The evolution and expansion of regional disease surveillance networks and their role in mitigating the threat of infectious disease outbreaks.
We examine the emergence, development, and value of regional infectious disease surveillance networks that neighboring countries worldwide are organizing to control cross-border outbreaks at their source. The regional perspective represented in the paper is intended to serve as an instructive framework for others who decide to launch such networks as new technologies and emerging threats bring countries even closer together. Distinct from more formal networks in geographic regions designated by the World Health Organization (WHO), these networks usually involve groupings of fewer countries chosen by national governments to optimize surveillance efforts. Sometimes referred to as sub-regional, these "self-organizing" networks complement national and local government recognition with informal relationships across borders among epidemiologists, scientists, ministry officials, health workers, border officers, and community members. Their development over time reflects both incremental learning and growing connections among network actors; and changing disease patterns, with infectious disease threats shifting over time from local to regional to global levels. Not only has this regional disease surveillance network model expanded across the globe, it has also expanded from a mostly practitioner-based network model to one that covers training, capacity-building, and multidisciplinary research. Today, several of these networks are linked through Connecting Organizations for Regional Disease Surveillance (CORDS). We explore how regional disease surveillance networks add value to global disease detection and response by complementing other systems and efforts, by harnessing their power to achieve other goals such as health and human security, and by helping countries adapt to complex challenges via multi-sectoral solutions. We note that governmental commitment and trust among participating individuals are critical to the success of regional infectious disease surveillance networks.


Variation in access to hemophilia A treatments in the United States.
US commercial health plans have been found to vary in how they cover specialty drugs indicated for a range of diseases. In this study, we examined patients' access to hemophilia A (HemA) treatments across a set of large commercial health plans. To examine variation in health plans' coverage policies for HemA treatments. We reviewed HemA treatment coverage policies (current as of August 2019) issued by 17 commercial health plans primarily using the Tufts Medical Center Specialty Drug Evidence and Coverage Database. We categorized policies as: covered without conditions (coverage consistent with the FDA label); covered with conditions (conditions on coverage beyond the FDA label); broader coverage (coverage for a broader patient population than the FDA label); and mixed (conditions on coverage beyond the FDA label in one way, but coverage was broader than the FDA label in another). We identified 296 coverage policies for 26 HemA treatments, including 15 short half-life factor VIII (FVIII) products, five extended half-life FVIII products, three bypassing agents, two desmopressin products, and emicizumab. We classified 36% of policies as coverage without conditions, 50% as covered with conditions, 7% as broader coverage, and 7% as mixed. Plans applied conditions on coverage with different frequencies: two did not apply conditions in any policies; ten applied conditions in ≥50%; four applied conditions in <40%. One plan did not publish coverage policies for any HemA products. Conditions on coverage most often related to bleeding frequency (36%), although specific requirements varied. Plans applied step therapy protocols in 17% of policies. How health plans covered HemA treatments varied. Plans added conditions on coverage beyond the FDA label roughly half the time. Conditions most often related to bleeding frequency. Variable coverage affects patients' access to treatment, and potentially has clinical implications on disease management and disease progression.


Response to rimiterol and salbutamol aerosols administered by intermittent positive-pressure ventilation.
The bronchodilator and cardiac effects produced by aerosols of 0.5% salbutamol and 0.5% and 1% rimiterol administered for three minutes in 40% oxygen by intermittent positive-pressure ventilation (I.P.P.V.) were compared in 15 asthmatic patients. Salbutamol and both the concentrations of rimiterol were equipotent in peak bronchodilator effect, but salbutamol had a significantly longer duration of bronchodilator action. There was significantly less increase in heart rate after rimiterol than after salbutamol. Aerosols of 0.5% rimiterol, 0.5% salbutamol, and saline were administered by I.P.P.V. to 10 normal volunteers. There was no difference between the mean heart rates after 0.5% rimiterol and saline but a highly significant increase in mean heart rate was observed after 0.5% salbutamol. It was concluded that 0.5% rimiterol was an effective short-acting bronchodilator drug with little or no cardiac beta(1)-adrenergic activity when administered for three minutes by I.P.P.V. in 40% oxygen.


Interstitial Lung Disease and Pulmonary Fibrosis: A Practical Approach for General Medicine Physicians with Focus on the Medical History.
Interstitial lung disease (ILD) and pulmonary fibrosis comprise a wide array of inflammatory and fibrotic lung diseases which are often confusing to general medicine and pulmonary physicians alike. In addition to the myriad of clinical and radiologic nomenclature used in ILD, histopathologic descriptors may be particularly confusing, and are often extrapolated to radiologic imaging patterns which may further add to the confusion. We propose that rather than focusing on precise histologic findings, focus should be on identifying an accurate etiology of ILD through a comprehensive and detailed medical history. Histopathologic patterns from lung biopsy should not be dismissed, but are often nonspecific, and overall treatment strategy and prognosis are likely to be determined more by the specific etiology of ILD rather than any particular histologic pattern. In this review, we outline a practical approach to common ILDs, highlight important aspects in obtaining an exposure history, clarify terminology and nomenclature, and discuss six common subgroups of ILD likely to be encountered by general medicine physicians in the inpatient or outpatient setting: Smoking-related, hypersensitivity pneumonitis, connective tissue disease-related, occupation-related, medication-induced, and idiopathic pulmonary fibrosis. Accurate diagnosis of these forms of ILD does require supplementing the medical history with results of the physical examination, autoimmune serologic testing, and chest radiographic imaging, but the importance of a comprehensive environmental, avocational, occupational, and medication-use history cannot be overstated and is likely the single most important factor responsible for achieving the best possible outcomes for patients.


Acute-phase-response induction in rat hepatocytes co-cultured with rat liver epithelial cells.
The response of rat hepatocytes co-cultured with rat liver epithelial cells to conditioned medium (CM) from lipopolysaccharide (LPS)-activated monocytes was investigated by measuring the concentration of alpha 2-macroglobulin (alpha 2M), alpha 1-acid glycoprotein (AGP), albumin and transferrin, as well as the changes in glycosylation of alpha 1-acid glycoprotein. During an initial 8-day treatment with CM, concentrations of alpha 2M and AGP increased markedly over those of control culture, whereas concentrations of albumin and transferrin decreased. The glycosylation pattern of AGP indicated an important relative increase of the concanavalin A-strongly-reactive (SR) variant upon treatment. When CM addition to hepatocyte culture medium was stopped, the concentrations of the four proteins and the glycosylation pattern of AGP reverted to those of control cultures. Further addition (on day 15) to cultures of CM increased the concentration of alpha 2M and decreased albumin and transferrin concentrations. Although AGP concentrations did not increase above those of controls, the appearance of the SR variant was again stimulated by CM. These results show that, in co-culture, rat hepatocytes remain able to respond to repeated inflammatory stimuli.


Maternal and fetal adrenocortical function in the diabetic rabbit.
To investigate whether maternal or fetal glucocorticoid secretion is altered during pregnancy complicated by diabetes mellitus, in vitro production of corticosterone (B) and cortisol (F) was measured on day 28 of gestation in rabbits made alloxan diabetic prior to pregnancy. In addition, plasma B and F were followed throughout the experimental period. Fetuses of diabetic mothers were hyperglycemic and hyperinsulinemic, and mortality was much higher (18%) than that of control animals (1.5%). No significant differences were found in maternal plasma B or F during gestation, whereas F was significantly lower in fetuses of diabetic mothers. In vitro production of both B and F by maternal and fetal adrenals was lower in the diabetic animals, and responses to ACTH or insulin added to the incubation were the same in both groups. These results suggest that the ability of the adrenal cortex to secrete glucocorticoids may be impaired both in the mother and fetus when maternal diabetes is present. This could have effects both on maturational events in the fetus that are accelerated by glucocorticoids and on the ability to respond to stress.


What's retinoic acid got to do with it? Retinoic acid regulation of the neural crest in craniofacial and ocular development.
Retinoic acid (RA), the active derivative of vitamin A (retinol), is an essential morphogen signaling molecule and major regulator of embryonic development. The dysregulation of RA levels during embryogenesis has been associated with numerous congenital anomalies, including craniofacial, auditory, and ocular defects. These anomalies result from disruptions in the cranial neural crest, a vertebrate-specific transient population of stem cells that contribute to the formation of diverse cell lineages and embryonic structures during development. In this review, we summarize our current knowledge of the RA-mediated regulation of cranial neural crest induction at the edge of the neural tube and the migration of these cells into the craniofacial region. Further, we discuss the role of RA in the regulation of cranial neural crest cells found within the frontonasal process, periocular mesenchyme, and pharyngeal arches, which eventually form the bones and connective tissues of the head and neck and contribute to structures in the anterior segment of the eye. We then review our understanding of the mechanisms underlying congenital craniofacial and ocular diseases caused by either the genetic or toxic disruption of RA signaling. Finally, we discuss the role of RA in maintaining neural crest-derived structures in postembryonic tissues and the implications of these studies in creating new treatments for degenerative craniofacial and ocular diseases.


The pattern of indoor and outdoor respiratory allergens in asthmatic adult patients in a humid and desert newly developed country.
Studies have shown that allergens are very important sensitizing agents in patients with asthma. Respiratory disorders such as asthma and allergic rhinitis are common in the State of Qatar. To characterize the most frequent indoor and outdoor respiratory allergens involved in bronchial asthma and allergic rhinitis in the State of Qatar. A hospital-based prospective study conducted. Allergy Laboratory at the Hamad General Hospital and Hamad Medical Corporation, Doha, State of Qatar. Adult patients over 12 years of age diagnosed with bronchial asthma and/or allergic rhinitis who were referred for allergy skin pick test. 1106 adult patients recruited with respiratory diseases of suspected allergic origin who attended Allergy Clinic at the Hamad General Hospital, during three years from January 2001 to April 2003. Total of 1106 whom 607 were females (54.9%) and 499 were males (45.1%) and their mean was age 30 years (12-48). Skin Prick Test [SPT] was performed on 1106 patients for common allergens whom The blood sample was taken for measuring specific IgE concentration. There were 1106 patients studied and 569 patients (51.4%) had positive skin prick test. All patients expressed clinical allergy, 464 patients (52%) had asthma and rhinitis, 286 patients (32%) had rhinitis alone and 137 patients (15%) had asthma alone. The population sample had a higher prevalence of diagnosed asthma among females (32.7%) than in males (29.8%) and also skin conditions such as eczema, pruritus, and urticaria higher in females (9.1%%) than males (7.0%). Similarly, males had higher prevalence of allergic rhinitis (86.0%) than in females. There were 318 (55.9%) patients whose asthma developed before they were 10 years old. The percentage of asthmatic patients with a positive family history of asthma was 44%. The most common allergens detected in order of frequency were Dermatophagoides Pteronyssimus (Der p l) in 248 patients (41.6%), Dermatophagoides Farinae (Der f l) in 220 patients (36.9%), Cockroach allergen (Bla g l) in 192 patients (32.2%). The study showed that females are more exposed to pollen, grasses and tress, but males are mostly exposed to mites and insects. Furthermore, Molds and Yeast were common among males. In conclusion, the frequency of indoor and outdoor allergens in state of Qatar, based on skin prick test study showed the dominance of house dust mites, pollen, grasses which are more or less same to other countries with similar and even with different climate. Reduced exposure to these agents will help control raising severity of these disease.


[The specific features of the heliophysical situation in the period of preconceiving and early ontogenesis in patients with pulmonary tuberculosis].
The specific features of the heliophysical situation in preconceiving and early ontogenesis in patients with pulmonary tuberculosis were studied. There were significant differences in solar radioradiation intensity a week before the conception of an organism in healthy individuals and patients with tuberculosis.


Coevolutionary chase on exploiter-victim systems with polygenic characters.
I study the dynamics of a simple quantitative genetic model describing coevolution of two antagonistic species of the victim-exploiter type. In this model, individuals are different with respect to an additive polygenic character that is under direct stabilizing selection and which also determines the strength of within and between species interactions. The model assumes that between species interactions are most intense when the victim's and exploiter's phenotypes match. I show that a cyclic coevolutionary chase is possible under a broad range of conditions. In most cases, the system cycles if the "victim" has a stronger incentive to win and/or a larger genetic variance, and is under stronger stabilizing selection than the "exploiter". The results presented here provide counter-examples to recent studies that (1) question the applicability of "Red Queen" and "arms race" metaphors for continuously varying traits; (2) argue for the existence of crucial differences between major and minor loci dynamics; and (3) attribute a stabilizing role to coevolution.


Development of a universal anti-polyethylene glycol reporter gene for noninvasive imaging of PEGylated probes.
A reporter gene can provide important information regarding the specificity and efficacy of gene or cell therapies. Although reporter genes are increasingly used in experimental and clinical studies, a highly specific yet nonimmunogenic reporter that can track genes and cells in vivo by multiple imaging technologies still awaits development. In this study, we constructed a versatile and nonimmunogenic reporter gene to noninvasively image gene expression or cell delivery by optical imaging, MRI, and small-animal PET. We cloned and expressed a membrane-anchored anti-polyethylene glycol (PEG) reporter that consists of the Fab fragment of a mouse anti-PEG monoclonal antibody, AGP3, fused to the C-like extracellular-transmembrane-cytosolic domains of the mouse B7-1 receptor. Binding of PEGylated probes (PEG-NIR797 for optical imaging, PEG-superparamagnetic iron oxide for MRI, and (124)I-PEG for small-animal PET) were examined in vitro and in vivo. In addition, we compared the specificity, immunogenicity, and probe toxicity of the anti-PEG reporter with the gold standard reporter gene, type 1 herpes simplex virus thymidine kinase (HSV-tk). Finally, we derived a humanized anti-PEG reporter and evaluated its imaging function in vivo with subcutaneous and metastatic tumor models in mice. The cells or tumors that stably expressed anti-PEG reporters selectively accumulated various PEGylated imaging probes and could be detected by optical imaging, MRI, and small-animal PET. Importantly, the anti-PEG reporter displayed an imaging specificity comparable to the HSV-tk reporter but did not provoke immune responses or cause toxicity to the host. Furthermore, the humanized anti-PEG reporter retained high imaging specificity in vivo. The highly specific and nonimmunogenic anti-PEG reporter may be paired with PEGylated probes to provide a valuable system to image gene expression or cell delivery in experimental and clinical studies.


Rotavirus Surveillance at a WHO-Coordinated Invasive Bacterial Disease Surveillance Site in Bangladesh: A Feasibility Study to Integrate Two Surveillance Systems.
The World Health Organization (WHO) currently coordinates rotavirus diarrhea and invasive bacterial disease (IBD) surveillance at 178 sentinel sites in 60 countries. However, only 78 sites participate in both surveillance systems using a common sentinel site. Here, we explored the feasibility of extending a WHO-IBD surveillance platform to generate data on the burden of rotaviral diarrhea and its epidemiological characteristics to prepare the countries to measure the impact of rotaviral vaccine. A six-month (July to December, 2012) surveillance, managed by IBD team, collected stool samples and clinical data from under-five children with acute watery diarrhea at an IBD sentinel site. Samples were tested for rotavirus antigen by ELISA and genotyped by PCR at the regional reference laboratory (RRL). Specimens were collected from 79% (n=297) of eligible cases (n=375); 100% of which were tested for rotavirus by ELISA and 54% (159/297) of them were positive. At RRL, all the cases were confirmed by PCR and genotyped (99%; 158/159). The typing results revealed the predominance of G12 (40%; 64/159) genotype, followed by G1 (31%; 50/159) and G9 (19%; 31/159). All in all, this exploratory surveillance collected the desired demographic and epidemiological data and achieved almost all the benchmark indicators of WHO, starting from enrollment number to quality assurance through a number of case detection, collection, and testing of specimens and genotyping of strains at RRL. The success of this WHO-IBD site in achieving these benchmark indicators of WHO can be used by WHO as a proof-of-concept for considering integration of rotavirus surveillance with WHO-IBD platforms, specifically in countries with well performing IBD site and no ongoing rotavirus surveillance.


Protective effect of zinc aspartate on long-term ischemia-reperfusion injury in rat skeletal muscle.
The present study investigated the protective effect of zinc aspartate, in connection with reactive oxygen species and nitric oxide, on long-term ischemia-reperfusion injury (IRI) in rat skeletal muscle. Following ketamine anesthesia, 24 rats were randomly assigned to four groups: groups 1 and 2, each without tourniquet application, received no drug and zinc, respectively; groups 3 and 4, each subjected to tourniquet-induced IRI (3 + 24 h), received no drug and zinc, respectively. IRI was achieved by the application of an elastic rubber band in the left hind limb of the anesthetized rats. Gastrocnemius muscle samples were obtained for biochemical measurements. Malondialdehyde levels were lower in group 2 and higher in group 3 than those seen in group 1. However, zinc aspartate (group 4) totally reversed malondialdehyde levels to control levels. Superoxide dismutase activity was increased in group 2 compared with group 1; however, there was no difference between groups 1 and 3, and Zn injection (group 4) increased superoxide dismutase activity. While catalase values were similar in groups 1 and 2, significant increments were observed in 3 and 4. A similar enhancement in glutathione levels were observed in groups 2 and 4 compared with group 1. Nitric oxide levels were lower in group 2 than 1, and no difference between groups 1 and 3 was demonstrated. In conclusion, zinc seems to be an effective treatment option against IRI.


Despotism, democracy, and the evolutionary dynamics of leadership and followership.
Responds to comments made by George B. Graen and Stephen J. Guastello on the current author's article Leadership, followership, and evolution: Some lessons from the past by Van Vugt, Hogan, and Kaiser. In the original article my co-authors and I proposed a new way of thinking about leadership, informed by evolutionary (neo-Darwinian) theory. In the first commentary, Graen noted that we ignored a number of recently developed psychological theories of leadership that take into account the leader-follower relationship, most notably LMX theory. LMX theory asserts that leadership effectiveness and team performance are affected by the quality of working relationships between superior and subordinates. Because the original article primarily dealt with questions about the origins of leadership--the phylogenetic and evolutionary causes--we had to be concise in our review of proximate psychological theories of leadership. In the second commentary, Guastello concurred with the importance of an evolutionary game analysis for studying leadership but disagreed with certain details of our analysis. (PsycINFO Database Record (c) 2009 APA, all rights reserved).


The BRIDGE trial: What the hospitalist should know.
Atrial fibrillation patients often require warfarin interruption for an invasive procedure or surgery. Heparin bridging therapy has been frequently used during warfarin interruption under the premise of providing a theoretical mitigation against thromboembolism that overweighs expected higher rates of bleeding. Up until recently, little definite clinical evidence was available to guide the hospitalist on optimal perioperative anticoagulant management. The landmark BRIDGE (Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation) trial provided high-quality evidence that a simple interruption of warfarin in the average atrial fibrillation patient undergoing an elective procedure or surgery is noninferior to bridging therapy for efficacy and superior to bridging therapy in preventing major bleeding. To guide the hospitalist, we propose a treatment algorithm based on these recent data. We review the literature that led to the trial and highlight its practice-changing implications as a proof of concept that calls to question the premise of heparin bridging therapy beyond the atrial fibrillation population. Journal of Hospital Medicine 2016;11:652-657. © 2016 Society of Hospital Medicine.


Fatty liver and drugs: the two sides of the same coin.
Drug-induced liver injury (DILI) is a common and underestimated cause of liver disease. Several drugs and other xenobiotics can be the cause of different clinicopathologic patterns of liver disease. Steatosis and steatohepatitis are rare but well-documented types of DILI. Over the past decades commonly used drugs like amiodarone, tamoxifen, irinotecan, methotrexate, valproic acid and glucocorticoids have been recognized to be associated with steatosis. Even though the pathophysiological pathways are still only partially understood, inhibition of mitochondrial beta-oxidation, reduced very low-density lipoprotein secretion, insulin resistance induction and increased de novo synthesis or increased liver uptake of fatty acids are considered the main pathogenic mechanisms through which drugs can lead to hepatic steatosis. On the other hand, fatty liver itself is a very common clinical condition, and there is a growing awareness of the potential risk factors for DILI due to the underlying metabolic condition itself.


Baclofen analgesia in mice: a GABAB-mediated response.
The effect of baclofen, a GABAB agonist, has been studied in three antinociceptive tests (tail flick latency, hot plate method and acetic acid-induced writhing) in mice. In all three models, baclofen was found to elicit a dose-dependent antinociceptive effect. The observed antinociceptive effect was stereospecific, as the levo isomer of baclofen was found to be more potent than the racemic mixture. Baclofen also potentiated morphine analgesia. The antinociceptive effect of baclofen was reversed by both CGP 35348, a GABAB antagonist, and naloxone, an opioid antagonist, but not by bicuculline or picrotoxin, GABAA antagonists. However, in acetic acid-induced writhing, naloxone failed to reverse baclofen analgesia. The data suggest that the antinociceptive effect of baclofen is GABAB receptor-mediated and that there may be a GABAergic and opiate/or non-opiate interaction in eliciting the analgesic effect.


Efficacy of antidepressants for dysthymia: a meta-analysis of placebo-controlled randomized trials.
The authors sought to determine the efficacy of antidepressants in dysthymic disorder and to compare antidepressant and placebo response rates between major depressive disorder (MDD) and dysthymic disorder. PubMed/MEDLINE databases were searched for double-blind, randomized, placebo-controlled trials of antidepressants used as monotherapy for treatment of MDD or dysthymic disorder. We defined antidepressants as those with a letter of approval by the US, Canadian, or European Union drug regulatory agencies for treatment of MDD or dysthymic disorder, which included the following: amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, dothiepin, doxepin, lofepramine, amoxapine, maprotiline, amineptine, nomifensine, bupropion, phenelzine, tranylcypromine, isocarboxazid, moclobemide, brofaromine, fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, zimelidine, tianeptine, ritanserin, trazodone, nefazodone, agomelatine, venlafaxine, desvenlafaxine, duloxetine, milnacipran, reboxetine, mirtazapine, and mianserin. Eligible studies were identified by cross-referencing the search term placebo with each of the above-mentioned agents. The search was limited to articles published between January 1, 1980, and November 20, 2009 (inclusive). To expand our database, we also reviewed the reference lists of the identified studies. We selected randomized, double-blind, placebo-controlled trials of antidepressants for either MDD or dysthymic disorder according to preset criteria relating to comorbidities, patient age, drug formulation, study duration, diagnostic criteria, choice of assessment scales, and whether or not the study reported original data. Final selection of articles was determined by consensus among the authors. A total of 194 studies were found that were eligible for inclusion in our analysis. Of these, 177 focused on the treatment of MDD and 17 on the treatment of dysthymic disorder. We found that antidepressant therapy was significantly more effective than placebo in dysthymic disorder (risk ratio = 1.75; 95% CI, 1.49-2.04; P < .0001), while placebo response rates in dysthymic disorder trials were significantly lower compared to MDD trials (29.9% vs 37.9%, respectively; P = .042). Meta-regression suggested a statistically significant difference in the risk ratio of responding to antidepressants versus placebo when comparing studies either on dysthymic disorder or on MDD, suggesting a greater risk ratio for response in favor of antidepressant therapy versus placebo in patients with dysthymic disorder versus MDD (coefficient of -0.113; P = .007). These results support the utility of antidepressants for dysthymic disorder. In fact, the margin of efficacy of antidepressants for dysthymic disorder was larger than for MDD. Future studies providing longer-term data on the treatment of dysthymic disorder with antidepressants are essential.


Morpho-functional modifications of human neutrophils induced by aqueous cigarette smoke extract: comparison with chemiluminescence activity.
Cigarette smoking plays an important role as a cause of morbidity and mortality in humans, involving respiratory, cardiovascular, digestive and reproductive systems. Tobacco smoke contains a large number of molecules, some of which are proven carcinogens. Although not fully understood, polymorphonuclear leukocytes seem to play a crucial role in the mechanisms by which tobacco smoke compounds are implicated in smoke-related diseases. In this paper the effects of an aqueous cigarette smoke extract on the expression of adhesion molecules of polymorphonuclear leukocytes together with the changes in the cell morphology have been related to the chemiluminescence activity. The results obtained show that polymorphonuclear leukocytes treated with aqueous cigarette smoke extract are significantly impaired, as suggested by the changes of chemiluminescence activity, of membrane receptors (CD18, CD62), myeloperoxidase expression and of cell morphology. Altogether the present data indicate that treated polymorphonuclear leukocytes are ineffectively activated and therefore unable to phagocytize zymosan particles.


A systematic review of the prophylactic role of chloroquine and hydroxychloroquine in coronavirus disease-19 (COVID-19).
The pandemic coronavirus disease-19 (COVID-19) has pushed the global healthcare system to a crisis and amounted to a huge economic burden. Different drugs for prophylaxis against COVID-19 including chloroquine (CQ) or hydroxychloroquine (HCQ) have been tried. This study was performed to systematically review the role of CQ and HCQ in preventing the spread of COVID-19. PubMed, EMBASE, ClinicalTrials.gov, International Clinical Trials Registry Platform and Cochrane Library databases were searched for studies that evaluated the prophylactic role of CQ or HCQ on SARS-CoV-2 (pre-clinical studies) or COVID-19 (clinical studies) until 30 March 2020. The available literature was critically appraised. A total of 45 articles were screened and 5 (3 in vitro pre-clinical studies and 2 clinical opinions) were included. The pre-clinical studies showed the prophylactic effects of CQ and HCQ against SARS-CoV-2. On the other hand, the clinical opinions advocated the prophylactic use of CQ and HCQ against COVID-19. However, no original clinical studies on the prophylactic role of CQ or HCQ on COVID-19 were available. Although pre-clinical results are promising, to date there is a dearth of evidence to support the efficacy of CQ or HCQ in preventing COVID-19. Considering potential safety issues and the likelihood of imparting a false sense of security, prophylaxis with CQ or HCQ against COVID-19 needs to be thoroughly evaluated in observational studies or high-quality randomized controlled studies.


Astrovirus in Reunion Free-Tailed Bat (Mormopterus francoismoutoui).
Astroviruses (AstVs) are RNA viruses infecting a large diversity of avian and mammalian species, including bats, livestock, and humans. We investigated AstV infection in a free-tailed bat species, Mormopterus francoismoutoui, endemic to Reunion Island. A total of 380 guano samples were collected in a maternity colony during 38 different sampling sessions, from 21 June 2016 to 4 September 2018. Each sample was tested for the presence of the AstV RNA-dependent RNA-polymerase (RdRp) gene using a pan-AstV semi-nested polymerase chain reaction assay. In total, 27 guano samples (7.1%) tested positive, with high genetic diversity of the partial RdRp gene sequences among positive samples. Phylogenetic analysis further revealed that the detected viruses were genetically related to AstVs reported in rats, reptiles, dogs, and pigs, but did not cluster with AstVs commonly found in bats. Although more investigations need to be conducted to assess the prevalence of infected bats in the studied population, our findings show that Reunion free-tailed bats are exposed to AstVs, and suggest that cross-species transmission may occur with other hosts sharing the same habitat.


PEGylated Phthalocyanine-Functionalized Graphene Oxide with Ultrahigh-Efficient Photothermal Performance for Triple-Mode Antibacterial Therapy.
This study proposes a novel multifunctional synergistic antibacterial phototherapy technique for the rapid healing of bacteria-infected wounds. By binding PEGylated phthalocyanines to the surface of graphene oxide via noncovalent functionalization, the photothermal conversion efficiency of the obtained nanocomposites can be significantly increased, which shows that the sample temperature can achieve nearly 100 °C after only 10 min of 450 nm light illumination at a concentration ≥25 μg/mL. Moreover, the nanocomposites can rapidly generate singlet oxygen under 680 nm light irradiation and physically cut bacterial cell membranes. The triple effects are expected to obtain a synergistic antibacterial efficiency and reduce the emergence of bacterial resistance. After dual-light irradiation for 10 min, the generation of hyperthermia and singlet oxygen can cause the death of Gram-positive and Gram-negative bacteria. The results of an in vivo experiment revealed that the as-prepared nanocomposites combined with dual-light-triggered antibacterial therapy can effectively restrain the inflammatory reaction and accelerate the healing of bacteria-infected wounds. These were confirmed by the examination of pathological tissue sections and inflammatory factors in rats with bacteria-infected wounds. This nanotherapeutic platform is a potential photoactivated antimicrobial strategy for the prevention and treatment of bacterial infection.


Fragile x premutation.
Whereas full mutation CGG-repeat expansions (>200 repeats) of the fragile X gene (FMR1) give rise to the neurodevelopmental disorder, fragile X syndrome (FXS); smaller, 'premutation' expansions (55 to 200 repeats) are now gaining increasing recognition as the basis for a spectrum of clinical involvement, from neurodevelopmental problems; to mid-adult disorders, such as primary ovarian insufficiency and mood and psychiatric disorders; to the late-adult-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). The premutation disorders are thought to arise through a molecular mechanism involving toxicity of the elevated levels of expanded CGG-repeat mRNA ('RNA toxicity'), a process that is entirely distinct from the FMR1 protein-deficiency that gives rise to FXS. However, despite the importance of the spectrum of clinical disorders associated with the premutation, and a high prevalence rate (1 in 130 to 250 females and 1 in 250 to 810 males), relatively little attention has been paid to these disorders and there is a general lack of awareness among clinicians as to the distinction between the premutation disorders and FXS. To address this lack of awareness, an international conference on the premutation was held in Perugia, Italy, in June 2013. The conference covered the expanding range of clinical involvement, refinements of the assessments and tools for characterizing such involvement, and the rapidly expanding understanding of the pathogenic molecular and cellular mechanisms that give rise to the spectrum of involvement among premutation carriers. All of these advances support ongoing efforts to develop new targeted treatments for the premutation disorders. As an outgrowth of the meeting, papers were solicited from the conference attendees such that groups of scientists and clinicians would develop works that broadly covered the topics of the meeting. The following papers represent that effort.


TNAP, a novel repressor of NF-kappaB-inducing kinase, suppresses NF-kappaB activation.
NF-kappaB-inducing kinase (NIK) has been implicated as an essential component of NF-kappaB activation. However, the regulatory mechanism of NIK signaling remains elusive. We have identified a novel NIK interacting protein, TNAP (for TRAFs and NIK-associated protein). In mammalian cells, TNAP physically interacts with NIK, TRAF2, and TRAF3 but not IKK1 or IKK2. TNAP specifically inhibits NF-kappaB activation induced by tumor necrosis factor (TNF)-alpha, TNF receptor 1, TRADD, RIP, TRAF2, and NIK but does not affect IKK1- and IKK2-mediated NF-kappaB activation. Knockdown of TNAP by lentiviral-mediated small interference RNA potentiates TNF-alpha-induced NF-kappaB activation. TNAP suppresses NIK kinase activity and subsequently reduces p100 processing, p65 phosphorylation, and IkappaBalpha degradation. These data suggest that TNAP is a repressor of NIK activity and regulates both the classical and alternative NF-kappaB signaling pathways.


Secondary deuterium kinetic isotope effect for aquation, solvolysis, and isomerization reactions of trans-[Co(en)2(OSMe2)N3]2+, and the resolution of a mechanistic anomaly.
The two closely spaced NH signals in the (1)H NMR spectrum of trans-[Co(en)(2)(OSMe(2))(N(3))](2+) have been reassigned using 2D NMR and other techniques. Thus, the unusual syn to anti (to Co-N(3)) NH rearrangement on base catalyzed substitution of the selectively deuterated complex in ND(3)(l) has been reinterpreted as "normal", with inversion of the effective deprotonation site accompanying the act of substitution. The re-examination of this system required a repeat study of the secondary isotope effect for the acid hydrolysis reaction, previously used to assign syn and anti amine sites, and this has been extended to other solvents (Me(2)SO, MeCN). The relative NH proton exchange rates are also reconsidered. A systematic rate reduction for Me(2)SO substitution is observed for deuterium incorporation into the cis-NH centers, irrespective of whether these are syn or anti, and the effect is much greater in Me(2)SO than in water. The results are interpreted in terms of zero point energy effects and coupled vibrations.


Using proteomics for stratification and risk prediction in patients with solid tumors.
Proteomics, the study of proteins and their functions, has greatly evolved due to advances in analytical chemistry and computational biology. Unlike genomics or transcriptomics, proteomics captures the dynamic and diverse nature of proteins, which play crucial roles in cellular processes. This is exemplified in cancer, where genomic and transcriptomic information often falls short in reflecting actual protein expression and interactions. Liquid chromatography-mass spectrometry (LC-MS) is pivotal in proteomic data generation, enabling high-throughput analysis of protein samples. The MS-based workflow involves protein digestion, chromatographic separation, ionization, and fragmentation, leading to peptide identification and quantification. Computational biostatistics, particularly using tools in R (R Foundation for Statistical Computing, Vienna, Austria; www.R-project.org ), aid in data analysis, revealing protein expression patterns and correlations with clinical variables. Proteomic studies can be explorative, aiming to characterize entire proteomes, or targeted, focusing on specific proteins of interest. The integration of proteomics with genomics addresses database limitations and enhances peptide identification. Case studies in intrahepatic cholangiocarcinoma, glioblastoma multiforme, and pancreatic ductal adenocarcinoma highlight proteomics' clinical applications, from subtyping cancers to identifying diagnostic markers. Moreover, proteomic data augment molecular tumor boards by providing deeper insights into pathway activities and genomic mutations, supporting personalized treatment decisions. Overall, proteomics contributes significantly to advancing our understanding of cellular biology and improving clinical care.


Evaluation and management of increased intracranial pressure.
: Persistent elevation of intracranial pressure (ICP) can lead to cerebral ischemia, brain herniation, and possibly death. Understanding the fundamental mechanism that contributes to the rise in ICP and recognizing the specific intracranial compartment involved (brain, CSF, or blood) can lead to early diagnosis and effective treatment. This article reviews the conceptual approach to a patient with elevated ICP. : The overall goal for patients with intracranial hypertension is to lower ICP below 20 mm Hg and to maintain cerebral perfusion pressure (CPP) between 60 mm Hg and 90 mm Hg to provide sufficient cerebral perfusion. Commonly used therapeutic interventions to lower ICP include decompressive surgery, osmotherapy, hyperventilation, barbiturate-induced metabolic suppression, and hypothermia; however, the selection of these interventions must be tailored to each patient by considering the particular diagnosis and intracranial pathophysiology. Emerging evidence suggests that cerebral autoregulation may fail at excessively high CPP (CPP greater than 100 mm Hg) as well as at low CPP (CPP less than 60 mm Hg) and that maximal cerebral autoregulation capacity may be achieved at an optimal CPP of 70 mm Hg to 90 mm Hg. : Increased ICP is a neurologic emergency that requires immediate intervention. However, the treatment itself is not without risk; thus, the risks and benefits of medical and surgical intervention must be carefully evaluated and individualized for each patient.


Distribution, feeding behavior and control strategies of the exotic land snail Achatina fulica (Gastropoda: Pulmonata) in the northeast of Brazil.
The goal of this study was to document the distribution and establishment A. fulica such as their feeding preference and behavior in situ. The study was carried out at the city of Lauro de Freitas, Bahia state, Brazil, between November 2001 and November 2002. We used catch per unit effort methods to determine abundance, distribution, habitat choice and food preferences. The abundance and distribution of A. fulica was most representative in urban area, mainly near to the coastline. Lots and house gardens were the most preferred sites during active hours. The results indicated that A. fulica started their activity at the end of the evening and stopped in mid-morning. Their preferred food were vascular plants such as Hibiscus syriacus, Ricinus communis, Carica papaya, Galinsonga coccinea, Lippia alba, Ixora coccinea, Musa parasidisiaca, Mentha spicata and Cymbopogon citrates. Our results indicate that A. fulica are well adapted and established in this city and modified environments facilitate their establishment and dispersion. However, human perturbation, such as clearance of lots could be limiting for the persistence of A. fulica populations.


The Feasibility of Thoracoscopic Resection in Bronchiectasis.
Minimally invasive surgery is the treatment of choice in early-stage lung cancer. However, experience in infectious lung disease, primarily bronchiectasis, is limited probably because of the presence of dense pleural adhesions, multiple lymph nodes, and spiral bronchial arteries. The present study shows our experience of video-assisted thoracoscopic surgery (VATS) lobectomy and segmentectomy in the treatment of bronchiectasis. Patients who underwent VATS lobectomy or segmentectomy in our clinic between April 2008 and 2015 were retrospectively evaluated. Surgery was indicated in patients with radiologic localized bronchiectasis who also had a history of recurrent lower respiratory tract infection or expectorating mucopurulent secretion. The patients were analyzed in terms of age, sex, thoracotomy conversion rate, postoperative drainage amount, chest tube removal time, length of hospital stay, morbidity, and mortality. A total of 44 patients initially underwent VATS pulmonary anatomic resection and 41 procedures were completed on 40 patients. One patient had bilateral resection. Fifteen patients were male individuals and 26 were female individuals. The average age was 31.4 (15 to 57) years. Forty lobectomies and 1 segmentectomy were performed. The conversion rate was 6.8%. VATS was performed on 28 patients by 3 ports, 8 patients by 2 ports, and 5 patients by a single port. In terms of anatomic resections, 18 patients underwent left lower lobectomy, 8 right lower lobectomy, 8 middle lobectomy, 6 right upper lobectomy, and 1 patient underwent lingular segmentectomy. No major postoperative complication or mortality was observed. Prolonged air leak was observed in 2 patients and subcutaneous emphysema occurred in 2 patients. The average postoperative drainage amount, chest tube removal time, and length of hospital stay were 320 mL, 3.1 (1 to 11) days, and 4.6 (2 to 11) days, respectively. VATS pulmonary resection is a safe, feasible, and effective treatment in the surgery of bronchiectasis with low morbidity and mortality rates. Moreover, because of cosmetic results, patients with benign diseases such as bronchiectasis could be initiated by minimally invasive surgery options just like patients with malignancies.


Hook, Line and Infection: A Guide to Culturing Parasites, Establishing Infections and Assessing Immune Responses in the Three-Spined Stickleback.
The three-spined stickleback (Gasterosteus aculeatus) is a model organism with an extremely well-characterized ecology, evolutionary history, behavioural repertoire and parasitology that is coupled with published genomic data. These small temperate zone fish therefore provide an ideal experimental system to study common diseases of coldwater fish, including those of aquacultural importance. However, detailed information on the culture of stickleback parasites, the establishment and maintenance of infections and the quantification of host responses is scattered between primary and grey literature resources, some of which is not readily accessible. Our aim is to lay out a framework of techniques based on our experience to inform new and established laboratories about culture techniques and recent advances in the field. Here, essential knowledge on the biology, capture and laboratory maintenance of sticklebacks, and their commonly studied parasites is drawn together, highlighting recent advances in our understanding of the associated immune responses. In compiling this guide on the maintenance of sticklebacks and a range of common, taxonomically diverse parasites in the laboratory, we aim to engage a broader interdisciplinary community to consider this highly tractable model when addressing pressing questions in evolution, infection and aquaculture.


Ranolazine. A metabolic modulator for the treatment of chronic stable angina.
Ranolazine is a novel new antianginal agent currently under investigation as monotherapy and adjunct therapy for the treatment of chronic stable angina. While the mechanism of action of ranolazine is not completely understood, it is believed to involve a reduction in fatty acid oxidation, ultimately leading to a shift in myocardial energy production from fatty acid oxidation to glucose oxidation. Since the oxidation of glucose requires less oxygen than the oxidation of fatty acids, ranolazine can help maintain myocardial function in times of ischemia. In addition, ranolazine has minimal effect on blood pressure and heart rate. Ranolazine, by inhibiting cellular ionic channels, prolongs the corrected QT interval. However, ranolazine has not yet been associated with any incidences of ventricular arrhythmia. The clinical data with ranolazine focuses on its use in chronic stable angina, where it has been shown to increase exercise tolerance and decrease angina compared with placebo, as well as in combination with beta-blockers and calcium channel blockers. The use of ranolazine for other cardiac conditions and the effect of ranolazine on morbidity and mortality remains to be determined. Ongoing clinical trials will help further establish the role of ranolazine in the treatment of cardiovascular disorders.


Needle Aspiration and Cytology for Suspected Osteoarticular Tuberculosis in Children.
Introduction: Early diagnosis of osteoarticular tuberculosis (OATB) is essential to prevent significant functional disability. There is no single test for diagnosis. Despite an array of investigations available, definitive diagnosis at early stage before starting antitubercular drugs is still a challenge. Materials and Methods: A cross sectional study was carried out between February 2016 and October 2017. All children less than 18 years of age with suspected osteoarticular tuberculosis were included. The cases were subjected to simple needle aspiration from whichever site was accessible. Multiple sample aspirations were done at site of involvement. Smears were prepared from the aspirated material. Results: Ziehl-Neelsen staining for Acid Fast Bacilli (AFB) showed deep pink red rods under light microscopy. Features suggestive of tuberculosis can be seen by May-Grünwald-Giemsa (MGG) staining. Auramine-O staining method of detecting AFB under fluorescent microscope shows the bacilli as greenish yellow slender curved rods in dark background. Fluorescent microscopy has higher sensitivity and comparable specificity. In our study, microbiological confirmation of OATB could be done in 100% cases where the lesion could be accessed for aspiration. The molecular techniques are relatively more expensive and not available everywhere. Conclusion: Meticulous search for AFB in a well stained smear using three different staining methods provides a direct evidence of infection over costly imaging especially in poor patients seen in resource limited settings.


Metabolic defects in immunodeficiency diseases.
There are two ways to find the cause of primary immunodeficiency diseases. One approach is to start with the immune defect and work backwards, using in vitro techniques to define where the primary abnormality lies in the immune response. Immunologists favour this approach for obvious reasons; and it is not without virtue since, for example, it has shown that the defect in most cases of primary hypogammaglobulinaemia is due to a failure of B lymphocyte maturation. The alternative approach is to screen empirically for defects in biochemical pathways in the hope of finding a clue which will eventually lead to the underlying disorder. This is a sensible approach in diseases which are clearly inherited (e.g. X-linked hypogammaglobulinaemia) but is less attractive in a disease such as late onset hypogammaglobulinaemia which is not obviously inherited. In practice, such procedures involve screening the urine for abnormalities in the quality or quantity of excreted compounds. Another way is to screen for abnormalities in organelle integrity by measuring the activity of various enzymes in subcellular fractions. In reality, the clue to the metabolic defect is usually discovered by accident, the prime example in our field being the discovery of adenosine deaminase (ADA) deficiency.


Characterizing the microbial colonization of a dolostone quarry: implications for stone biodeterioration and response to biocide treatments.
This study examines the microbial colonization of three fronts of an abandoned dolostone quarry (Redueña, Madrid, Spain) exposed to atmospheric conditions for different time periods since Roman times to the present. Through scanning electron microscopy in backscattered electron mode (SEM-BSE), endolithic colonization was predominantly detected in the most recently exposed front, while in the longer exposed quarry fronts, epilithic forms of growth were most often observed. These observations were confirmed by denaturing gradient gel electrophoresis (DGGE) analysis. Based on the distribution pattern of microbial colonization in the different quarry fronts, we then established a sequence of colonization events that took place over this long time frame. Bioalteration processes related to this sequential colonization were also identified. Characterizing these sequential processes can be useful for interpreting biodeterioration processes in historic dolostone monuments, especially those affecting constructions in the area of the Redueña stone quarry. In a second experimental stage, different biocide treatments were tested on this quarry rock to find the best way to avoid the microbial colonization effects identified. Through combined SEM-BSE/DGGE analysis, the efficacy of several biocides against the microorganisms inhabiting the dolostones was assessed after 4 and 16 months treatment. In general, all treatments were effective at reducing around 80% of the lichen cover, although effects on endolithic lithobiontic communities were dependent on how well the rock surface had been mechanically cleaned prior to treatment and gradually disappeared over time.


Surgical approaches to postcholecystectomy choledocholithiasis.
One hundred sixteen cases if postcholecystectomy choledocholithiasis were assessed after different methods of surgical approach. The evidence that previous surgery, advanced age, and long history of symptoms are associated with a high incidence of bile infection and with advanced histological changes in the biliary ductal apparatus was considered as an index of biliary stasis. It is for these patients that a drainage procedure supplementary to choledochotomy was thought to be warranted. Both choledochoduodenostomy and sphincteroplasty were carried out in this series of patients as drainage procedures supplementary to choledochotomy. Choledochoduodenostomy appears to offer a definitive solution to this problem, and it has been shown to be safe and simple to carry out without mortality and with a very low morbidity.


Ga(3+)/Ln(3+) Metallacrowns: A Promising Family of Highly Luminescent Lanthanide Complexes That Covers Visible and Near-Infrared Domains.
Luminescent lanthanide(III)-based molecular scaffolds hold great promises for materials science and for biological applications. Their fascinating photophysical properties enable spectral discrimination of emission bands that range from the visible to the near-infrared (NIR) regions. In addition, their strong resistance to photobleaching makes them suitable for long duration or repeated biological experiments using a broad range of sources of excitation including intense and focalized systems such as lasers (e.g., confocal microscopy). A main challenge in the creation of luminescent lanthanide(III) complexes lies in the design of a ligand framework that combines two main features: (i) it must include a chromophoric moiety that possesses a large molar absorptivity and is able to sensitize several different lanthanide(III) ions emitting in the visible and/or in the near-infrared, and (ii) it must protect the Ln(3+) cation by minimizing nonradiative deactivation pathways due to the presence of -OH, -NH and -CH vibrations. Herein, a new family of luminescent Ga(3+)/Ln(3+) metallacrown (MC) complexes is reported. The MCs with the general composition [LnGa4(shi)4(C6H5CO2)4(C5H5N) (CH3OH)] (Ln-1, Ln = Sm(3+)-Yb(3+)) were synthesized in a one pot reaction using salicylhydroxamic acid (H3shi) with Ga(3+) and Ln(3+) nitrates as reagents. The molecular structure of [DyGa4(shi)4(C6H5CO2)4(C5H5N) (CH3OH)] was obtained by X-ray analysis of single crystals and shows that the complex is formed as a [12-MCGa(III)shi-4] core with four benzoate molecules bridging the central Dy(3+) ion to the Ga(3+) ring metals. The powder X-ray diffraction analysis demonstrates that all other isolated complexes are isostructural. The extended analysis of the luminescence properties of these complexes, excited by the electronic states of the chromophoric ligands, showed the presence of characteristic, sharp f-f transitions that can be generated not only in the NIR (Sm, Dy, Ho, Er, Yb) but also in the visible (Sm, Eu, Tb, Dy, Tm). All Ln-1 complexes possess very high quantum yield values with respect to other literature compounds, indicating a good sensitization efficiency of the [12-MCGa(III)shi-4] scaffold. Especially, as of today, the Yb-1 complex exhibits the highest NIR quantum yield reported for a lanthanide(III) complex containing C-H bonds with a value of 5.88(2)% in the solid state. This work is a significant step forward toward versatile, easily prepared luminescent lanthanide(III) complexes suitable for a variety of applications including highly in demand biological imaging, especially in the NIR domain.


Sustained Inhibition of VEGF and TNF-α Achieves Multi-Ocular Protection and Prevents Formation of Blood Vessels after Severe Ocular Trauma.
This study aimed to develop a clinically feasible and practical therapy for multi-ocular protection following ocular injury by using a thermosensitive drug delivery system (DDS) for sustained delivery of TNF-α and VEGF inhibitors to the eye. A thermosensitive, biodegradable hydrogel DDS (PLGA-PEG-PLGA triblock polymer) loaded with 0.7 mg of adalimumab and 1.4 mg of aflibercept was injected subconjunctivally into Dutch-belted pigmented rabbits after corneal alkali injury. Control rabbits received 2 mg of IgG-loaded DDS or 1.4 mg of aflibercept-loaded DDS. Animals were followed for 3 months and assessed for tolerability and prevention of corneal neovascularization (NV), improvement of corneal re-epithelialization, inhibition of retinal ganglion cell (RGC) and optic nerve axon loss, and inhibition of immune cell infiltration into the cornea. Drug-release kinetics was assessed in vivo using an aqueous humor protein analysis. A single subconjunctival administration of dual anti-TNF-α/anti-VEGF DDS achieved a sustained 3-month delivery of antibodies to the anterior chamber, iris, ciliary body, and retina. Administration after corneal alkali burn suppressed CD45+ immune cell infiltration into the cornea, completely inhibited cornea NV for 3 months, accelerated corneal re-epithelialization and wound healing, and prevented RGC and optic nerve axon loss at 3 months. In contrast, anti-VEGF alone or IgG DDS treatment led to persistent corneal epithelial defect (combined: <1%; anti-VEGF: 15%; IgG: 10%, of cornea area), increased infiltration of CD45+ immune cells into the cornea (combined: 28 ± 20; anti-VEGF: 730 ± 178; anti-IgG: 360 ± 186, cells/section), and significant loss of RGCs (combined: 2.7%; anti-VEGF: 63%; IgG: 45%) and optic nerve axons at 3 months. The aqueous humor protein analysis showed first-order release kinetics without adverse effects at the injection site. Concomitant inhibition of TNF-α and VEGF prevents corneal neovascularization and ameliorates subsequent irreversible damage to the retina and optic nerve after severe ocular injury. A single subconjunctival administration of this therapy, using a biodegradable, slow-release thermosensitive DDS, achieved the sustained elution of therapeutic levels of antibodies to all ocular tissues for 3 months. This therapeutic approach has the potential to dramatically improve the outcomes of severe ocular injuries in patients and improve the therapeutic outcomes in patients with retinal vascular diseases.


Drug-loaded, bivalent-bottle-brush polymers by graft-through ROMP.
Graft-through ring-opening metathesis polymerization (ROMP) using ruthenium N-heterocyclic carbene catalysts has enabled the synthesis of bottle-brush polymers with unprecedented ease and control. Here we report the first bivalent-brush polymers; these materials were prepared by graft-through ROMP of drug-loaded polyethylene-glycol (PEG) based macromonomers (MMs). Anticancer drugs doxorubicin (DOX) and camptothecin (CT) were attached to a norbornene-alkyne-PEG MM via a photocleavable linker. ROMP of either or both drug-loaded MMs generated brush homo- and co-polymers with low polydispersities and defined molecular weights. Release of free DOX and CT from these materials was initiated by exposure to 365 nm light. All of the CT and DOX polymers were at least 10-fold more toxic to human cancer cells after photoinitiated drug release while a copolymer carrying both CT and DOX displayed 30-fold increased toxicity upon irradiation. Graft-through ROMP of drug-loaded macromonomers provides a general method for the systematic study of structure-function relationships for stimuli-responsive polymers in biological systems.


Combined radiomics of primary tumour and bone metastasis improve the prediction of EGFR mutation status and response to EGFR-TKI therapy for NSCLC.
To develop radiomics models of primary tumour and spinal metastases to predict epidermal growth factor receptor (EGFR) mutations and therapeutic response to EGFR-tyrosine kinase inhibitor (TKI) in patients with metastatic non-small-cell lung cancer (NSCLC). We enrolled 203 patients with spinal metastases between December 2017 and September 2021, classified as patients with the EGFR mutation or EGFR wild-type. All patients underwent thoracic CT and spinal MRI scans before any treatment. Radiomics analysis was performed to extract features from primary tumour and metastases images and identify predictive features with the least absolute shrinkage and selection operator. Radiomics signatures (RS) were constructed based on primary tumour (RS-Pri), metastases (RS-Met), and in combination (RS-Com) to predict EGFR mutation status and response to EGFR-TKI. Receiver operating characteristic (ROC) curve analysis with 10-fold cross-validation was applied to assess the performance of the models. To predict the EGFR mutation status, the RS based on the combination of primary tumour and metastases improved the prediction AUCs compared to those based on the primary tumour or metastasis alone in the training (RS-Com-EGFR: 0.927) and validation (RS-Com-EGFR: 0.812) cohorts. To predict response to EGFR-TKI, the developed RS based on combined primary tumour and metastasis generated the highest AUCs in the training (RS-Com-TKI: 0.880) and validation (RS-Com-TKI: 0.798) cohort. Primary NSCLC and spinal metastases can provide complementary information to predict the EGFR mutation status and response to EGFR-TKI. The developed models that integrate primary lesions and metastases may be potential imaging markers to guide individual treatment decisions.


Cutting edge: the class II transactivator prevents activation-induced cell death by inhibiting Fas ligand gene expression.
The Fas:Fas ligand pathway is critical in regulating immune homeostasis by eliminating activated T cells that proliferated in response to an infection. Here, we show that the MHC class II transactivator (CIITA) can suppress this pathway by inhibiting transcription of the Fas ligand gene. CIITA can effectively repress transcription from the Fas ligand promoter in both T cell lines as well as primary cells. The repression appears to be at least partly due to interference of NFAT-mediated induction of Fas ligand gene transcription. T cells that express CIITA constitutively do not up-regulate Fas ligand on the cell surface after activation via the TCR. Consequently, these cells lack the ability to undergo activation-induced cell death, and to kill Fas-bearing target cells.


[A role of traumatic brain injury in the dynamics of combat posttraumatic stress disorder].
To explore dynamics of clinical signs of posttraumatic stress disorder (PTSD) and their causal relationship with organic brain changes. A longitudinal observational study of 87 combatants of the Karabakh war (1992-1994) was conducted in 2009-2011. Two groups of patients were singled out. The first group included 45 veterans with mild combat cranial/brain injury with the following development of PTSD; the second group consisted of 42 veterans with organic brain lesions of traumatic origin. Somatic and neurological examination of patients and evaluation of their status using psychometric and other scales (CAPS, the Mississippi Scale for Combat-Related PTSD) were performed. The analysis of patient's status at examination period and at the moment of injury demonstrated that PTSD patients, despite the relative reduction of posttraumatic symptoms, had higher level of all PTSD symptoms during the whole period of the disease (15-18 years) with the simultaneous aggravation of organic mental symptoms. In patients with organic brain lesions, the symptoms were more pronounced immediately after the traumatic event compared to the period of observation.


Systolic Function and Intraventricular Mechanical Dyssynchrony Assessed by Advanced Speckle Tracking Imaging with N-terminal Prohormone of Brain Natriuretic Peptide for Outcome Prediction in Chronic Heart Failure Patients.
The aim of this study was to assess longitudinal systolic function and mechanical synchrony parameters derived from advanced speckle tracking echocardiography (STE) and to determine their correlation with N-terminal prohormone of brain natriuretic peptide (NT-proBNP). Their influence on heart failure (HF) outcomes at a one-year follow-up, not clarified in previous studies, was also examined. Advanced STE was performed from August 2009 to January 2012 in 103 chronic HF patients at the University Kebangsaan Malaysia Medical Center to assess their longitudinal systolic function and synchrony parameters; NT-proBNP blood measurement was taken at the same time. Longitudinal cardiac velocity; strain; strain rate; displacement; intraventricular mechanical dyssynchrony based on the standard deviation (SD) of time to peak systolic strain rate (Tsr-SD); displacement, and antero-septal to posterior (AS-P) delay were associated with cardiac events. In multivariate analysis, NT-proBNP and AS-P delay were identified as independent predictors for cardiac events. Significant correlations were found between NT-proBNP and longitudinal velocity; displacement; strain; strain rate, and ejection fraction. Log NT-proBNP levels correlated moderately with the SD of time to peak displacement and to peak strain, and there was a small correlation with maximal differences and SD of time to peak velocity. A multiple linear analysis revealed that NT-proBNP levels significantly correlated to age, ejection fraction and velocity. Advanced STE is a promising technique which accelerates the clinical application of the quantification of myocardial function and synchrony. STE parameters and NT-proBNP have the ability to identify patients at higher risk of death and hospitalisation.


Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification.
Vascular calcification powerfully predicts mortality and morbidity from cardiovascular disease. Men have a greater risk of cardiovascular disease, compared to women of a similar age. These gender disparities suggest an influence of sex hormones. Testosterone is the primary and most well-recognised androgen in men. Therefore, we addressed the hypothesis that exogenous androgen treatment induces vascular calcification. Immunohistochemical analysis revealed expression of androgen receptor (AR) in the calcified media of human femoral artery tissue and calcified human valves. Furthermore, in vitro studies revealed increased phosphate (Pi)-induced mouse vascular smooth muscle cell (VSMC) calcification following either testosterone or dihydrotestosterone (DHT) treatment for 9 days. Testosterone and DHT treatment increased tissue non-specific alkaline phosphatase (Alpl) mRNA expression. Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM-ARKO) VSMCs compared to WT. Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression. However, intriguingly, a counter-intuitive increase in Alpl was observed. These novel data demonstrate that androgens play a role in inducing vascular calcification through the AR. Androgen signalling may represent a novel potential therapeutic target for clinical intervention.


Evaluation of psychological symptoms in patients before and after simultaneous pancreas-kidney transplantation: a single-center cross-sectional study.
Simultaneous pancreas-kidney transplantation (SPKT) brings several benefits for insulin-dependent type-1 diabetic patients associated with end-stage renal disease (ESRD). However, data on psychological outcomes for the waiting list and the transplanted patients are still lacking. Using the psychological Beck inventories of anxiety (BAI) and depression (BDI), 39 patients on the waiting list were compared to 88 post-transplanted patients who had undergone SPKT. Significant differences were found regarding depression (p = 0.003) but not anxiety (p = 0.161), being the pretransplant patients more vulnerable to psychological disorders. Remarkable differences were observed relative to the feeling of punishment (p < 0.001) and suicidal thoughts (p = 0.008) between the groups. It was observed that patients who waited a longer period for the transplant showed more post-transplant anxiety symptoms due to the long treatment burden (p = 0.002). These results demonstrated the positive impact of SPKT on psychological aspects related to depression when comparing the groups. The high number of stressors in the pretransplant stage impacts more severely the psychosocial condition of the patient.


Local field potentials and spikes in the human medial temporal lobe are selective to image category.
Local field potentials (LFPs) reflect the averaged dendrosomatic activity of synaptic signals of large neuronal populations. In this study, we investigate the selectivity of LFPs and single neuron activity to semantic categories of visual stimuli in the medial temporal lobe of nine neurosurgical patients implanted with intracranial depth electrodes for clinical reasons. Strong selectivity to the category of presented images was found for the amplitude of LFPs in 8% of implanted microelectrodes and for the firing rates of single and multiunits in 14% of microelectrodes. There was little overlap between the LFP- and spike-selective microelectrodes. Separate analysis of the power and phase of LFPs revealed that the mean phase was category-selective around the theta frequency range and that the power of the LFPs was category-selective for high frequencies around the gamma rhythm. Of the 36 microelectrodes with amplitude-selective LFPs, 30 were found in the hippocampus. Finally, it was possible to readout information about the category of stimuli presented to the patients with both spikes and LFPs. Combining spiking and LFP activity enhanced the decoding accuracy in comparison with the accuracy obtained with each signal alone, especially for short time intervals.


Pbx-Hox heterodimers recruit coactivator-corepressor complexes in an isoform-specific manner.
Homeobox (hox) proteins have been shown to regulate cell fate and segment identity by promoting the expression of specific genetic programs. In contrast to their restricted biological action in vivo, however, most homeodomain factors exhibit promiscuous DNA binding properties in vitro, suggesting a requirement for additional cofactors that enhance target site selectivity. In this regard, the pbx family of homeobox genes has been found to heterodimerize with and thereby augment the DNA binding activity of certain hox proteins on a subset of potential target sites. Here we examine the transcriptional properties of a forced hox-pbx heterodimer containing the pancreas-specific orphan homeobox factor pdx fused to pbx-1a. Compared to the pdx monomer, the forced pdx-pbx1a dimer, displayed 10- to 20-fold-higher affinity for a consensus hox-pbx binding site but was completely unable to bind a hox monomer recognition site. The pdx-pbx dimer stimulated target gene expression via an N-terminal trans-activation domain in pdx that interacts with the coactivator CREB binding protein. The pdx-pbx dimer was also found to repress transcription via a C-terminal domain in pbx-1a that associates with the corepressors SMRT and NCoR. The transcriptional properties of the pdx-pbx1 complex appear to be regulated at the level of alternative splicing; a pdx-pbx polypeptide containing the pbx1b isoform, which lacks the C-terminal extension in pbx1a, was unable to repress target gene expression via NCoR-SMRT. Since pbx1a and pbx1b are differentially expressed in endocrine versus exocrine compartments of the adult pancreas, our results illustrate a novel mechanism by which pbx proteins may modulate the expression of specific genetic programs, either positively or negatively, during development.


Who benefits most from THC:CBD spray? Learning from clinical experience.
Patients with multiple sclerosis (MS) represent a diverse and heterogeneous population varying in terms of disease type, its severity and variable progression/time-course, and with regard to the wide range of presenting symptoms. Consequently, detailed experience with individual patients is important to provide examples of therapy to specific patient types. In this article, real-life data from clinical practice showing specific aspects relating to use of 9-delta-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex®) in patients with moderate to severe spasticity resistant to usual therapy will be presented. Three common clinical scenarios will be considered: MS patients with resistance to usual spasticity therapies; patients with impairment in MS spasticity symptoms; MS patients with relevant impairment in quality of life/activities of daily living (QoL/ADL). These case reports highlight the diverse nature of the MS spasticity population and they show the possible usefulness of THC:CBD oromucosal spray in individual patients with moderate to severe spasticity resistant to existing therapies, within the frame of use approved after large clinical trial results. Perhaps the most important finding is the possibility of obtaining relevant improvements in QoL/ADL in some patients with resistant MS spasticity, allowing them to engage back in physical and social activities.


An evaluation of the costs and outcome of adult intensive care in two units in the UK.
To test the feasibility and value of an economic appraisal of intensive care, a retrospective follow-up study was performed in two intensive care units in England. Clinical activity data was extracted from the records of 100 consecutive admissions to each unit and used to cost the care received by each patient during their stay in the units. Outcome was measured in terms of survival and quality of life six months after admission. Mortality at discharge from the units was 25% and 15% rising to 31% and 38% respectively six months after admission. Between one-third and one-half of patients alive at six months reported that their health continued to restrict aspects of their daily activities and one-fifth reported serious disability or distress. Total costs averaged 2,000 pounds and 2,280 pounds, equivalent to 525 pounds and 465 pounds per in-patient day. Poor outcome was associated, though not always significantly, with increased age, severity of illness and increased costs. The small sample size and heterogeneous nature of intensive care prevent firm conclusions being drawn from this study but the results indicate that such investigations are both feasible and potentially rewarding.


Sinomenine sensitizes human gastric cancer cells to cisplatin through negative regulation of PI3K/AKT/Wnt signaling pathway.
Sinomenine (SIN) has been reported its antitumor effects on various types of human cancers, but there is no available information regarding the antitumor effects of SIN and cisplatin on gastric cancer. Here, we examined the antitumor effects of SIN combined with cisplatin on gastric cancer cells as well as the underlying biological mechanisms. CCK-8 assay and Calcusyn 2.0 software analysis, Hoechst 33258 staining and flow cytometry, transwell assay showed that SIN and cisplatin synergistically inhibited growth, induced apoptosis, and suppressed invasion than did either drug alone in gastric cancer cells. Interestingly, no change in the AKT level was found, whereas SIN and cisplatin led to a dramatic decrease in p-AKT level compared with either alone treatment. SIN and cisplatin further decreased the Bcl-2, procaspase-3, and β-catenin, but increased Bax, cleaved dcaspase 3, MMP9, and MMP2 in combined group than in either alone group. Immunofluorescence staining showed again a significant decrease in nucleus β-catenin was found in combined group. These data suggested that SIN sensitizes human gastric cancer cells to cisplatin through negative regulation of PI3K/AKT/Wnt signaling pathway. In conclusion, SIN and cisplatin exerted synergistic antitumor effects in gastric cancer cells and might constitute a promising therapeutic approach for gastric cancer.


Highly prevalent TERT promoter mutations in aggressive thyroid cancers.
Mutations 1 295 228 C>T and 1 295 250 C>T (termed C228T and C250T respectively), corresponding to -124 C>T and -146 C>T from the translation start site in the promoter of the telomerase reverse transcriptase (TERT) gene, have recently been reported in human cancers, but not in thyroid cancers yet. We explored these mutations in thyroid cancers by genomic sequencing of a large number of primary tumor samples. We found the C228T mutation in 0 of 85 (0.0%) benign thyroid tumors, 30 of 257 (11.7%) papillary thyroid cancers (PTC), 9 of 79 (11.4%) follicular thyroid cancers (FTC), 3 of 8 (37.5%) poorly differentiated thyroid cancers (PDTC), 23 of 54 (42.6%) anaplastic thyroid cancers (ATC), and 8 of 12 (66.7%) thyroid cancer cell lines. The C250T mutation was uncommon, but mutually exclusive with the C228T mutation, and the two mutations were collectively found in 11 of 79 (13.9%) FTC, 25 of 54 (46.3%) ATC, and 11 of 12 (91.7%) thyroid cancer cell lines. Among PTC variants, the C228T mutation was found in 4 of 13 (30.8%) tall-cell PTC (TCPTC), 23 of 187 (12.3%) conventional PTC, and 2 of 56 (3.6%) follicular variant PTC samples. No TERT mutation was found in 16 medullary thyroid cancer samples. The C228T mutation was associated with the BRAF V600E mutation in PTC, being present in 19 of 104 (18.3%) BRAF mutation-positive PTC vs 11 of 153 (7.2%) the BRAF mutation-negative PTC samples (P=0.0094). Conversely, BRAF mutation was found in 19 of 30 (63.3%) C228T mutation-positive PTC vs 85 of 227 (37.4%) C228T mutation-negative PTC samples (P=0.0094). We thus for the first time, to our knowledge, demonstrate TERT promoter mutations in thyroid cancers, that are particularly prevalent in the aggressive thyroid cancers TCPTC, PDTC, ATC and BRAF mutation-positive PTC, revealing a novel genetic background for thyroid cancers.


Enteric-coated mycophenolate sodium versus azathioprine in patients with active systemic lupus erythematosus: a randomised clinical trial.
To compare the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS) versus azathioprine (AZA) in patients with active systemic lupus erythematosus (SLE) disease. A multicentre, 24-month, superiority, open-label, randomised controlled trial (NCT01112215) was conducted with 240 patients (120 per arm) receiving either EC-MPS (target dose: 1440 mg/day) or AZA (target dose: 2 mg/kg/day) in addition to prednisone and/or antimalarials. The primary endpoint was the proportion of patients achieving clinical remission, assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG), at 3 and 24 months. Secondary endpoints included time to clinical remission, BILAG A and B flare rates, time to flare, corticosteroid reduction and adverse events (AEs). Proportion of patients achieving clinical remission (clinical SLEDAI=0) was higher in the EC-MPS group at 3 (32.5% vs 19.2%; treatment difference, 13.3 (CI 2.3 to 24), p=0.034) and 24 months (71.2% vs 48.3%; treatment difference, 22.9 (CI 10.4 to 34.4), p<0.001). EC-MPS was superior with respect to time to clinical remission (HR 1.43; 95% CI 1.07 to 1.91; p=0.017). BILAG A/B and B flares occurred more frequently in the AZA group (71.7% vs 50%, p=0.001 and 21.67% vs 8.3%, p=0.004, respectively). EC-MPS was superior with respect to time to first BILAG A/B (HR 1.81; 95% CI 1.3 to 2.56; p=0.0004) and BILAG A flare (HR 2.84; 95% CI 1.37 to 5.89; p=0.003). AEs were similar in both groups except for leucopenia that occurred more frequently with AZA. EC-MPS was superior to AZA in treating SLE and preventing further relapses. NCT01112215; Results.


Energetics and the evolution of human brain size.
The human brain stands out among mammals by being unusually large. The expensive-tissue hypothesis explains its evolution by proposing a trade-off between the size of the brain and that of the digestive tract, which is smaller than expected for a primate of our body size. Although this hypothesis is widely accepted, empirical support so far has been equivocal. Here we test it in a sample of 100 mammalian species, including 23 primates, by analysing brain size and organ mass data. We found that, controlling for fat-free body mass, brain size is not negatively correlated with the mass of the digestive tract or any other expensive organ, thus refuting the expensive-tissue hypothesis. Nonetheless, consistent with the existence of energy trade-offs with brain size, we find that the size of brains and adipose depots are negatively correlated in mammals, indicating that encephalization and fat storage are compensatory strategies to buffer against starvation. However, these two strategies can be combined if fat storage does not unduly hamper locomotor efficiency. We propose that human encephalization was made possible by a combination of stabilization of energy inputs and a redirection of energy from locomotion, growth and reproduction.


Implementation of a Universal Screening Process for Substance Use in Pregnancy.
To implement a standardized universal substance use screening process in an outpatient prenatal clinic at an urban tertiary care hospital. Using a quality-improvement framework that involved process modeling, stakeholder analyses, and plan-do-study-act cycles, we implemented universal substance use screening for prenatal patients using a modified 5Ps screening tool (Parents, Peers, Partner, Past, Present). Implementation included an operational workflow based on the SBIRT (Screening, Brief Intervention, Referral to Treatment) model. The primary outcome measure was percentage of patients who were screened for substance use, with a goal of 90% screened. Secondary outcome measures were percentage who screened positive and percentage of the time a positive screen resulted in documentation of a brief intervention by a health care practitioner. Over a 19-month implementation period, 733 patient encounters were sampled. A substance use screen was completed in 618 (84%). We exceeded our goal of screening 90% of eligible patients for the final 6 months of data collection. Of the 618 completed screens, 124 (20%) screened positive. Health care practitioner documentation of brief interventions for patients with a positive screen reached 80% in the final phase of implementation, but then declined to 50% by the completion of the study period. A sustainable and generalizable process to carry out substance use screening within a large prenatal practice is feasible, and assisted with identification of patients not known to be at risk. Further efforts are needed to evaluate how to sustain health care practitioner documentation of intervention in response to positive screens.


Sound localization in anurans. I. Evidence of binaural interaction in dorsal medullary nucleus of bullfrogs (Rana catesbeiana).
1. The response patterns of single cells to monaural and binaural acoustic stimuli were studied in the dorsal medullary nucleus of the bullfrog (Rana catesbeiana). This nucleus represents the first ascending center in the anuran's central auditory nervous system. 2. Of the 142 cells isolated, 75 units responded only to monaural stimulation. Approximately 80% of these monaural cells could be excited by the ipsilateral ear, while the remaining 20% received their excitatory input from the contralateral ear. The other 67 units responded to binaural stimuli. Of these binaural cells, 14 could be excited by either contralateral or ipsilateral stimuli, and the threshold and best excitatory frequency were similar for each ear (EE). The other 53 binaural cells (EI) could be excited by stimulation of one ear and inhibited by stimulation of the other ear; for almost all of these cells the contralateral ear was excitatory and the ipsilateral ear was inhibitory. The best inhibitory frequency for one ear was approximately the same as the best excitatory frequency for the other ear, and the threshold for inhibition was near the threshold for excitation. 3. The tuning curves for all of the cells in the dorsal medullary nucleus were unimodal with "Q" values ranging from 0.4 to 4. The excitatory thresholds were widely scattered between 22 and 115 dB SPL. 4. The distribution of best excitatory frequencies for the monaural cells comprised three groups: 200-300, 500-800, and 900-1,600 Hz. The best excitatory frequencies of the binaural cells were scattered over this entire range, with a broad peak around 200-800 Hz. 5. Approximately 80% of the cells in the dorsal nucleus responded tonically throughout the duration of an excitatory tone burst. The remaining 20% of the cells responded phasically during the transient stages of a tone burst over a wide intensity range. 6. Response latencies were compared for the two types of monaural cells to tones at their best exciatatory frequencies at 10 dB above threshold. The latencies for the contralaterally excitable cells were just a few milliseconds longer than the latencies for the ipsilaterally excitable cells. For binaural cells the latency for contralateral stimulation was only 1-2 ms longer than for ipsilateral stimulation. It was concluded that the contralateral input to the dorsal medullary nucleus is not of efferent descending origin from higher auditory centers. 7. All of the binaural EI cells were sensitive to small interaural intensity differences and many were also sensitive to minute interaural time differences. These cells likely play a role in localization of sounds of significance to anurans.


Analysis of slug tests in formations of high hydraulic conductivity.
A new procedure is presented for the analysis of slug tests performed in partially penetrating wells in formations of high hydraulic conductivity. This approach is a simple, spreadsheet-based implementation of existing models that can be used for analysis of tests from confined or unconfined aquifers. Field examples of tests exhibiting oscillatory and nonoscillatory behavior are used to illustrate the procedure and to compare results with estimates obtained using alternative approaches. The procedure is considerably simpler than recently proposed methods for this hydrogeologic setting. Although the simplifications required by the approach can introduce error into hydraulic-conductivity estimates, this additional error becomes negligible when appropriate measures are taken in the field. These measures are summarized in a set of practical field guidelines for slug tests in highly permeable aquifers.


Clinical management and mortality among COVID-19 cases in sub-Saharan Africa: A retrospective study from Burkina Faso and simulated case analysis.
Absolute numbers of COVID-19 cases and deaths reported to date in the sub-Saharan Africa (SSA) region have been significantly lower than those across the Americas, Asia and Europe. As a result, there has been limited information about the demographic and clinical characteristics of deceased cases in the region, as well as the impacts of different case management strategies. Data from deceased cases reported across SSA through 10 May 2020 and from hospitalized cases in Burkina Faso through 15 April 2020 were analyzed. Demographic, epidemiological and clinical information on deceased cases in SSA was derived through a line-list of publicly available information and, for cases in Burkina Faso, from aggregate records at the Centre Hospitalier Universitaire de Tengandogo in Ouagadougou. A synthetic case population was probabilistically derived using distributions of age, sex and underlying conditions from populations of West African countries to assess individual risk factors and treatment effect sizes. Logistic regression analysis was conducted to evaluate the adjusted odds of survival for patients receiving oxygen therapy or convalescent plasma, based on therapeutic effectiveness observed for other respiratory illnesses. Across SSA, deceased cases for which demographic data were available were predominantly male (63/103, 61.2%) and aged >50 years (59/75, 78.7%). In Burkina Faso, specifically, the majority of deceased cases either did not seek care at all or were hospitalized for a single day (59.4%, 19/32). Hypertension and diabetes were often reported as underlying conditions. After adjustment for sex, age and underlying conditions in the synthetic case population, the odds of mortality for cases not receiving oxygen therapy were significantly higher than for those receiving oxygen, such as due to disruptions to standard care (OR 2.07; 95% CI 1.56-2.75). Cases receiving convalescent plasma had 50% reduced odds of mortality than those who did not (95% CI 0.24-0.93). Investment in sustainable production and maintenance of supplies for oxygen therapy, along with messaging around early and appropriate use for healthcare providers, caregivers and patients could reduce COVID-19 deaths in SSA. Further investigation into convalescent plasma is warranted until data on its effectiveness specifically in treating COVID-19 becomes available. The success of supportive or curative clinical interventions will depend on earlier treatment seeking, such that community engagement and risk communication will be critical components of the response.


A Beacon in the Dark: Canakinumab. A New Therapeutic Perspective in Chronic Tophaceous Gout.
Gout is the most common form of arthritis in adults. It is often associated with other comorbidities, which contraindicate the use of conventional therapies. The discovery of the role of interleukin-1β (IL-1β) in orchestrating the monosodium urate crystal-induced inflammatory response offered new therapeutic prospects to refractory patients, or to those in whom standard therapies are contraindicated. This paper describes a clinical case of a 65-year-old man with chronic tophaceous gouty arthropathy and subintrant flares, who had comorbidities contraindicating the use of conventional gout therapies-to which he did not respond-who was treated with canakinumab, a monoclonal selective inhibitor of IL-1β. The patient reported a gradual, rapid, and significant reduction in pain, with a response observed within 12 h of the administration of the drug. Consistent with previous clinical studies, canakinumab appeared to be a viable, safe, and effective alternative to conventional therapies in this patient with gout who had limited therapeutic options. Novartis Farma, Italy.


Antagonistic cross-regulation between Sox9 and Sox10 controls an anti-tumorigenic program in melanoma.
Melanoma is the most fatal skin cancer, but the etiology of this devastating disease is still poorly understood. Recently, the transcription factor Sox10 has been shown to promote both melanoma initiation and progression. Reducing SOX10 expression levels in human melanoma cells and in a genetic melanoma mouse model, efficiently abolishes tumorigenesis by inducing cell cycle exit and apoptosis. Here, we show that this anti-tumorigenic effect functionally involves SOX9, a factor related to SOX10 and upregulated in melanoma cells upon loss of SOX10. Unlike SOX10, SOX9 is not required for normal melanocyte stem cell function, the formation of hyperplastic lesions, and melanoma initiation. To the contrary, SOX9 overexpression results in cell cycle arrest, apoptosis, and a gene expression profile shared by melanoma cells with reduced SOX10 expression. Moreover, SOX9 binds to the SOX10 promoter and induces downregulation of SOX10 expression, revealing a feedback loop reinforcing the SOX10 low/SOX9 high ant,m/ii-tumorigenic program. Finally, SOX9 is required in vitro and in vivo for the anti-tumorigenic effect achieved by reducing SOX10 expression. Thus, SOX10 and SOX9 are functionally antagonistic regulators of melanoma development.


The aftiphilin/p200/gamma-synergin complex.
Aftiphilin is a protein that was recently identified in database searches for proteins with motifs that interact with AP-1 and clathrin, but its function is unknown. Here we demonstrate that aftiphilin has a second, atypical clathrin binding site, YQW, that colocalizes with AP-1 by immunofluorescence, and that is enriched in clathrin-coated vesicles (CCVs), confirming that it is a bona fide component of the CCV machinery. By gel filtration, aftiphilin coelutes with two other AP-1 binding partners, p200a and gamma-synergin. Antibodies against any one of these three proteins immunoprecipitate the other two, and knocking down any of the three proteins by siRNA causes a reduction in the levels of the other two, indicating that they form a stable complex. Like AP-1-depleted cells, aftiphilin-depleted cells missort a CD8-furin chimera and the lysosomal enzyme cathepsin D. However, whereas AP-1-depleted cells recycle endocytosed transferrin more slowly than untreated cells, aftiphilin-depleted cells accumulate endocytosed transferrin in a peripheral compartment and recycle it more rapidly. These observations show that in general, the aftiphilin/p200/gamma-synergin complex facilitates AP-1 function, but the complex may have additional functions as well, because of the opposing effects of the two knockdowns on transferrin recycling.


Sun's procedure for complex aortic arch repair: total arch replacement using a tetrafurcate graft with stented elephant trunk implantation.
The Sun's procedure is a surgical technique proposed by Dr. Li-Zhong Sun in 2002 that integrates total aortic arch replacement using a tetrafurcated graft with implantation of a specially designed frozen elephant trunk (Cronus(®)) in the descending aorta. It is used as a treatment option for extensive aortic dissections or aneurysms involving the ascending aorta, aortic arch and the descending aorta. The technical essentials of Sun's procedure include implantation of the special open stented graft into the descending aorta, total arch replacement with a 4-branched vascular graft, right axillary artery cannulation, selective antegrade cerebral perfusion for brain protection, moderate hypothermic circulatory arrest at 25 °C, a special anastomotic sequence for aortic reconstruction (i.e., proximal descending aorta → left carotid artery → ascending aorta → left subclavian artery → innominate artery), and early rewarming and reperfusion after distal anastomosis to minimize cerebral and cardiac ischemia. The core advantage of Sun's procedure lies in the use of a unique stented graft, which has superior technical simplicity, flexibility, inherent mechanical durability and an extra centimeter of attached regular vascular graft at both ends. Since its introduction in 2003, the Sun's procedure has produced satisfactory early and long-term results in over 8,000 patients in China and more than 200 patients in South American countries. In a series of 1,092 patients, the authors have achieved an in-hospital mortality rate of 6.27% (7.98% in emergent or urgent vs. 3.98% in elective cases). Given the accumulating clinical experience and the consequent, continual evolution of surgical indications, the Sun's procedure is becoming increasingly applied/used worldwide as an innovative and imaginative enhancement of surgical options for the dissected (or aneurysmal) ascending aorta, aortic arch and proximal descending aorta, and may become the next standard treatment for type A aortic dissections requiring repair of the aortic arch.


The effect of exposure to intimate partner violence of female nurses on communication skills and burnout levels.
Although intimate partner violence is a type of violence that women are frequently exposed to, its victims are adversely affected by violence at various levels, bio-psycho-socially. This study was conducted to determine the relationship between exposure to spousal violence, communication skills and burnout levels in female nurses. The study was carried out in a descriptive and cross-sectional research design. The study was conducted in a university hospital in the Black Sea region of Turkey in September 2021. Sample selection was not made in the study, and female nurses who agreed to participate in the study were included in the study. The study's sample size is 165 female nurses. A personal Information Form, Intimate Partner Violence Scale, Communication Skills Scale, and Burnout Scale were used to collect data. It was concluded that the exposure of female nurses to spouse violence significantly affects their communication skills and there is a significant relationship between nurses' communication skills and burnout levels (P = 0.001). The attitudes and behaviors of nurses who are strong in the caregiving process are very important. Personal characteristics, communication styles and body language of nurses who are exposed to partner violence are reflected in nursing care practices and affect the caregiving process. In this context, prevention and intervention approaches for intimate partner violence of female nurses should be known.


Automatic MRI Quantifying Methods in Behavioral-Variant Frontotemporal Dementia Diagnosis.
We assessed the value of automated MRI quantification methods in the differential diagnosis of behavioral-variant frontotemporal dementia (bvFTD) from Alzheimer disease (AD), Lewy body dementia (LBD), and subjective memory complaints (SMC). We also examined the role of the C9ORF72-related genetic status in the differentiation sensitivity. The MRI scans of 50 patients with bvFTD (17 C9ORF72 expansion carriers) were analyzed using 6 quantification methods as follows: voxel-based morphometry (VBM), tensor-based morphometry, volumetry (VOL), manifold learning, grading, and white-matter hyperintensities. Each patient was then individually compared to an independent reference group in order to attain diagnostic suggestions. Only VBM and VOL showed utility in correctly identifying bvFTD from our set of data. The overall classification sensitivity of bvFTD with VOL + VBM achieved a total sensitivity of 60%. Using VOL + VBM, 32% were misclassified as having LBD. There was a trend of higher values for classification sensitivity of the C9ORF72 expansion carriers than noncarriers. VOL, VBM, and their combination are effective in differential diagnostics between bvFTD and AD or SMC. However, MRI atrophy profiles for bvFTD and LBD are too similar for a reliable differentiation with the quantification methods tested in this study.