Clinical Outcomes Associated with Switching or Discontinuation from Anti-TNF Inhibitors for Nonmedical Reasons.
This study evaluated clinical outcomes and health care resource utilization associated with nonmedical switching from or discontinuation of anti-tumor necrosis factor (TNF) therapies in US clinical practice. Responding physicians extracted data from the medical charts of patients with Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, or psoriatic arthritis who achieved response on an anti-TNF therapy. Physicians selected 2 cohorts of patients that were matched on diagnosis: patients who were switched/discontinued, for nonmedical reasons, from the anti-TNF therapy on which they achieved response (switchers/discontinuers), and patients who continued on their anti-TNF (continuers). Switchers/discontinuers were followed up for 12 months from the date of discontinuation (index date); continuers were followed up for 12 months from the date of an office visit within 2 months of the matched switcher/discontinuer׳s index date. Multivariate regression was used to compare disease flares, disease control, and health care resource utilization between cohorts, with adjustment for baseline characteristics. Subgroup analyses compared data from the continuer cohort to those from (1) patients who were switched to another biologic therapy and (2) patients who were switched to conventional therapy or discontinued from all therapy. A total of 377 matched pairs of continuers and switchers/discontinuers were analyzed (N = 754), with the latter cohort comprising 284 patients (73.3%) who were and 93 (24.7%) who did not switch to another treatment (biologic or conventional treatment) immediately after discontinuation. Switchers/discontinuers had more frequent flares than did continuers, across severity levels (adjusted incidence rate ratios = 1.67, 2.36, and 3.48 for mild, moderate, and severe flares, respectively; all, P < 0.05). Switchers/discontinuers had a lower rate of well-controlled disease symptoms (46.9% vs 88.1%; adjusted odds ratio = 0.11; P < 0.001). Switchers/discontinuers also had more frequent inpatient hospitalizations, emergency department visits, and outpatient visits (adjusted incidence rate ratios = 3.58, 5.73, and 1.12, respectively; all, P < 0.001). Findings from the subgroup analyses of data from the 183 patients who switched to a biologic therapy and 194 who switched to conventional therapy or discontinued from all therapy were largely consistent with the overall analysis. In this study, switching/discontinuation from an anti-TNF therapy for nonmedical reasons was associated with significantly worse clinical outcomes and increased health care resource utilization-factors that should be considered when developing treatment algorithms.


Total cholesterol and triglycerides are associated with the development of new bone marrow lesions in asymptomatic middle-aged women - a prospective cohort study.
Given the emerging evidence that osteoarthritis (OA) may have a vascular basis, the aim of this study was to determine whether serum lipids were associated with change in knee cartilage, presence of bone marrow lesions (BMLs) at baseline and the development of new BMLs over a 2-year period in a population of pain-free women in mid-life. One hundred forty-eight women 40 to 67 years old underwent magnetic resonance imaging (MRI) of their dominant knee at baseline and 2.2 (standard deviation 0.12) years later. Cartilage volume and BMLs were determined for both time points. Serum lipids were measured from a single-morning fasting blood test approximately 1.5 years prior to the MRI. The incidence of BML at follow-up was associated with higher levels of total cholesterol (odds ratio [OR] 1.84, 95% confidence interval [CI] 1.01, 3.36; P = 0.048) and triglycerides (OR 8.4, 95% CI 1.63, 43.43; P = 0.01), but not high-density lipoprotein (HDL) (P = 0.93), low-density lipoprotein (LDL) (P = 0.20) or total cholesterol/HDL ratio (P = 0.17). No association between total cholesterol, triglycerides, HDL, LDL or total cholesterol/HDL ratio and presence of BMLs at baseline or annual change in total tibial cartilage volume was observed. In this study of asymptomatic middle-aged women with no clinical knee OA, serum cholesterol and triglyceride levels were associated with the incidence of BMLs over 2 years. This provides support for the hypothesis that vascular pathology may have a role in the pathogenesis of knee OA. Further work is warranted to clarify this and whether treatments aimed at reducing serum lipids may have a role in reducing the burden of knee OA.


Suggestive evidence of erythropoietin level abnormality in patients with sporadic and familial cases of the restless legs syndrome.
The restless legs syndrome (RLS) is divided into two forms: idiopathic and secondary. About half the cases of the former are found to have a positive family history. The lack of objective and quantitative parameters in familial RLS also represents a drawback for genetic studies. We tried to find a feature distinguishing the sporadic from the familial forms of the RLS. RLS patients were examined for clinical picture and laboratory markers including erythropoietin levels. Patients with a priori known causes of secondary RLS, were excluded. All biochemical and hematological parameters were standardized for sex and age groups relative to the population mean and standard deviation. In our set of 311 patients (65.3% women, mean age 54.6 years, SD 14.7 years) 96 reported positive family history (64.6% women, mean age 53.1 years, SD 15.8 years). We found a significantly lower age at the onset of RLS symptoms in familial cases (mean 29.3 vs. 44.0, Z 5.9, p<0.0001), and, in sporadic cases, a significantly lower absolute count of red blood cells (Z -2.02, p=0.043 respectively). Erythropoietin levels in the familial cases were significantly lower than in the reference population (median -2.26 SDs from the mean). None of the other parameters were significantly different between the groups. Our results confirm previously published lower age at symptom onset in familial RLS and provide the first evidence of lower erythropoietin levels in RLS patients. These observations might help to identify the specific phenotype for genetic association studies.


Distinct interactions of GTP, UTP, and CTP with G(s) proteins.
Early studies showed that in addition to GTP, the pyrimidine nucleotides UTP and CTP support activation of the adenylyl cyclase (AC)-stimulating G(s) protein. The aim of this study was to elucidate the mechanism by which UTP and CTP support G(s) activation. As models, we used S49 wild-type lymphoma cells, representing a physiologically relevant system in which the beta(2)-adrenoreceptor (beta(2)AR) couples to G(s), and Sf9 insect cell membranes expressing beta(2)AR-Galpha(s) fusion proteins. Fusion proteins provide a higher sensitivity for the analysis of beta(2)AR-G(s) coupling than native systems. Nucleoside 5'-triphosphates (NTPs) supported agonist-stimulated AC activity in the two systems and basal AC activity in membranes from cholera toxin-treated S49 cells in the order of efficacy GTP > or = UTP > CTP > ATP (ineffective). NTPs disrupted high affinity agonist binding in beta(2)AR-Galpha(s) in the order of efficacy GTP > UTP > CTP > ATP (ineffective). In contrast, the order of efficacy of NTPs as substrates for nucleoside diphosphokinase, catalyzing the formation of GTP from GDP and NTP was ATP > or = UTP > or = CTP > or = GTP. NTPs inhibited beta(2)AR-Galpha(s)-catalyzed [gamma-(32)P]GTP hydrolysis in the order of potency GTP > UTP > CTP. Molecular dynamics simulations revealed that UTP is accommodated more easily within the binding pocket of Galpha(s) than CTP. Collectively, our data indicate that GTP, UTP, and CTP interact differentially with G(s) proteins and that transphosphorylation of GDP to GTP is not involved in this G protein activation. In certain cell systems, intracellular UTP and CTP concentrations reach approximately 10 nmol/mg of protein and are higher than intracellular GTP concentrations, indicating that G protein activation by UTP and CTP can occur physiologically. G protein activation by UTP and CTP could be of particular importance in pathological conditions such as cholera and Lesch-Nyhan syndrome.


Neuronal localization of the cyclophilin A protein in the adult rat brain.
Cyclophilin A is a small, soluble protein which binds the immunosuppressive drug cyclosporin A. Cyclophilin A is a peptidyl-prolyl isomerase and is widely expressed in a multitude of tissues, but is present in highest concentration in the brain. A role for this protein in the maturation and folding of neuron-specific membrane proteins has been hypothesized. Immunohistochemical staining for cyclophilin A was used to determine whether cyclophilin A is present in neurons, and whether there is variation in the level of expression with respect to brain regions and cell types. The specificity of the antibody used was demonstrated by Western blot analysis and cyclosporin affinity purification. Immunohistochemical staining of sections of adult rat brain showed labelled neurons throughout the neuraxis. The intensity of the immunostaining observed was roughly equivalent to neuronal cell density and was restricted to gray matter. On a cellular level, staining was present in cytosol and nuclei and extended into neuronal processes. Fluorescent double-labelling experiments on hippocampal cell cultures revealed that all cells labelled with the cyclophilin A antibody also showed staining for the neuron-specific marker for microtubule-associated protein (MAP)2, and could, therefore, be identified as neurons. Immunoreactivity in these neurons is present in punctate, spinelike structures along dendrites. Cyclophilin A immunoreactivity was undetectable in glial fibrillary acidic protein (GFAP)-positive cells. The pattern of cyclophilin. A expression is consistent with a role of cyclophilin A in neuronal protein maturation and folding in vivo.


Effect of ascorbic acid and X-irradiation on HL-60 human leukemia cells: the kinetics of reactive oxygen species.
Ascorbic acid (AsA) treatment is expected to be a potential cancer therapy strategy with few side-effects that can be used alone or in combination with chemotherapy. However, the combination of AsA, a free radical scavenger, with radiation is not clearly understood; conflicting data are reported for cancer cell death. We conducted this study to determine the effect of AsA treatment combined with X-irradiation and the role of reactive oxygen species (ROS) in HL-60 human promyelocytic leukemia cells. Additive cytotoxic effects were observed when the cells were exposed to 2 Gy X-irradiation after 2.5 mM AsA treatment. When catalase was added to the culture with AsA alone, the cytotoxic effects of AsA disappeared. X-irradiation increased intercellular ROS levels and mitochondrial superoxide levels. By contrast, AsA alone and in combination with X-irradiation decreased ROS levels. However, in the presence of catalase neutralizing H2O2, AsA alone or in combination with X-irradiation only slightly decreased the intercellular ROS. Moreover, AsA decreased the mitochondrial membrane potential, which is commonly associated with apoptosis. These results suggest that the reduction of ROS did not result from ROS scavenging by AsA, and AsA induced apoptosis through a ROS-independent pathway. This study reports that a combination of AsA with radiation treatment is effective in cancer therapy when considering ROS in cancer cells.


Clinicopathological correlates and prognostic significance of glutathione S-transferase Pi expression in 468 patients after potentially curative resection of node-positive colonic cancer.
This study investigated the association between glutathione S-transferase Pi (GST Pi) expression, histopathology and overall survival in 468 patients after resection of stage C colonic adenocarcinoma. Data were drawn from a prospective hospital registry of consecutive bowel cancer resections with a minimum follow-up of 5 years. Nuclear and cytoplasmic GST Pi expression, assessed by both intensity of staining and percentage of stained cells at both the central part of the tumour and the invasive tumour front, were evaluated retrospectively by tissue microarray immunohistochemistry on archival specimens. The most effective measure of GST Pi expression was the percentage of immunostained nuclei in central tumour tissue, where >40% stained was associated significantly with high grade, invasion beyond the muscularis propria, involvement of a free serosal surface or apical node, and invasion into an adjacent organ or structure. After adjustment of other predictors, GST Pi expression remained independently prognostic for reduced overall survival (hazard ratio 1.4, P = 0.002). In patients with clinicopathological stage C colonic cancer, GST Pi expression is associated with features of tumour aggressiveness and with reduced overall survival. Further appropriately designed studies should aim to discover whether GST Pi can predict response to adjuvant chemotherapy.


Correlation and comparison of magnetic and electric detection of small intestinal electrical activity.
The small intestinal basic electrical rhythm (BER) was detected simultaneously with serosal electrodes and a transabdominal superconducting quantum interference device (SQUID) magnetometer in anesthetized rabbits. We induced mesenteric ischemia to correlate serosal electrode recording of changes in BER with the SQUID magnetometer. The BER frequency was obtained by spectral analysis of the data using Fourier and autoregressive techniques. There was a high degree of correlation (r = 0.96) between the BER frequency determined using the serosal electrodes and the BER frequency ascertained from SQUID data. Additionally, the effects of an electrical insulator on the external electric and magnetic fields were studied in the rabbit model. The presence of an insulator profoundly attenuates external electric potentials recorded by cutaneous electrodes but does not significantly affect external magnetic fields or serosal potentials. We conclude that SQUID magnetometers could noninvasively record small intestinal BER that was highly correlated with the activity recorded by invasive serosal electrodes. The advantages of magnetic field measurements have encouraged us to investigate clinical applications.


Effectiveness of public-access automated external defibrillators at Tokyo railroad stations.
To investigate the effectiveness of public-access automated external defibrillators (AEDs) at Tokyo railroad stations. We analysed data from a population-based registry of out-of-hospital cardiac arrests in Tokyo, Japan (2014-2018). We identified patients aged ≥18 years who experienced bystander-witnessed cardiac arrest due to ventricular fibrillation of presumed cardiac origin at railroad stations. The primary outcome was survival at 1 month after cardiac arrest with favourable neurological outcomes (cerebral performance category 1-2). Among 280 eligible patients who had bystander-witnessed cardiac arrest and received defibrillation at railroad stations, 245 patients (87.5%) received defibrillation using public-access AEDs and 35 patients (12.5%) received defibrillation administered by emergency medical services (EMS). Favourable neurological outcomes at 1 month after cardiac arrest were significantly more common in the group that received defibrillation using public-access AEDs (50.2% vs. 8.6%; adjusted odds ratio: 11.2, 95% confidence interval: 1.43-88.4) than in the group that received defibrillation by EMS. Over a 5-year period, favourable neurological outcomes at 1 month after cardiac arrest of 101.9 cases (95% confidence interval: 74.5-129.4) were calculated to be solely attributable to public-access AED use. The incremental cost-effectiveness ratio to gain one favourable neurological outcome obtained from public-access AEDs at railroad stations was lower than that obtained from nationwide deployment (48.5 vs. 2133.4 AED units). Deploying public-access AEDs at Tokyo railroad stations presented significant benefits and cost-effectiveness. Thus, it may be prudent to prioritise metropolitan railroad stations in public-access defibrillation programs.


Integration of viral DNA into the genome of the adenovirus type 2-transformed hamster cell line HE5 without loss or alteration of cellular nucleotides.
Hamster cell line HE5 has been established from primary LSH hamster embryo cells by transformation with adenovirus type 2 (Ad2) (1). Each cell contains two to three copies of integrated Ad2 DNA (2, 3). We cloned and sequenced the sites of junction between viral and cellular DNAs. The terminal 10 and 8 nucleotides of Ad2 DNA were deleted at the left and right sites of junction, respectively. The integrated viral DNA had an internal deletion between map units 35 and 82 on the Ad2 genome. At the internal site of deletion, the remaining viral sequences were linked via a GT dinucleotide of unknown origin. From HE5 DNA, the unoccupied sequence corresponding to the site of insertion was also cloned and sequenced. Part of this sequence was shown to be expressed as cytoplasmic RNA in HE5 and primary LSH hamster embryo cells. The viral DNA had been inserted into cellular DNA without deletions, rearrangements or duplications of cellular nucleotides at the site of insertion. Thus, insertion of Ad2 DNA appeared to have been effected by a mechanism different from that of bacteriophage lambda in Escherichia coli and from that of retroviral genomes in vertebrates. It was conceivable that the terminal viral protein (4) was somehow involved in integration either on a linear or a circularized viral DNA molecule.


Effects of elevated concentrations of atmospheric CO2 and tropospheric O3 on decomposition of fine roots.
Rising atmospheric carbon dioxide (CO2) concentration ([CO2]) could alter terrestrial carbon (C) cycling by affecting plant growth, litter chemistry and decomposition. How the concurrent increase in tropospheric ozone (O3) concentration ([O3]) will interact with rising atmospheric [CO2] to affect C cycling is unknown. A major component of carbon cycling in forests is fine root production, mortality and decomposition. To better understand the effects of elevated [CO2] and [O3] on the dynamics of fine root C, we conducted a combined field and laboratory incubation experiment to monitor decomposition dynamics and changes in fine root litter chemistry. Free-air CO2 enrichment (FACE) technology at the FACTS-II Aspen FACE project in Rhinelander, Wisconsin, elevated [CO2] (535 microl 1-1) and [O3] (53 nl 1-1) in intact stands of pure trembling aspen (Populus tremuloides Michx.) and in mixed stands of trembling aspen plus paper birch (Betula papyrifera Marsh.) and trembling aspen plus sugar maple (Acer saccharum Marsh.). We hypothesized that the trees would react to increased C availability (elevated [CO2]) by increasing allocation to C-based secondary compounds (CBSCs), thereby decreasing rates of decomposition. Because of its lower growth potential, we reasoned this effect would be greatest in the aspen-maple community relative to the aspen and aspen-birch communities. As a result of decreased C availability, we expected elevated [O3] to counteract shifts in C allocation induced by elevated [CO2]. Concentrations of CBSCs were rarely significantly affected by the CO2 and O3 treatments in decomposing fine roots. Rates of microbial respiration and mass loss from fine roots were unaffected by the treatments, although the production of dissolved organic C differed among communities. We conclude that elevated [CO2] and [O3] induce only small changes in fine root chemistry that are insufficient to significantly influence fine root decomposition. If changes in soil C cycling occur in the future, they will most likely be brought about by changes in litter production.


COVID-19 and HIV viral load suppression in children and adolescents in Durban, South Africa.
The coronavirus disease 2019 (COVID-19) pandemic poses challenges to paediatric and adolescent HIV treatment programme. Modelling exercises raised concerns over potential impact of disruptions. To describe the impact of the COVID-19 pandemic on viral load (VL) testing among infants, children and adolescents on antiretroviral treatment (ART) in Durban, South Africa. Routinely collected, aggregated data of monthly VL counts done on all those less than 19 years old from January 2018 to January 2022 was analysed. An interrupted time series analysis using a Prais-Winsten linear regression model, including terms for lockdowns and excess mortality determined VL trends. The unadjusted mean VL was 2166 (confidence interval [CI]: 252.2) and 2016 (CI: 241.9), P = 0.039, and percentage VL suppression rates (72.9%, CI: 2.4% vs 73.6%, CI: 1.8%) across COVID and pre-COVID periods, showing no significant difference, P = 0.262. In the interrupted time series analysis, modelled monthly VL counts did not differ significantly by lockdown level (e.g., level 5 lockdown: -210.5 VLs, 95% CI: -483.0 to +62.1, P = 0.138) or excess mortality (-0.1, 95% CI: -6.3 to 6.1, P = 0.969). A significant downward trend in VL testing over time, including during the pre-COVID-19 period (-6.6 VL per month, 95% CI: -10.4 to -2.7, P = 0.002), was identified. Viral load suppression for children and adolescents were not negatively affected by COVID-19. A trend of decrease in VL testing predated COVID-19. Evidence presented that HIV VL testing and suppression rates in children and adolescents in a high burden setting were sustained through the COVID pandemic.


Nuclear medicine in primary breast cancer imaging.
The application of nuclear medicine techniques to study patients with breast cancer has recently raised its profile, particularly in the investigation 'indeterminate mammographic lesions'. This review briefly points out some of the difficulties encountered with other more conventional imaging modalities and describes the radionuclide techniques most frequently employed in the investigation of those patients with breast cancer. Both planar and single photon emission tomography methods are discussed including the use of monoclonal antibodies, perfusion ligands, receptor binding hormones and other specific radiotracers, non-specific tumour markers, as well as deoxyglucose and other amino acids labelled with positron emitting radionuclides.


Chest CT and Coronavirus Disease (COVID-19): A Critical Review of the Literature to Date.
OBJECTIVE. Coronavirus disease (COVID-19) is a global pandemic. Studies in the radiology literature have suggested that CT might be sufficiently sensitive and specific in diagnosing COVID-19 when used in lieu of a reverse transcription-polymerase chain reaction test; however, this suggestion runs counter to current society guidelines. The purpose of this article is to critically review some of the most frequently cited studies on the use of CT for detecting COVID-19. CONCLUSION. To date, the radiology literature on COVID-19 has consisted of limited retrospective studies that do not substantiate the use of CT as a diagnostic test for COVID-19.


The aldose reductase inhibitory capacity of Sorbus domestica fruit extracts depends on their phenolic content and may be useful for the control of diabetic complications.
Aldose reductase (ALR2) is a rate-limiting enzyme in the polyol pathway associated with the conversion of glucose to sorbitol and whose activity is implicated in the development of the long-term diabetic complications. Upon previous years, several scientific efforts were focused towards the development of ALR2 inhibitors as effective secondary anti-diabetic drugs. To this regard and during our extensive phytochemical analysis of Sorbus domestica (fam. Rosaceae), twenty nine different extracts, fractions and residues of five different maturity stages of Sorbus domestica fruits were evaluated for their in vitro ALR2 inhibitory capacity. The data obtained thus far have indicated that the diethyl ether and ethyl acetate fractions possess high aldose reductase inhibitory activity. Furthermore, detailed phytochemical LC-DAD-MS (ESI+) analysis of such extracts has shown that this aldose reductase inhibitory activity could be attributed to the high content of flavonoids and hydroxycinnamoyl esters. These results suggest that Sorbus domestica fruit consumption may be a promising way for lowering the incidence of long-term complications of diabetes mellitus, especially at early stages, a possibility being discussed in this paper.


Differential Inhibition of HIV Replication by the 12 Interferon Alpha Subtypes.
Type I interferons (IFNs) are a family of cytokines that represent a first line of defense against virus infections. The 12 different IFN-α subtypes share a receptor on target cells and trigger similar signaling cascades. Several studies have collectively shown that this apparent redundancy conceals qualitatively different responses induced by individual subtypes, which display different efficacies of inhibition of HIV replication. Some studies, however, provided evidence that the disparities are quantitative rather than qualitative. Since RNA expression analyses show a large but incomplete overlap of the genes induced, they may support both models. To explore if the IFN-α subtypes induce functionally relevant different anti-HIV activities, we have compared the efficacies of inhibition of all 12 subtypes on HIV spread and on specific steps of the viral replication cycle, including viral entry, reverse transcription, protein synthesis, and virus release. Finding different hierarchies of inhibition would validate the induction of qualitatively different responses. We found that while most subtypes similarly inhibit virus entry, they display distinctive potencies on other early steps of HIV replication. In addition, only some subtypes were able to target effectively the late steps. The extent of induction of known anti-HIV factors helps to explain some, but not all differences observed, confirming the participation of additional IFN-induced anti-HIV effectors. Our findings support the notion that different IFN-α subtypes can induce the expression of qualitatively different antiviral activities. IMPORTANCE The initial response against viruses relies in large part on type I interferons, which include 12 subtypes of IFN-α. These cytokines bind to a common receptor on the cell surface and trigger the expression of incompletely overlapping sets of genes. Whether the anti-HIV responses induced by IFN-α subtypes differ in the extent of expression or in the nature of the genes involved remains debated. Also, RNA expression profiles led to opposite conclusions, depending on the importance attributed to the induction of common or distinctive genes. To explore if relevant anti-HIV activities can be differently induced by the IFN-α subtypes, we compared their relative efficacies on specific steps of the replication cycle. We show that the hierarchy of IFN potencies depends on the step analyzed, supporting qualitatively different responses. This work will also prompt the search for novel IFN-induced anti-HIV factors acting on specific steps of the replication cycle.


Factors associated with testing for HIV and hepatitis C among behaviorally vulnerable men in Germany: a cross-sectional analysis upon enrollment into an observational cohort.
HIV and hepatitis C virus (HCV) have shared routes of transmission among men who have sex with men (MSM). Routine testing facilitates early diagnosis and treatment, thereby preventing morbidity and onward transmission. We evaluated factors associated with HIV and HCV testing in a behaviorally vulnerable cohort of predominantly MSM. From June 2018 through June 2019, the BRAHMS study enrolled adults at ten German outpatient clinics that serve gender and sexual minority populations. Participants completed behavioral questionnaires that captured prior experience with HIV and HCV testing. Multivariable robust Poisson regression was used to evaluate factors potentially associated with testing in the previous 6 months. Among 1017 participants with median age 33 (interquartile range 28-39) years, 1001 (98.4%) reported any lifetime history of HIV testing and 787 (77.4%) reported any HCV testing, including 16 (1.6%) known to be living with HCV. Testing within the last 6 months was reported by 921 (90.6%) and 513 (50.4%) for HIV and HCV, respectively. Recent HIV testing was more common among participants with higher education level and recent HCV testing. Recent HCV testing was more common among participants with non-cisgender identity, lifetime history of illicit drug use, hepatitis B immunity or infection, and recent HIV testing. Prior testing for HIV was common in this cohort, but interventions are needed to improve HCV risk stratification and access to testing. HIV testing infrastructure can be successfully leveraged to support HCV testing, but differentiated preventive care delivery is needed for some vulnerable populations.


[In vivo chemosensitivity tests of Plasmodium falciparum to chloroquine in Senegal: the development of resistance and the assessment of therapeutic efficacy].
The efficacity of oral chloroquine was assessed in 360 out-clinic patients with symptomatic Plasmodium falciparum malaria who were enrolled at five sites, in four administrative regions of Senegal, between 1991 and 1995. They were three rural areas: Mlomp (Casamance), Bandafassilbel (Eastern Senegal), Diohine (Sine-Saloum) and one urban area: Pikine (agglomeration of Dakar). Parasitological failure at Day-7 was observed in 108 patients (30%) and ranged from 14% to 50% according to the study areas. The proportion of RI, RII and RIII responses were 6%, 23% and 1%, respectively. Chloroquine resistance was lowest in Bandafassi, one of the most remote area of Senegal. It was highest in Mlomp where a malaria control programme with mass chemoprophylaxis had been carried out since 1975. The therapeutic failure rate defined by the persistence or reappearance of fever and P. falciparum trophozoites on days 4-7 was 6%. The percentages of therapeutic failure for RI, RII and RIII patients were respectively 14%, 19% and 100%. These results and those of previous studies in Senegal suggest that chloroquine resistance, which first emerged in vivo in 1988 in Dakar, spread between 1990 and 1993 in all regions of this country. The limitations of in vivo tests for the determination of the therapeutic efficacy of chloroquine in malaria endemic regions with increasing chemoresistance are discussed. The low proportion of potentially severe malaria infections in semi-immune persons, the biases in patients selection, and the possibility of delayed complications, considerably limit the potential of these tests for guiding the choice of the best adapted first line treatment.


Chronic Toxoplasma infection affects gene expression of drug-metabolizing enzymes in mouse liver.
Toxoplasma gondii is an intracellular protozoan parasite causing toxoplasmosis, an infectious disease affecting warm-blooded vertebrates worldwide. Many drug-metabolizing enzymes are located in the liver, a major organ of drug metabolism, and their function can be affected by pathogen infection.Using next-generation sequencing (RNA-seq) and quantitative polymerase chain reaction (qPCR), changes in the hepatic expressions of drug-metabolizing enzymes were analysed in mice chronically infected with T. gondii. The analysis found that, among drug-metabolizing enzymes, 22 genes were upregulated and 28 genes were downregulated (≥1.5-fold); of these 5 and 17 genes, respectively, were cytochromes P450 (Cyp or P450).Subsequent qPCR analysis showed that six P450 genes were upregulated significantly (≥1.5-fold, p < 0.05), namely, Cyp1b1, Cyp2c29, Cyp2c65, Cyp2d9, Cyp2d12, and Cyp3a59, whereas nine P450 genes were downregulated significantly (≥1.5-fold, p < 0.05), namely, Cyp2c38, Cyp2c39, Cyp2c44, Cyp2c69, Cyp2d40, Cyp2e1, Cyp3a11, Cyp3a41, and Cyp3a44.Moreover, metabolic assays in infected mouse liver using typical P450 substrates revealed that midazolam 1'-hydroxylation and testosterone 2-hydroxylation activities decreased significantly (≥1.5-fold, p < 0.05), whereas testosterone 16-hydroxylation activity increased significantly (≥1.5-fold, p < 0.05).Chronic Toxoplasma infection affects drug metabolism, at least partly, by altering the gene expressions of drug-metabolizing enzymes, including P450s.


A plasticity-based theory of the pathogenesis of Alzheimer's disease.
Amyloid plaques (APs) and neurofibrillary tangles (NFTs) are the two diagnostic markers of Alzheimer's disease (AD). The neuropsychological features of AD are closely correlated with the distribution of the NFTs and therefore favor a disease process revolving around neurofibrillary degeneration. The genetics, however, favor a disease process revolving around the APs, principally because mutations in the amyloid precursor protein (A beta PP) are sufficient to cause AD. The inability to reconcile these two aspects of AD has prevented the formulation of a unified theory of pathogenesis. It is interesting to note that all genetic causes and risk factors of AD can increase the physiological burden of neuroplasticity. My hypothesis is that the resultant intensification of the plasticity burden leads to an initially adaptive upregulation of tau phosphorylation and A beta PP turnover, to the subsequent formation of NFTs and APs as independent consequences of excessive plasticity-related cellular activity, and to the eventual loss of neurons, dendrites, and synapses as the ultimate expression of plasticity failure. The two pathological markers of AD are therefore independent manifestations of a more fundamental process through which the many different genotypes of AD trigger an identical clinical and neuropathological phenotype.


Education for all in action: Measuring teachers' competences for inclusive education.
While inclusive education has achieved international importance, there is no valid instrument to measure teachers' competences in creating quality classrooms for diverse learners, which this study aims to remedy. Exploratory and confirmatory factor analyses with 975 pre-service teachers and 600 in-service teachers were used. Central to teachers' inclusive teaching competency is both beliefs and efficacy. Results show that teachers hold professional beliefs on student diversity, organized in four factors mapping unto axes of diversity (specifically ethnicity, disability, SES, and gender & sexuality). Teachers also hold beliefs on the responsibility of the educational field to create inclusion, organized in three factors: general school policy, initiatives geared specifically towards ethnic minority students, and initiatives for students with a disability. Furthermore, the results show five factors related to self-efficacy: noticing student diversity, enabling high-quality student-interactions, creating stimulating learning environments, collaborating with colleagues and diverse parents. The factorial structure and scale-scores are discussed for what they unveil of teachers' thinking about diversity in the classroom.


Chemerin promotes angiogenesis in vivo.
Chemerin acts as a chemotactic factor for leukocyte populations expressing the G protein-coupled receptor CMKLR1 (ChemR23). It is also an adipocytokine involved in obesity and metabolic syndromes. Previous studies have demonstrated that chemerin promotes angiogenesis in vitro, although the precise mechanism has not been elucidated. In this study, we have investigated whether chemerin regulates angiogenic processes and validated the associated mechanisms. In this study, chemerin stimulated angiogenesis in mice, which was demonstrated using Matrigel plug implantation assay, mouse corneal models of angiogenesis, and ex vivo rat aortic ring assay. To explore the mechanisms by which chemerin induced angiogenesis, we examined the effects of chemerin in human umbilical vein endothelium cells (HUVECs). Chemerin stimulated the differentiation of HUVECs into capillary-like structures, promoted the proliferation of HUVECs, and functioned as a chemoattractant in migration assays. Chemerin induced the phosphorylation of Akt and p42/44 extracellular signal-regulated kinase (ERK) in HUVECs and chemerin promotes angiogenesis via Akt and ERK. SiRNA against the chemerin receptor CMKLR1 but not that against another chemerin receptor, CCRL2, completely inhibited the chemerin-induced migration and angiogenesis of HUVECs, which indicates that chemerin promotes the migration and angiogenic activities of HUVECs mainly through CMKLR1.


Blastomycosis presenting as multiple splenic abscesses: Case report and review of the literature.
A 31-year-old Canadian Aboriginal man from northwestern Ontario presented with left upper quadrant pain and a tender left upper quadrant mass. Evaluation with a computed tomography scan showed multiple lesions within the spleen, a collection between the splenic tip and splenic flexure of the colon, and several small adrenal lesions. Computed tomographic-guided needle biopsy showed necrotizing granulomatous inflammation and multinucleated giant cells. Gomori's methenamine silver stain showed broad-based budding yeast consistent with Blastomyces dermatitidis. Abdominal symptoms resolved after two months of oral itraconazole. Multiple splenic abscesses are a rare presentation of blastomycosis and should be considered in the differential diagnosis of left upper quadrant abdominal pain in a patient with a history of travel or residence in a region endemic for B dermatitidis.


Femtosecond-laser-induced shockwaves in water generated at an air-water interface.
We report generation of femtosecond-laser-induced shockwaves at an air-water interface by millijoule femtosecond laser pulses. We document and discuss the main processes accompanying this phenomenon, including light emission, development of the ablation plume in the air, formation of an ablation cavity, and, subsequently, a bubble developing in water. We also discuss the possibility of remotely controlling the characteristics of laser-induced sound waves in water through linear acoustic superposition of sound waves that results from millijoule femtosecond laser-pulse interaction with an air-water interface, thus opening up the possibility of remote acoustic applications in oceanic and riverine environments.


Perceptions on site-specific advanced practice roles for radiation therapists in Singapore - A single centre study.
Perception of the radiation oncologists (ROs) and radiation therapists (RTTs) on site-specific advanced practice (SSAP) roles for RTTs, the establishment of SSAP in radiotherapy and the possible implication on current services in Singapore were assessed. Opinions of ROs and RTTs on management support, driving forces, restraints and implication upon successful establishment of SSAP were obtained. Main findings include strong RO's support for SSAP development and RTTs' requisition for fair opportunities on role development. Other potential benefits include RTTs' career advancement, job satisfaction and retention. Enhancement of inter-professional relationship, service quality and patient satisfaction is anticipated with greater communication and collaboration.


Identification and Characterization of Avoidable Hospital Admissions in Patients With Lung Cancer.
More than 50% of patients with lung cancer are admitted to the hospital while receiving treatment, which is a burden to patients and the healthcare system. This study characterizes the risk factors and outcomes of patients with lung cancer who were admitted to the hospital. A multidisciplinary oncology care team conducted a retrospective medical record review of patients with lung cancer admitted in 2018. Demographics, disease and admission characteristics, and end-of-life care utilization were recorded. Following a multidisciplinary consensus review process, admissions were determined to be either "avoidable" or "unavoidable." Generalized estimating equation logistic regression models assessed risks and outcomes associated with avoidable admissions. In all, 319 admissions for 188 patients with a median age of 66 years (IQR, 59-74 years) were included. Cancer-related symptoms accounted for 65% of hospitalizations. Common causes of unavoidable hospitalizations were unexpected disease progression causing symptoms, chronic obstructive pulmonary disease exacerbation, and infection. Of the 47 hospitalizations identified as avoidable (15%), the median overall survival was 1.6 months compared with 9.7 months (hazard ratio, 2.07; 95% CI, 1.34-3.19; P<.001) for unavoidable hospitalizations. Significant reasons for avoidable admissions included cancer-related pain (P=.02), hypervolemia (P=.03), patient desire to initiate hospice services (P=.01), and errors in medication reconciliation or distribution (P<.001). Errors in medication management caused 26% of the avoidable hospitalizations. Of admissions in patients receiving immunotherapy (n=102) or targeted therapy (n=44), 9% were due to adverse effects of treatment. Patients receiving immunotherapy and targeted therapy were at similar risk of avoidable hospitalizations compared with patients not receiving treatment (P=.3 and P=.1, respectively). We found that 15% of hospitalizations among patients with lung cancer were potentially avoidable. Uncontrolled symptoms, delayed implementation of end-of-life care, and errors in medication reconciliation were associated with avoidable inpatient admissions. Symptom management tools, palliative care integration, and medication reconciliations may mitigate hospitalization risk.


FIRST RECORD OF AEDES JAPONICUS IN ST. TAMMANY PARISH, LOUISIANA.
Information of species presence and abundance is useful for taking a targeted approach to controlling populations of medically important and nuisance mosquito species. In April 2023, staff at St. Tammany Parish Mosquito Abatement District (STPMAD), in Slidell, Louisiana, identified Aedes japonicus (Theobald, 1901) mosquitoes from a larval sample brought in from the field for identification. Although invasive Aedes species like Aedes albopictus are commonly found in Louisiana, this is the first record of Ae. japonicus in St. Tammany Parish.


Circadian distribution of autostimulations in rVNS therapy in patients with refractory focal epilepsy.
Responsive vagus nerve stimulation (rVNS) utilizes an electrocardiograph (ECG)-based algorithm to detect rapid sympathetic activations associated with the onset of a seizure. Abrupt sympathetic activation may also be associated with nocturnal arousals between sleep cycles or transitioning from sleep to wakefulness, a period in which many patients with epilepsy experience seizures. Because of circadian changes in autonomic function, we hypothesized that the autostimulation feature might also behave in a circadian fashion. The aim of this study was to assess the circadian rhythmicity of autostimulations in rVNS treatment in patients with drug-resistant epilepsy (DRE). We performed a retrospective follow-up study of 30 patients with DRE treated with rVNS including 17 new implantations and 13 battery replacements at a single center in Finland. After initiation of autostimulation mode, the exact rVNS stimulation parameters and the timestamps of all individual autostimulations delivered were registered. A clustered autostimulation was defined as any autostimulation that occurred within the duration of the therapeutic cycle during the therapy "OFF" time compared with both the previous autostimulation and the following autostimulation. Autostimulations and especially autostimulation clusters show a higher probability of occurring in the morning and less at night. This trend appeared to follow the circadian rhythm of cortisol concentration. Early morning peaks of autostimulations at low thresholds may reflect awakening-induced activation of the cardiovascular system, which is associated with a shift towards the dominance of the sympathetic branch of the autonomic nervous system. Cortisol release occurs in parallel driven by wakening-induced activation of the hypothalamic-pituitary-adrenal axis, which is fine-tuned by direct sympathetic input to the adrenal gland. This is of interest considering the known sympathetic hyperactivity in patients with epilepsy.


Vancomycin- and erythromycin-resistant enterococci in a pig farm and its environment.
A high prevalence of vancomycin- and erythromycin-resistant enterococci (VRE and ERE respectively) in a pig farm and its environment was observed. A similar structure and composition of enterococcal populations was detected between urban sewage and those associated with the pig environment. Enterococcus faecium was the most predominant species among VRE isolates from both animal and human origin. The high population similarity index (Sp) obtained comparing VRE and ERE isolates from urban sewage and pig slurry suggests that there are certain strains circulating through the food chain from farms to humans. Erythromycin resistance was present in a wider variety of clones and species of enterococci in both pigs and humans than vancomycin resistance.


In vitro chemosensitivity of human lung cancer cell lines.
Human lung cancer cell lines, established from patients with both small cell cancer (SCLC) and non-small cell cancer (non-SCLC; squamous cell, large cell, anaplastic, and adenocarcinoma), were tested for their in vitro chemosensitivity to a panel of drugs. Drug sensitivity was assayed by either soft agar clonogenicity or a novel dye-exclusion assay. Eleven non-SCLC lines (eight continuous, three recently cultured) and five SCLC lines (all continuous) were tested. Four of eight continuous non-SCLC lines cloned sufficiently to permit limited in vitro drug testing, as did two of the five SCLC lines. All 16 cell lines could be tested for multiple drugs using the dye-exclusion assay. Drug concentrations for the nonclonogenic assay more closely approximated the area under the concentration-time curve for a given concentration of each agent. There was considerable variation in the relative sensitivity of the cell lines and the patterns of individual drug sensitivity. The majority of non-SCLC cell lines were refractory to most drugs. Cell lines derived from two previously treated SCLC patients and from three untreated SCLC patients showed greater sensitivity. Concurrent clonogenic and dye-exclusion assays showed similar drug rankings but different absolute values for percent survival. The nonclonogenic dye-exclusion assay is more rapid than the soft agar clonogenic assay (4 days vs. 2-3 weeks), could be performed on all cell lines tested, and appears to reflect the clinical diversity of human lung cancer.


An 84-Year-Old Man with Acute Atraumatic Compartment Syndrome of the Upper Extremity Due to Streptococcus pyogenes Cellulitis.
BACKGROUND Acute compartment syndrome represents a surgical emergency to restore blood supply by fasciotomy and decompression. Compartment syndrome is most commonly associated with crush-related injuries and fractures; however, other non-traumatic etiologies can occur. This report illustrates a rare case of acute atraumatic compartment syndrome of the upper extremity due to Streptococcus pyogenes cellulitis in an 84-year-old man, presenting a challenging clinical scenario. CASE REPORT An 84-year-old man presented to the Emergency Department with 24 h of significant right-arm pain and swelling. Due to the amount of increased swelling and significant pain, compartment pressure was obtained. He underwent emergency fasciotomy of his right forearm, hand, and carpal tunnel release. Both blood and intraoperative wound cultures grew Streptococcus pyogenes (Group A Streptococcus). The patient suffered a prolonged hospital course requiring multiple subsequent surgeries and eventual skin grafting. Despite his complicated hospital course, he made a remarkable recovery and was discharged home in excellent condition. CONCLUSIONS This report illustrates that compartment syndrome should be considered as a complication of cellulitis in patients with severe pain, even without a history of trauma. Early diagnosis, antibiotic therapy, and emergency fasciotomy are required to preserve the affected limb.


When to close a patent foramen ovale.
Transcatheter closure of the patent foramen ovale was the most common interventional procedure performed in our adult congenital heart disease unit in 2006. Although the prevalence of patent foramen ovale is similar in children, closure is rarely performed in this group despite susceptibility to similar defect-related morbidity. In this review we question whether this should remain the case.


Helsingør statement on poly- and perfluorinated alkyl substances (PFASs).
In this discussion paper, the transition from long-chain poly- and perfluorinated alkyl substances (PFASs) to fluorinated alternatives is addressed. Long-chain PFASs include perfluoroalkyl carboxylic acids (PFCAs) with 7 or more perfluorinated carbons, perfluoroalkyl sulfonic acids (PFSAs) with 6 or more perfluorinated carbons, and their precursors. Because long-chain PFASs have been found to be persistent, bioaccumulative and toxic, they are being replaced by a wide range of fluorinated alternatives. We summarize key concerns about the potential impacts of fluorinated alternatives on human health and the environment in order to provide concise information for different stakeholders and the public. These concerns include, amongst others, the likelihood of fluorinated alternatives or their transformation products becoming ubiquitously present in the global environment; the need for more information on uses, properties and effects of fluorinated alternatives; the formation of persistent terminal transformation products including PFCAs and PFSAs; increasing environmental and human exposure and potential of adverse effects as a consequence of the high ultimate persistence and increasing usage of fluorinated alternatives; the high societal costs that would be caused if the uses, environmental fate, and adverse effects of fluorinated alternatives had to be investigated by publicly funded research; and the lack of consideration of non-persistent alternatives to long-chain PFASs.


Regional cost variation for acute pancreatitis in the U.S.
Acute pancreatitis is one of the most common causes for acute hospitalization related to digestive disease. This study aimed to examine regional variation in national healthcare expenditure for management of acute pancreatitis. The Nationwide Inpatient Sample from 2010 was utilized to examine hospitalizations for acute pancreatitis. Total costs per hospitalization were calculated from charges using a cost-to-charge ratio and adjusted for suspected cost determinants from multivariable regression analysis. States were then ranked by costs and divided into tertiles for evaluation of outcome measures, including in-hospital mortality. Acute pancreatitis accounted for 288,597 hospitalizations in 2010. Regional variation was demonstrated after adjustment with a mean cost per hospitalization of $12,446.48. There was a difference of $4,870 per hospitalization between states in low cost and high cost tertiles. High cost states had a greater use of mechanical ventilation and infusion of supplemental nutrition (P<0.0001). Despite these differences, in-hospital mortality remained similar across cost tertiles (P=0.44). Several low-cost states were identified in traditionally high-cost regions. Significant regional variation in costs for acute pancreatitis persisted after adjusting for patient demographics, hospital characteristics and case mix variables. This variation suggests opportunities for increasing efficiency without compromising quality of care for acute pancreatitis.


Periodic acid‑Schiff staining method for function detection of liver cells is affected by 2% horse serum in induction medium.
Developing a thorough understanding of experimental methods of hepatic differentiation in hepatic progenitor cells (HPCs) should expand the knowledge of hepatocyte induction in vitro and may help to develop cell transplantation therapies for the clinical usage of HPCs in liver diseases. A previous induction method effectively induced differentiation and metabolic abilities in HPCs. Periodic acid‑Schiff (PAS) staining is used to identify glycogen synthesis and hepatocyte function; however, this method failed to detect induced hepatocytes. The present study aimed to investigate the possible factors affecting the previous confusing results of PAS staining. Removal of single induction factors, including dexamethasone, hepatic growth factor and fibroblast growth factor 4 from the induction media did not restore PAS staining, whereas replacement of 2% horse serum (HS) with 10% fetal bovine serum (FBS) significantly increased the number of PAS positive cells. Following 12 days of basal induction, replacing the induction medium with media containing 10% FBS for 12‑72 h significantly improved PAS staining, but did not influence indocyanine green uptake. Furthermore, incubation in induction medium with 10% FBS following 12 days of normal induction did not affect the expression of hepatic markers and mature function of HPCs. Therefore, the present study suggested that 2% HS in the induction medium did not affect the hepatic function of induced cells, but did affect glycogen storage, whereas replacement of medium with 10% FBS in advance of PAS staining may restore the failure of PAS staining in low serum concentrations of induced hepatocytes.


A new transcutaneous bidirectional communication for monitoring implanted artificial heart using the human body as a conductive medium.
A transcutaneous communication system (TCS) is a key technology for monitoring and controlling artificial hearts and other artificial organs in the body. In this study, we developed a new TCS that uses the human body as a conductive medium. Direct data exchange provides a higher level of communication security compared to that of wireless methods without physical constraints such as an external wire. The external and internal units of the new TCS each consist mainly of a data transmitter and a data receiver. The data transmitter has an amplitude shift keying (ASK) modulator (carrier frequencies: 4 and 10 MHz) and an electrode. The ASK-modulated data current is led into the body through the electrode, and it flows back to the energy source through the body, the data receiver, and the earth ground that includes all conductors and dielectrics in the environment that are in close proximity to the patient. Performance of the TCS was evaluated by a communication test on the surface of the human body and in an animal experiment using a goat. The TCS was able to transmit data concurrently for 4 weeks between everywhere on the surface of the body and everywhere inside the body under full-duplex communication at a transmission rate of 115 kbps. The power consumption of each TCS unit was 125 mW with an ASK-modulated current of 7 mA (root-mean-square). While further study is required to secure its safety, the newly developed TCS has promise to be a next-generation transcutaneous communication device.


The evaluation of cerebral oxygenation by oximetry in patients with ischaemic stroke.
To evaluate the clinical significance of estimation of the regional cerebral oxygen saturation (rSO2) in the patients with ischaemic stroke by the cerebral oximetry during acute, sub-acute and chronic phases. In this prospective study, 24 patients with ischaemic stroke in the middle cerebral artery territory were included. A detailed clinical examination and appropriate laboratory investigations were carried out. The rSO2 was determined by oximetery (INVOS 3100-SD) bilaterally on the first, third, seventh, and fifteenth days. The blood pressure, the peripheral capillary oxygen saturation and the arterial blood gas values were noted too. the changes were evaluated along with Glasgow coma scale (GCS) using unpaired student t-test and one way ANOVA test. There were significant differences between the rSO2 values in acute, subacute and chronic phases on the side of the lesion (p value < 0.05). The values of oxygen saturation gradually increased throughout the chronic phase. These values showed a positive correlation with GCS, but the results were not significant statistically. The rSO2 values were also significantly higher on the non-lesional side than those on the lesion side in the acute phase (p= 0.0034), the discrepancy disappeared during the sub-acute and chronic phases. Cerebral oximetry can be used as a measure to evaluate the cerebral oxygenation during the various phases of ischaemic stroke. It has a potential to serve as a useful marker for detection of cerebral oxygenation imbalances, to judge the effectiveness of the management and for the follow-up of patients with ischaemic stroke.


Detection Rates and Trends of Asymptomatic Unruptured Intracranial Aneurysms From 2005 to 2019.
The trend in detection rates of asymptomatic unruptured intracranial aneurysms (UIAs) on brain computed tomography angiography/magnetic resonance angiography (CTA/MRA) is not well established. Our objective was to evaluate time trends in asymptomatic UIA detection rates on brain CTA/MRA between 2005 and 2019. We conducted a retrospective study of all brain computed tomography/magnetic resonance scans (n = 288 336 scans in 130 621 patients) performed between January 2005 and December 2019 at a tertiary referral hospital. Patients who underwent brain CTA/MRA examinations were included (n = 81 261 scans in 48 037 patients). The annual detection rate of new UIA cases was calculated based on the first brain CTA/MRA imaging. Detection rates were compared between three periods and across different age groups. The number of first CTA/MRA examinations increased significantly from 2005 to 2009 (n = 12 190 patients) to 2010-2014 (n = 14 969 patients) and 2015-2019 (n = 20 878 patients) (P < .001). The UIA detection rate also increased significantly from 1.7% in 2005-2009 to 2.5% in 2010-2014 and 3.4% in 2015-2019 (P < .001). The UIA detection rate increased significantly from 2010-2014 to 2015-2019 (relative risk [RR], 1.33; 95% CI, 1.17-1.51), particularly in patients aged 60-69 years (RR, 1.29; 95% CI, 1.01-1.63), 70-79 years (RR, 1.71; 95% CI, 1.30-2.25), and >79 years (RR, 2.33; 95% CI, 1.56-3.47). Furthermore, the detection rate of <5-mm UIAs increased from 2010-2014 to 2015-2019 (RR, 1.51; 95% CI, 1.28-1.77). The detection rate of asymptomatic UIAs, particularly in elderly patients, has increased significantly over the past 15 years, coinciding with the increased use of CTA/MRA imaging. Furthermore, the size of the identified UIAs has decreased. These findings raise concerns about the management strategies for UIAs, indicating the need for further research.


Contributions of unique intracellular domains to switchlike biosensing by Toll-like receptor 4.
Toll-like receptors (TLRs) mediate immune recognition of both microbial infections and tissue damage. Aberrant TLR signaling promotes disease; thus, understanding the regulation of TLR signaling is of medical relevance. Although downstream mediators of TLR signaling have been identified, the detailed mechanism by which ligand binding-mediated dimerization induces downstream signaling remains poorly understood. Here, we investigate this question for TLR4, which mediates responsiveness to bacterial LPS and drives inflammatory disease. TLR4 exhibits structural and functional features that are unique among TLRs, including responsiveness to a wide variety of ligands. However, the connection between these structural features and the regulation of signaling is not clear. Here, we investigated how the unique intracellular structures of TLR4 contribute to receptor signaling. Key conclusions include the following. 1) The unique intracellular linker of TLR4 is important for achieving LPS-inducible signaling via Toll/IL-1 receptor (TIR) domain-containing adapter-inducing interferon-β (TRIF) but less so for signaling via myeloid differentiation primary response 88 (MyD88). 2) Membrane-bound TLR4 TIR domains were sufficient to induce signaling. However, introducing long, flexible intracellular linkers neither induced constitutive signaling nor ablated LPS-inducible signaling. Thus, the initiation of TLR4 signaling is regulated by a mechanism that does not require tight geometric constraints. Together, these observations necessitate refining the model of TLR4 signal initiation. We hypothesize that TLR4 may interact with an inhibitory partner in the absence of ligand, via both TIR and extracellular domains of TLR4. In this speculative model, ligand binding induces dissociation of the inhibitory partner, triggering spontaneous, switchlike TIR domain homodimerization to initiate downstream signaling.


Effect of hyperbaric oxygen and ozone preconditioning on oxidative/nitrosative stress induced by tourniquet ischemia/reperfusion in rat skeletal muscle.
The aim of the study was to investigate the effect of hyperbaric oxygen-preconditioning (HBO-PC) and ozone-preconditioning (O3-PC) on oxidative/nitrosative stress induced by tourniquet ischemia/reperfusion (I/R) in rat skeletal muscle. Thirty-two Wistar-Albino-type male rats included in the study were divided into four groups of equal number: 1) sham operation, 2) I/R, 3) I/R+HBO-PC, or 4) I/R+O3-PC. One session of 3-4 L/min 100% oxygenation for 60 min at 3 absolute atmosphere (ATA) was defined as one dose of HBO; in total, 7 doses of HBO-PC were administered before ischemia. One dose of O3 comprised 0.7 mg/kg ozone/oxygen mixture, administered intraperitoneally; a total of 4 doses of O3-PC were administered before ischemia. The I/R model was performed in anesthetized rats by clipping right femoral artery to induce 2 h ischemia followed by 22 h of reperfusion. The right gastrocnemius muscle and venous blood samples were harvested. Tissue was assayed for levels of malondialdehyde (MDA), inducible nitric oxide synthase (iNOS), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px). Serum was assayed to measure the level of nitrite-nitrate (NOx). Tissue MDA level, SOD activity, and serum NOx level were increased, whereas GSHPx was decreased in the I/R group. MDA and NOx levels were decreased, whereas GSH-Px activity was increased in both the I/R+HBO-PC and I/R+O3-PC groups. SOD activity was increased in the I/R+O3-PC group, but did not change significantly in the I/R+HBO-PC group. iNOS staining score and intensity were lower in the I/R+HBO-PC and I/R+O3-PC groups than I/R group. Both O3-PC and HBO-PC reduced tissue lipid peroxidation, NOx levels, and iNOS staining scores in the experimental I/R model. Our data suggest that HBO-PC and O3-PC protect against oxidative/nitrosative stress induced by I/R in rat skeletal muscle.


Two distinct mechanisms of selection in working memory: Additive last-item and retro-cue benefits.
In working memory research, individual items are sometimes said to be in the "focus of attention". According to one view, this occurs for the last item in a sequentially presented list (last-item benefit). According to a second view, this occurs when items are externally cued during the retention interval (retro-cue benefit). We investigated both phenomena at the same time to determine whether both result from the same cognitive mechanisms. If that were the case, retro-cue benefits should be reduced when the retro-cue is directed to the item that already benefits from being presented last. We measured speed-accuracy-tradeoff functions with the response-deadline paradigm to measure retrieval dynamics in a short-term recognition task. Across three experiments, we found that retro-cues benefited the last item and other items to the same extent. The additivity of the last-item benefit and the retro-cue benefit points towards the co-existence of at least two distinct forms of attentional prioritization in working memory.


Indomethacin increases severity of Clostridium difficile infection in mouse model.
To evaluate the effect on the nonsteroidal anti-inflammatory drug indomethacin on Clostridium difficile infection (CDI) severity. Indomethacin was administered in two different mouse models of antibiotic-associated CDI in two different facilities, using a low and high dose of indomethacin. Indomethacin administration caused weight loss, increased the signs of severe infection and worsened histopathological damage, leading to 100% mortality during CDI. Indomethacin-treated, antibiotic-exposed mice infected with C. difficile had enhanced intestinal inflammation with increased expression of KC, IL-1β and IL-22 compared with infected mice unexposed to indomethacin. These results demonstrate a negative impact of nonsteroidal anti-inflammatory drugs on antibiotic-associated CDI in mice and suggest that targeting the synthesis or signaling of prostaglandins might be an approach to ameliorating the severity of CDI.


Differential efficiency among DNA extraction methods influences detection of the amphibian pathogen Batrachochytrium dendrobatidis.
Chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), is responsible for massive declines and extinctions of amphibians worldwide. The most common method for detecting Bd is quantitative polymerase chain reaction (qPCR). qPCR is a highly sensitive detection technique, but its ability to determine the presence and accurately quantify the amount of Bd is also contingent on the efficiency of the DNA extraction method used prior to PCR. Using qPCR, we compared the extraction efficiency of 3 different extraction methods commonly used for Bd detection across a range of zoospore quantities: PrepMan Ultra Reagent, Qiagen DNeasy Blood and Tissue Kit, and Mobio PowerSoil DNA Isolation Kit. We show that not all extraction methods led to successful detection of Bd for the low zoospore quantities and that there was variation in the estimated zoospore equivalents among the methods, which demonstrates that these methods have different extraction efficiencies. These results highlight the importance of considering the extraction method when comparing across studies. The Qiagen DNeasy kit had the highest efficiency. We also show that replicated estimates of less than 1 zoospore can result from known zoospore concentrations; therefore, such results should be considered when obtained from field data. Additionally, we discuss the implications of our findings for interpreting previous studies and for conducting future Bd surveys. It is imperative to use the most efficient DNA extraction method in tandem with the highly sensitive qPCR technique in order to accurately diagnose the presence of Bd as well as other pathogens.


A rationale for staged teaching of basic life support.
Basic life support is a crucial part of the Chain of Survival. Unfortunately, however the skill is complex and cannot readily be acquired--let alone retained--in the course of a single training session. Although the problem has long been recognised, no new strategies have been widely implemented to counter the problem. We believe that staged teaching of CPR might provide a solution, and we have devised a program to test this new method. It involves three stages of instruction that we have called bronze, silver, and gold standards. The bronze standard involves opening the airway and providing chest compression without active ventilation: this alone may widen the window of opportunity for successful defibrillation in adult victims in out-of-hospital cardiac arrest. Ventilation is introduced at silver stage using a ratio of 50:5, with emphasis on its value in the resuscitation of children being used as motivation to bring people back for a second period of instruction. The gold stage teaches conventional CPR. A pilot study has been encouraging and a randomized trial on skill acquisition and skill retention is planned.


Factors associated with presenting late or with advanced HIV disease in the Netherlands, 1996-2014: results from a national observational cohort.
Early testing for HIV and entry into care are crucial to optimise treatment outcomes of HIV-infected patients and to prevent spread of HIV. We examined risk factors for presentation with late or advanced disease in HIV-infected patients in the Netherlands. HIV-infected patients registered in care between January 1996 and June 2014 were selected from the ATHENA national observational HIV cohort. Risk factors for late presentation and advanced disease were analysed by multivariable logistic regression. Furthermore, geographical differences and time trends were examined. Of 20,965 patients, 53% presented with late-stage HIV infection, and 35% had advanced disease. Late presentation decreased from 62% (1996) to 42% (2013), while advanced disease decreased from 46% to 26%. Late presentation only declined significantly among men having sex with men (MSM; p <0.001), but not among heterosexual males (p=0.08) and females (p=0.73). Factors associated with late presentation were: heterosexual male (adjusted OR (aOR), 1.59; 95% CI 1.44 to 1.75 vs MSM), injecting drug use (2.00; CI 1.69 to 2.38), age ≥ 50 years (1.46; CI 1.33 to 1.60 vs 30-49 years), region of origin (South-East Asia 2.14; 1.80 to 2.54, sub-Saharan Africa 2.11; 1.88 to 2.36, Surinam 1.59; 1.37 to 1.84, Caribbean 1.31; 1.13 to 1.53, Latin America 1.23; 1.04 to 1.46 vs the Netherlands), and location of HIV diagnosis (hospital 3.27; 2.94 to 3.63, general practitioner 1.66; 1.50 to 1.83, antenatal screening 1.76; 1.38 to 2.34 vs sexually transmitted infection clinic). No association was found for socioeconomic status or level of urbanisation. Compared with Amsterdam, 2 regions had higher adjusted odds and 2 regions had lower odds of late presentation. Results were highly similar for advanced disease. Although the overall rate of late presentation is declining in the Netherlands, targeted programmes to reduce late HIV diagnoses remain needed for all risk groups, but should be prioritised for heterosexual males, migrant populations, people aged ≥ 50 years and certain regions in the Netherlands.


C-reactive protein inhibits adiponectin gene expression and secretion in 3T3-L1 adipocytes.
C-reactive protein (CRP) is considered as one of the most sensitive markers of inflammation. The aim of the present study is to investigate the effects of CRP on the production of adiponectin in 3T3-L1 adipocytes. Northern and western blot analysis revealed that CRP treatment inhibited adiponectin mRNA expression and secretion in a dose- and time-dependent manner. Co-incubation of adipocytes with rosiglitazone and CRP decreased induction of adiponectin gene expression by rosiglitazone. However, luciferase reporter assays did not show that CRP affected the activity of approximately 2.1 kb adiponectin gene promoter, which was increased by rosiglitazone alone. Pharmacological inhibition of phosphatidylinositol (PI)-3 kinase by LY294002 partially reversed inhibition of adiponectin gene expression by CRP. These results collectively suggest that CRP suppresses adiponectin gene expression partially through the PI-3 kinase pathway, and that decreased production of adiponectin might represent a mechanism by which CRP regulates insulin sensitivity.


Cleft Lip and Palate: Demographic Patterns and the Associated Communication Disorders.
This study investigated demographical characteristics, health status, and associated communication disorders in patients with orofacial clefts (OFCs) in Northern Jordan. A retrospective study of 226 cleft patients and their families was carried out between March 2012 and September 2016 at the Speech and Hearing Clinic and the Maxillofacial Center at King Abdullah University Hospital. Data were collected by interviewing patients and caregivers, having patients or caregiver to complete a questionnaire and reviewing the patient's medical records. The frequencies of OFC type, demographic, health status, and communication disorders variables were calculated. χ analysis was used to test for significance of associated demographic and communication disorders variables with OFC type. Results revealed higher percentage of males compared with female patients. The majority of OFC patients were born to families who lived in urban areas, obtained high school diploma or lower educational level, lived below poverty cutoff, and showed nonconsanguineous marriages. Most mothers took the prescribed pregnancy supplements. Only one-third of the families received health education and reported other incidences of OFCs. Twenty percent of the patients had other congenital anomalies, 80% experienced dysphagia prior to the cleft repair, dropped to 14% after the repair. Higher percentage of patients with isolated cleft palate and cleft lip and palate exhibited hearing loss, hypernasality, articulation and phonological disorders, and dysphagia compared with those with cleft lip only. None of the demographic variables was associated with OFC type. Data suggested that families who had children with OFCs displayed poor socioeconomic status and low educational level which may impede the delivery of health education by health practitioners. Increased risk of comorbid communication disorders and malformations in OFC patients must be emphasized and disseminated to health professionals involved in the management of patients with OFC.


Measurement of glomerular basement membrane thickness and its application to the diagnosis of thin-membrane nephropathy.
Morphometry is a valuable diagnostic aid when the glomerular basement membrane is suspected of being abnormally thin. Determination of overall width by the harmonic mean method has been described in detail. Results were given of measurements in 20 control subjects with histologically normal basement membranes and 41 allograft kidneys. Mean +/- 1.5 SDs of a series was found to be the most useful empiric guide to basement membrane widths. It was confirmed that the membrane was thinner in females than in males. The lower end of the respective mean +/- 1.5 SDs range overlapped with thicknesses that occurred in "thin-membrane nephropathy" in women but not in men, although the threshold width below which hematuria was liable to occur was similar, at approximately 340 nm, in both sexes. It is suggested that the higher incidence of symptomatic thin-membrane nephropathy in females is related to their normally thinner glomerular basement membranes, in the context of the common threshold level. Other histologic findings, and the clinical picture, remain relevant to the diagnosis of thin-membrane diseases.


Pain and satisfaction: the case of isolated COVID-19 patients of Pakistan.
Over 3 million people lost their lives across the globe due to the COVID-19 related pandemic. The unprecedented restrictions on mobility have imposed in the form of isolation, quarantines, and lockdowns to curb the profound effects of the pandemic and retain physical health. This study examined the relationship between various pain levels, demographic variables and patient satisfaction with COVID-19 during isolation. The primary data in this study were collected from isolated patients during their isolation and treatment in a public hospital. We obtained information from patients with COVID-19 (N = 100) about their demographic characteristics, varying levels of pain, and satisfaction with the services provided during the isolation period. We computed the descriptive statistics to explain the profile of participants, ANOVA was used to find out the difference between various groups on patient satisfaction, and structural equation modeling was performed to examine the link between pain levels, demographic factors, and patient satisfaction. This analysis was performed with STATA and SmartPLS-3. The findings of this study ascertained that respondent's education (Beta, β = 2.961, p = 0.003), assets such as possession of a house (β = 4.563, p = 0.000), perception of income adequacy during the lockdown (=2.299, p = 0.022), and negligence in prevention (β = 1.975, p = 0.049) significantly affects patient satisfaction during the isolation period. Moreover, satisfaction with life, physicians and medicine, income adequacy, and fear of the participants was significantly linked to the pain level (Model F-stat = 86.323, p = 0.0001). Patients who were satisfied with their treatment had significantly lower odds of having pain (OR 0.023, 95% CI [0.001-0.0452]). Patients who had enough income to meet their basic necessities were found to have significantly lower odds of having pain (OR 0.155, 95% CI [0.032-0.740]. We conclude that a higher level of education, low income, and living in a rented house contributes significantly to the feeling of more satisfaction with the provided services. This implies that people with more affluent backgrounds are less likely to be satisfied with the provided services as low-income and living in rented house groups are more satisfied during isolation than others. The pain level is also affected by subjective factors such as fear and satisfaction which need to be considered while doing patient management. This study can be helpful in improving the delivery of public services of isolation centers by considering various characteristics and demographic factors of patients.


[Sensory neurons and Schwann cells during pharmacologic stimulation of the nerve regeneration].
Using the model of rat sciatic nerve transection and crush injury we studied influence of pyrimidine derivative xymedon on efficacy of regeneration of myelinated axons, number and phenotype of surviving sensory neurons (expressing GAP-43 and Bcl-2) and Schwann cells (S100, GAP-43, PCNA) on the 7th, 15th, 30th, 60th and 90th day after nerve injury. We found out that xymedon counteracts posttraumatic death of sensory neurons, stimulates regeneration of myelinated fibres and proliferation of Schwann cells.


Cost-effectiveness and affordability of community mobilisation through women's groups and quality improvement in health facilities (MaiKhanda trial) in Malawi.
Understanding the cost-effectiveness and affordability of interventions to reduce maternal and newborn deaths is critical to persuading policymakers and donors to implement at scale. The effectiveness of community mobilisation through women's groups and health facility quality improvement, both aiming to reduce maternal and neonatal mortality, was assessed by a cluster randomised controlled trial conducted in rural Malawi in 2008-2010. In this paper, we calculate intervention cost-effectiveness and model the affordability of the interventions at scale. Bayesian methods are used to estimate the incremental cost-effectiveness of the community and facility interventions on their own (CI, FI), and together (FICI), compared to current practice in rural Malawi. Effects are estimated with Monte Carlo simulation using the combined full probability distributions of intervention effects on stillbirths, neonatal deaths and maternal deaths. Cost data was collected prospectively from a provider perspective using an ingredients approach and disaggregated at the intervention (not cluster or individual) level. Expected Incremental Benefit, Cost-effectiveness Acceptability Curves and Expected Value of Information (EVI) were calculated using a threshold of $780 per disability-adjusted life-year (DALY) averted, the per capita gross domestic product of Malawi in 2013 international $. The incremental cost-effectiveness of CI, FI, and combined FICI was $79, $281, and $146 per DALY averted respectively, compared to current practice. FI is dominated by CI and FICI. Taking into account uncertainty, both CI and combined FICI are highly likely to be cost effective (probability 98% and 93%, EVI $210,423 and $598,177 respectively). Combined FICI is incrementally cost effective compared to either intervention individually (probability 60%, ICER $292, EIB $9,334,580 compared to CI). Future scenarios also found FICI to be the optimal decision. Scaling-up to the whole of Malawi, CI is of greatest value for money, potentially averting 13.0% of remaining annual DALYs from stillbirths, neonatal and maternal deaths for the equivalent of 6.8% of current annual expenditure on maternal and neonatal health in Malawi. Community mobilisation through women's groups is a highly cost-effective and affordable strategy to reduce maternal and neonatal mortality in Malawi. Combining community mobilisation with health facility quality improvement is more effective, more costly, but also highly cost-effective and potentially affordable in this context.


Low temperature regeneration of activated carbons using microwaves: revising conventional wisdom.
The purpose of this work was to explore the application of microwaves for the low temperature regeneration of activated carbons saturated with a pharmaceutical compound (promethazine). Contrary to expectations, microwave-assisted regeneration did not lead to better results than those obtained under conventional electric heating. At low temperatures the regeneration was incomplete either under microwave and conventional heating, being this attributed to the insufficient input energy. At mild temperatures, a fall in the adsorption capacity upon cycling was obtained in both devices, although this was much more pronounced for the microwave. These results contrast with previous studies on the benefits of microwaves for the regeneration of carbon materials. The fall in the adsorption capacity after regeneration was due to the thermal cracking of the adsorbed molecules inside the carbon porous network, although this effect applies to both devices. When microwaves are used, along with the thermal heating of the carbon bed, a fraction of the microwave energy seemed to be directly used in the decomposition of promethazine through the excitation of the molecular bonds by microwaves (microwave-lysis). These results point out that the nature of the adsorbate and its ability to interact with microwave are key factors that control the application of microwaves for regeneration of exhausted activated carbons.


The biology of environmental stress: molecular biomarkers in Sydney rock oysters (Saccostrea glomerata).
This review describes our recent work on environmental stress in Sydney rock oysters, focusing on the identification of molecular biomarkers for ecotoxicological analysis. We begin by describing the environmental pressures facing coastal estuaries in Australia, with particular reference to Sydney Harbour. After providing that context, we summarise our transcriptional and proteomic analyses of Sydney rock oysters responding to chemical contamination and other forms of environmental stress. This work has shown that the intracellular processes of oysters are highly responsive to environmental threats. Our data agree with the broader literature, which suggests that there is a highly conserved intracellular stress response in oysters involving a limited number of biological processes. We conclude that many effective molecular markers for environmental biomonitoring are likely to lie within these biological pathways.


History and plastic surgery: systems of recovering our past.
Plastic surgeons have taken uncommon interest in their past. Systematized approaches toward the collection of historical information have characterized the specialty. Plastic surgery is the only discipline to have compiled a complete bibliography of its world's literature. The Archives maintains an ongoing program of acquisition of the oral, written, and personal memorabilia of the notable leaders and events of plastic surgery.


Improvement of regeneration with predegenerated nerve transplants in silicone chambers.
We compared regeneration and reinnervation of target organs after sciatic nerve resection and repair with silicone tubes filled with saline solution or with a peroneal nerve segment as a nerve transplant versus an autologous sciatic nerve graft leaving either 4 mm or 6 mm gaps. The aims of this study were to evaluate the effects of predegeneration and donor immunogenicity of nerve transplants. Functional reinnervation was assessed by noninvasive methods to determine recovery of sweating, sensory and motor functions in the hindpaw after three months postoperation for 4 mm and four months postoperation for 6 mm gap groups. Morphometrical analysis of the regenerated nerve were performed at the end of the follow-up. The group with an autograft achieved faster and higher levels of reinnervation for the four functions tested than any of the groups repaired by tubulization. The introduction of a small nerve transplant improved regeneration and reinnervation with respect to a saline solution filled tube slightly with a 4 mm gap, but significantly with a 6 mm long gap. The beneficial effects of the nerve transplant were significantly increased when it was predegenerated, while disappearing when its cellular component was eliminated by repeated freezing. The immunogenicity of the nerve transplant dramatically affected nerve regeneration, as it was impeded by an heterologous transplant in the tube. In summary, the use of silicone chambers with an autologous predegenerated nerve transplant may be an alternative for repairing long gaps in injured nerves, approaching the level of success of an ideal autologous nerve graft.


Topical immunomodulators in dermatology.
Topical immunomodulators are agents that regulate the local immune response of the skin. They are now emerging as the therapy of choice for several immune-mediated dermatoses such as atopic dermatitis, contact allergic dermatitis, alopecia areata, psoriasis, vitiligo, connective tissue disorders such as morphea and lupus erythematosus, disorders of keratinization and several benign and malignant skin tumours, because of their comparable efficacy, ease of application and greater safety than their systemic counterparts. They can be used on a domiciliary basis for longer periods without aggressive monitoring. In this article, we have discussed the mechanism of action, common indications and side-effects of the commonly used topical immunomodulators, excluding topical steroids. Moreover, newer agents, which are still in the experimental stages, have also been described. A MEDLINE search was undertaken using the key words "topical immunomodulators, dermatology" and related articles were also searched. In addition, a manual search for many Indian articles, which are not indexed, was also carried out. Wherever possible, the full article was reviewed. If the full article could not be traced, the abstract was used.


Major histocompatibility complex gene organization in the mole rat Spalax ehrenbergi: evidence for transfer of function between class II genes.
A genomic DNA library prepared from the kidney of the mole rat Spalax ehrenbergi was screened with mouse probes representing major histocompatibility complex genes that encode alpha and beta polypeptide chains of class II molecules (alpha and beta genes). Restriction maps were constructed for the cross-hybridizing clones, and the class II genes borne by these clones were identified. By this procedure, five main regions containing class II genes were established. One region contained four genes and two gene fragments, the second region contained two genes, the third region contained one gene and one gene fragment, and the remaining two regions contained one gene each. Altogether, six beta genes, two alpha genes, and three alpha-gene fragments were identified. Two of the genes (one alpha and one beta) were established as belonging to the DQ subclass, and all other genes were found to be members of the DP subclass. (Subclass designations are based on the human HLA class II genes). No genes belonging to the DR and DO (DZ) subclasses were found in the library. The absence of DR genes in S. ehrenbergi was also indicated when other experimental methods were used. At least some of the DP loci are polymorphic and most likely also functional. Thus, in the evolution of the mole rat, the DR (and probably also the DO) loci have been deleted and their function(s) has been taken over by the DP loci, which have expanded to a great extent. These findings argue for functional interchangeability of the individual subclasses of class II loci.


Repeat microsphere delivery for serial measurement of regional blood perfusion in the chronically instrumented, conscious canine.
For chronic, repeat hemodynamic studies in conscious dogs, we designed and tested a chronically instrumented canine microsphere delivery model. The goals of this study were (1) to investigate the accuracy of repeated estimations of blood perfusion using fluorescent-labeled microspheres and (2) to develop and validate a chronic preparation that permits consecutive estimations in the same conscious animal over an extended protocol. Via thoracotomy, nine dogs were instrumented with left atrial appendage and aortic vascular access catheters connected to subcutaneous vascular access ports. Four animals received seven serial injections of 1.6 million 15 microm microspheres (total: 11.2 million), and five animals received 8 serial injections of 2.25 million microspheres (total: 18 million) over the course of 11 or 18 wk. All catheters have remained bidirectionally patent during protocol for 14.9 +/- 0.8 (mean +/- SEM) wk. Sphere accumulation did not significantly alter global myocardial (P = 0.69, P = 0.25), renal (P = 0.92, P = 0.12), hepatic (P = 0.84, P = 0.32), or splenic (P = 0.33, P = 0.70) blood perfusion in either set of animals. Catheters remained bidirectionally patent for months, did not interfere with the hemodynamic responses of the preparation, and allowed repeat percutaneous injection of microspheres and withdrawal of reference arterial blood from within conscious canines. Eight serial injections totaling 18 million microspheres over 18 weeks did not alter regional myocardial, hepatic, renal, or splenic blood flow. This dependable, chronic, percutaneous arterial access preparation provides a means for examining acute and long-term effects of pathophysiological, pharmaceutical, and environmental influences on regional arterial blood flow in conscious, large animals.


[A study on the surgical efficacy of modified laparoscopic levator ani muscle external abdominoperineal resection for the treatment of ultra-low rectal cancer patients].
Objective: Exploring the surgical effectiveness and post-operative recovery of modified laparoscopic levator ani muscle external abdominoperineal resection (L-ELAPE) in the treatment of ultra-low rectal cancer patients. Methods: In a retrospective study conducted at the Oncology Department of Xinxiang Central Hospital and the Fourth Clinical College of Xinxiang Medical University, we analyzed 107 patients with ultra-low rectal cancer who underwent surgical treatment from April 2017 to April 2022. Among them, 54 patients in the modified group were treated using the L-ELAPE technique, while 53 patients in the conventional group underwent the traditional ELAPE surgery. We compared the surgical operation metrics, post-operative pathological results, quality of life, and incidence of complications between the two groups. Results: The age of 54 patients in the modified group was (56.8±7.2) years old, with 53.7% (29 cases) being male; The age of 53 patients in the conventional group was (54.5±5.9) years old, with males accounting for 45.3% (24 cases). There was no statistically significant difference in surgical time between the modified group and the conventional group (P>0.05); The surgical bleeding volume, drainage tube placement time, first postoperative anal exhaust time, and hospitalization time of the modified group patients were (143.2±26.7) ml, (61.9±11.4) h, (5.5±1.6) d, and (10.5±2.2) d, respectively, which were shorter than those in the conventional group's (185.0±31.5) ml, (74.8±14.0) h, (6.4±1.7) d, and (12.2±2.8) d (all P values<0.05). There was no statistically significant difference in postoperative pathological TNM staging, vascular infiltration rate, nerve invasion rate, number of lymph nodes cleaned, and tumor differentiation degree between the two groups of patients (all P values>0.05); The incidence of surgical complications in the modified group was 7.41% (4 cases), lower than that in the conventional group (P<0.05) with 24.53%(13 cases). One month after surgery, the physiological health score of the modified group patients was (35.6±4.7) score, which was higher than the conventional group's (32.8±5.1) score (P<0.05). Conclusion: For patients with ultra-low rectal cancer, the use of the L-ELAPE treatment, compared to conventional methods, can effectively promote post-operative recovery and reduce the rate of surgical complications, which, to some extent, contributes to improving the post-operative quality of life for the patients.


Analysis of single nucleotide polymorphisms (SNPs) associated with antibiotic resistance genes in Chilean Piscirickettsia salmonis strains.
The aetiological agent of Piscirickettsiosis is Piscirickettsia salmonis, a Gram-negative intracellular pathogen, and high doses of antibiotics have regularly been employed to treat this infection. Seven florfenicol and/or oxytetracycline resistance genes (tet pump, tetE, Tclor/flor, Tbcr, TfloR, ompF and mdtN) were identified in strains by in silico genome analyses. Later, the number of single nucleotide polymorphisms (SNPs) and its relationship with the resistance to these antibiotics were identified and analysed, using the original LF-89 strain as reference. Trials to determine and compare the minimum inhibitory concentration (MIC) of oxytetracycline and florfenicol in each strain, as well as to quantify the gPCR transcripts levels in the selected genes, were performed. Therefore, variations in the resistance to both antibiotics were observed, where the strain with fewer SNPs showed the highest susceptibility. Consistently, the in silico 3D analyses of proteins encoded by the selected genes revealed structural changes, evident in the sequences with the highest number of SNPs. These results showed that the bacterial resistance to oxytetracycline was mainly linked to the presence of SNPs in relevant sites, antibiotic resistance genes and an OmpF porin, leading to important changes in the protein structure.


Effects and Safety of Sacubitril/Valsartan for Patients with Myocardial Infarction: A Systematic Review and Meta-Analysis.
Patients who develop heart failure (HF) after an acute myocardial infarction (AMI) are at higher risk of adverse fatal and nonfatal outcomes. Studies have shown sacubitril/valsartan can further reduce the risk of cardiovascular death or hospitalization for heart failure by 20% compared with enalapril. At the same time, its tolerance and safety are better. However, the current evidence regarding the efficacy of sacubitril/valsartan in patients with heart failure after acute myocardial infarction is controversial. To assess the effect of sacubitril/valsartan on heart failure after acute myocardial infarction, we conducted a systematic review of the literature and a meta-analysis of existing randomized clinical trials. Meta-analysis of randomized controlled trails is used where data are collected from PubMed, the Cochrane library, Embase, and Web of Science. Data about sacubitril/valsartan were available from 5 studies. Forest plots showed that the sacubitril/valsartan group had a 299% higher value of sacubitril/valsartan to the control group (MD = 2.99%, 95% CI: 2.01, 3.96, I 2 = 78%, P < 0.00001, Figure 2), and the difference was statistically significant. Forest plots showed that the sacubitril/valsartan group had a 531% lower value of LVEF to the control group (MD = -5.31%, 95% CI: -7.36, -3.26, I 2 = 91%, P < 0.00001, Figure 2), and the difference was statistically significant. Forest plots showed that the sacubitril/valsartan group had a 133% lower value of NT-proBNP to the control group (MD = -1.33%, 95% CI: -1.54, -1.12, I 2 = 96%, P < 0.00001, Figure 3). Forest plots showed that the sacubitril/valsartan group had a 49% lower risk of heart failure to the control group (MD = 0.49, 95% CI: 0.27, 0.89, I 2 = 0%, P=0.02, Figure 3). The patients in experimental showed an obviously lower OR of MACE (OR = 0.47, 95% CI: 0.27, 0.82, P=0.007, Figure 3). The data were statistically significant. We have observed that for patients with heart failure after acute myocardial infarction, early administration of sacubitril/valsartan can significantly reduce the incidence of heart rate, left ventricular ejection fraction, NT-proBNP, and MACE. Our meta-analysis suggests that taking sacubitril/valsartan is relatively safe and effective, especially if started early after acute myocardial infarction.


Deep-Learning-Based Pre-Diagnosis Assessment Module for Retinal Photographs: A Multicenter Study.
Artificial intelligence (AI) deep learning (DL) has been shown to have significant potential for eye disease detection and screening on retinal photographs in different clinical settings, particular in primary care. However, an automated pre-diagnosis image assessment is essential to streamline the application of the developed AI-DL algorithms. In this study, we developed and validated a DL-based pre-diagnosis assessment module for retinal photographs, targeting image quality (gradable vs. ungradable), field of view (macula-centered vs. optic-disc-centered), and laterality of the eye (right vs. left). A total of 21,348 retinal photographs from 1914 subjects from various clinical settings in Hong Kong, Singapore, and the United Kingdom were used for training, internal validation, and external testing for the DL module, developed by two DL-based algorithms (EfficientNet-B0 and MobileNet-V2). For image-quality assessment, the pre-diagnosis module achieved area under the receiver operating characteristic curve (AUROC) values of 0.975, 0.999, and 0.987 in the internal validation dataset and the two external testing datasets, respectively. For field-of-view assessment, the module had an AUROC value of 1.000 in all of the datasets. For laterality-of-the-eye assessment, the module had AUROC values of 1.000, 0.999, and 0.985 in the internal validation dataset and the two external testing datasets, respectively. Our study showed that this three-in-one DL module for assessing image quality, field of view, and laterality of the eye of retinal photographs achieved excellent performance and generalizability across different centers and ethnicities. The proposed DL-based pre-diagnosis module realized accurate and automated assessments of image quality, field of view, and laterality of the eye of retinal photographs, which could be further integrated into AI-based models to improve operational flow for enhancing disease screening and diagnosis.