, respectively. During the 12-month extension, peak Pi was in the normal range for 57.9-85.0% of subjects, and ≥25% maintained trough Pi levels within the normal range. Serum Pi did not exceed 4.5 mg/dL in any subject. Although 1,25(OH)2D levels increased transiently, mean serum and urinary calcium remained normal. KRN23 treatment increased biomarkers of skeletal turnover and had a favorable safety profile. Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH.


Assessing Toripalimab in NSCLC.
According to CHOICE-01, a phase III trial in China, the PD-1 inhibitor toripalimab plus chemotherapy improves progression-free survival in patients with untreated non-small cell lung cancer lacking actionable mutations. The findings boost combination chemo-immunotherapy, rather than chemotherapy alone, as the new standard for this population.


High-Dose Methylphenidate and Carboxylesterase 1 Genetic Variability in Patients With Attention-Deficit/Hyperactivity Disorder: A Case Series.
Methylphenidate (MPH) is widely used to reduce symptoms of attention-deficit/hyperactivity disorder. Methylphenidate is metabolized by the carboxylesterase 1 (CES1) enzyme. Some patients need a very high dose of MPH to reach desired clinical effects, without having adverse effects. This may be due to differences in MPH pharmacokinetics (PK), potentially caused by DNA variants in CES1, the gene encoding the enzyme that metabolizes MPH. Here we describe 3 patients requiring high-dose MPH and investigated the CES1 gene. The 3 patients were using short-acting MPH in a dose of 180 to 640 mg instead of the maximum advised dose of around 100 mg MPH in the Netherlands. Plasma concentrations of MPH were determined at scheduled time points (day-curve). Methylphenidate plasma concentrations were used for PK analysis using an earlier published 2-compartment PK population model of MPH. Individual data of the 3 patients were compared with simulated population data, when equivalent doses were used. In addition, CES1 was genotyped (number of gene copies and single nucleotide polymorphisms) using real-time polymerase chain reaction. Pharmacokinetic analysis in all 3 patients showed lower plasma concentrations of MPH in comparison with the population data. The mean absorption time and volume of distribution of the central compartment were equal, but the elimination clearance was higher. However, CES1 genotyping revealed no variations that could explain a higher metabolism of MPH. In these 3 cases, we could not demonstrate a correlation between MPH clearance and known genetic variants of the CES1 gene.


Gut Transcriptome Analysis Shows Different Food Utilization Efficiency by the Grasshopper Oedaleous asiaticus (Orthoptera: Acrididae).
Oedaleus asiaticus B. Bienko is a persistent pest occurring in north Asian grasslands. We found that O. asiaticus feeding on Stipa krylovii Roshev. had higher approximate digestibility (AD), efficiency of conversion of ingested food (ECI), and efficiency of conversion of digested food (ECD), compared with cohorts feeding on Leymus chinensis (Trin.) Tzvel, Artemisia frigida Willd., or Cleistogenes squarrosa (Trin.) Keng. Although this indicated high food utilization efficiency for S. krylovii, the physiological processes and molecular mechanisms underlying these biological observations are not well understood. Transcriptome analysis was used to examine how gene expression levels in O. asiaticus gut are altered by feeding on the four plant species. Nymphs (fifth-instar female) that fed on S. krylovii had the largest variation in gene expression profiles, with a total of 88 genes significantly upregulated compared with those feeding on the other three plants, mainly including nutrition digestive genes of protein, carbohydrate, and lipid digestion. GO and KEGG enrichment also showed that feeding S. krylovii could upregulate the nutrition digestion-related molecular function, biological process, and pathways. These changes in transcripts levels indicate that the physiological processes of activating nutrition digestive enzymes and metabolism pathways can well explain the high food utilization of S. krylovii by O. asiaticus.