Methaemoglobinaemia due to mephedrone ('snow').
Acquired methaemoglobinaemia is a serious complication caused by many oxidising drugs. It presents as cyanosis unresponsive to oxygen therapy. The case of 33-year-old male patient who presented in our department after noticing blue lips and fingers is presented. He had sniffed 1 g of 'snow' after buying it from a head shop. His oxygen saturation by pulse oximeter on room air at presentation was 90%, which did not improve with supplemental oxygen. Arterial blood gas analyses showed partial pressure of oxygen 37 kPa while on supplemental oxygen and a methaemoglobin concentration greater than 25%. The patient denied using any other recreational drugs and was not on regular treatment. Therefore, a diagnosis of methaemoglobinaemia due to mephedrone, which is the active ingredient of 'snow', was made. Treatment is with intravenous methylene blue. Our patient started to improve so methylene blue was not used and he was discharged after 8 h.


Impact of Postoperative Complications on Oncologic Outcomes After Rectal Cancer Surgery: An Analysis of the US Rectal Cancer Consortium.
Postoperative complications (POCs) are associated with worse oncologic outcomes in several cancer types. The implications of complications after rectal cancer surgery are not well studied. The United States Rectal Cancer Consortium (2007-2017) was reviewed for primary rectal adenocarcinoma patients who underwent R0/R1 resection. Ninety-day POCs were categorized as major or minor and were grouped into infectious, cardiopulmonary, thromboembolic, renal, or intestinal dysmotility. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS). Among 1136 patients, the POC rate was 46% (n = 527), with 63% classified as minor and 32% classified as major. Of all POCs, infectious complications comprised 20%, cardiopulmonary 3%, thromboembolic 5%, renal 9%, and intestinal dysmotility 19%. Compared with minor or no POCs, major POCs were associated with both worse RFS and worse OS (both p < 0.01). Compared with no POCs, a single POC was associated with worse RFS (p < 0.01), while multiple POCs were associated with worse OS (p = 0.02). Regardless of complication grade, infectious POCs were associated with worse RFS (p < 0.01), while cardiopulmonary and thromboembolic POCs were associated with worse OS (both p < 0.01). Renal POCs were associated with both worse RFS (p < 0.001) and worse OS (p = 0.01). After accounting for pathologic stage, neoadjuvant therapy, and final margin status, Multivariable analysis (MVA) demonstrated worse outcomes with cardiopulmonary, thromboembolic, and renal POCs for OS (cardiopulmonary: hazard ratio [HR] 3.6, p = 0.01; thromboembolic: HR 19.4, p < 0.01; renal: HR 2.4, p = 0.01), and renal and infectious POCs for RFS (infectious: HR 2.1, p < 0.01; renal: HR 3.2, p < 0.01). Major complications after proctectomy for cancer are associated with decreased RFS and OS. Given the association of infectious complications and postoperative renal dysfunction with earlier recurrence of disease, efforts must be directed towards defining best practices and standardizing care.


Compact Neural Interface Using a Single Multichannel Cuff Electrode for a Functional Neuromuscular Stimulation System.
Cuff electrodes have been introduced into functional neuromuscular stimulation systems to either obtain neural signals or elicit limb movements. Multiple electrodes must be implanted to construct a feedback control loop, including one electrode for acquisition and another for stimulation. Existing approaches require too much space inside the body and a complicated surgical procedure. This paper proposes a novel neural interface method that uses a single cuff electrode with multichannel capability to simultaneously acquire multichannel recordings and induce electrical stimulation at the proximal nerve trunk of the sciatic nerve. Recordings and stimulation are conducted in a time-shared manner using a path controller. Using the proposed method, joint positions are estimated from multichannel recorded neural signals during electrical stimulation as neural signals are continuously recorded. In addition, the proposed system is shown to be suitable for controlling joint position. The proposed neural interface method overcomes the spatial limitations of electrode implantation and thus offers a new approach to developing compact neural interface systems.


Characterisation of interstitial duplications and triplications of chromosome 15q11-q13.
Chromosome 15 is frequently involved in the formation of structural rearrangements. We report the molecular characterisation of 16 independent interstitial duplications, including those of one individual who carried a duplication on both of her chromosomes 15, and three interstitial triplications of the Prader-Willi/Angelman syndrome critical region (PWACR). In all probands except one, the rearrangement was maternal in origin. In one family, the duplication was paternal in origin, yet appeared to segregate in a sibship of three with an abnormal phenotype that included developmental delay and a behavioural disorder. Ten duplications were familial, five de novo and one unknown. All 16 duplications, including two not visible by routine G-banding, were of an almost uniform size and shared the common deletion breakpoints of Prader-Willi syndrome and Angelman syndrome. Like deletions, the formation of duplications can occur in both male and female meiosis and involve both inter- and intrachromosomal events. This implies that at least some deletions and duplications are the reciprocal products of each other. We observed no instances of meiotic instability in the transmission of a duplication, although recombination within the PWACR occurred in two members of the same family between the normal and the duplicated chromosome 15 homologues. All three triplications arose de novo and included alleles from both maternal chromosomes 15. Triplication breakpoints were more variable and extended distally beyond the PWACR. The molecular characteristics of duplications and triplications suggest that they are formed by different mechanisms.


Associations of persistent organic pollutants in human adipose tissue with retinoid levels and their relevance to the redox microenvironment.
Humans are exposed to a myriad of chemical substances in both occupational and environmental settings. Persistent organic pollutants (POPs) have drawn attention for their adverse effects including cancer and endocrine disruption. Herein, the objectives were 1) to describe serum and adipose tissue retinol levels, along with serum retinol binding protein 4 (RBP4) concentrations, and 2) to assess the associations of adipose tissue POP levels with these retinoid parameters, as well as their potential interaction with the previously-observed POP-related disruption of redox microenvironment. Retinol was measured in both serum and adipose tissue along with RBP4 levels in serum samples of 236 participants of the GraMo adult cohort. Associations were explored by multivariable linear regression analyses and Weighted Quantile Sum regression. Polychlorinated biphenyls (PCBs) 180, 153 and 138 were related to decreased adipose tissue retinol levels and increased serum RBP4/retinol ratio. Dicofol concentrations > limit of detection were associated with decreased retinol levels in serum and adipose tissue. Additionally, increased adipose tissue retinol levels were linked to an attenuation in previously-reported associations of adipose tissue PCB-153 with in situ superoxide dismutase activity. Our results revealed a suggestive link between retinoids, PCBs and redox microenvironment, potentially relevant for both mechanistic and public health purposes.


Regiospecific synthesis of prenylated flavonoids by a prenyltransferase cloned from Fusarium oxysporum.
Due to their impressive pharmaceutical activities and safety, prenylated flavonoids have a high potent to be applied as medicines and nutraceuticals. Biocatalysis is an effective technique to synthesize prenylated flavonoids. The major concern of this technique is that the microbe-derived prenyltransferases usually have poor regiospecificity and generate multiple prenylated products. In this work, a highly regiospecific prenyltransferase (FoPT1) was found from Fusarium oxysporum. It could recognize apigenin, naringenin, genistein, dihydrogenistein, kampferol, luteolin and hesperetin as substrates, and only 6-C-prenylated flavonoids were detected as the products. The catalytic efficiency of FoPT1 on flavonoids was in a decreasing order with hesperetin >naringenin >apigenin >genistein >luteolin >dihydrogenistein >kaempferol. Chalcones, flavanols and stilbenes were not active when acting as the substrates. 5,7-Dihydroxy and 4-carbonyl groups of flavonid were required for the catalysis. 2,3-Alkenyl was beneficial to the catalysis whereas 3-hydroxy impaired the prenylation reaction. Docking studies simulated the prenyl transfer reaction of FoPT1. E186 was involved in the formation of prenyl carbonium ion. E98, F89, F182, Y197 and E246 positioned apigenin for catalysis.


Use of amniotic fluid analysis in the management of preterm rupture of the membranes.
The management of preterm rupture of the membranes (PROM) must weigh the risks of respiratory distress from immediate delivery against those of expectant management. We divided 115 patients with PROM between 24 and 36 weeks of gestation into interventionist and expectant management groups on the basis of the amniotic fluid maturity. There was no difference between these groups with respect to gestational age and birth weight. Mature amniotic fluid was demonstrated in 41% of the patients. Interventionist management of infants with mature amniotic fluid irrespective of gestational age was associated with an improved outcome when compared to expectant management. Infants with PROM who can be shown to have mature amniotic fluid should be delivered promptly to avoid the small but real risks of expectant management.


Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial.
Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial. The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting). Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment). In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups. Celgene and Acceleron Pharma.


Rapamycin attenuates load-induced cardiac hypertrophy in mice.
Cardiac hypertrophy, or an increase in heart size, is an important risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) is a component of the insulin-phosphoinositide 3-kinase pathway, which is known to play a critical role in the determination of cell, organ, and body size. To examine the role of mTOR in load-induced cardiac hypertrophy, we administered rapamycin, a specific inhibitor of mTOR, to mice with ascending aortic constriction. Activity of p70 ribosomal S6 kinase 1 (S6K1), an effector of mTOR, was increased by 3.8-fold in the aortic-constricted heart. Pretreatment of mice with 2 mg. kg-1. d-1 of rapamycin completely suppressed S6K1 activation and S6 phosphorylation in response to pressure overload. The heart weight/tibial length ratio of vehicle-treated aortic-banded mice was increased by 34.4+/-3.6% compared with vehicle-treated sham-operated mice. Rapamycin suppressed the load-induced increase in heart weight by 67%. Attenuation of cardiac hypertrophy by rapamycin was associated with attenuation of the increase in myocyte cell size induced by aortic constriction. Rapamycin did not cause loss of body weight, lethality, or left ventricular dysfunction. mTOR or its target(s) seems to play an important role in load-induced cardiac hypertrophy. Because systemic administration of rapamycin has been used successfully for the treatment of transplant rejection in clinical practice, it may be a useful therapeutic modality to suppress cardiac hypertrophy in patients.


Lovastatin potentiates antitumor activity and attenuates cardiotoxicity of doxorubicin in three tumor models in mice.
Lovastatin, a drug commonly used in the clinic to treat hypercholesterolemia, has previously been reported to exert antitumor effects in rodent tumor models and to strengthen the antitumor effects of immune response modifiers (tumor necrosis factor alpha and IFN-gamma) or chemotherapeutic drugs (cisplatin). In the present report, we show in three murine tumor cell lines (Colon-26 cells, v-Ha-ras-transformed NIH-3T3 sarcoma cells, and Lewis lung carcinoma cells) that lovastatin can also effectively potentiate the cytostatic/cytotoxic activity of doxorubicin. In three tumor models (Co-ion-26 cells, v-Ha-ras-transformed NIH-3T3 sarcoma cells, and Lewis lung carcinoma cells) in vivo, we have demonstrated significantly increased sensitivity to the combined treatment with both lovastatin (15 mg/kg for 10 days) and doxorubicin (3 x 2.5 mg/kg; cumulative dose, 7.5 mg/kg) as compared with either agent acting alone. Lovastatin treatment also resulted in a significant reduction of troponin T release by cardiomyocytes in doxorubicin-treated mice. This observation is particularly interesting because lovastatin is known to reduce doxorubicin-induced cardiac injury.


Medical emergency team response for the non-hospitalized patient.
Rapid response systems (RRS) evolved to care for deteriorating hospitalized patients outside of the ICU. However, emergent critical care needs occur suddenly and unexpectedly throughout the hospital campus, including areas with non-hospitalized persons. The efficacy of RRS in this population has not yet been described or tested. We hypothesize that non-hospitalized patients accrue minimal benefit from ICU physician participation in the RRS. A retrospective review of all RRS events in non-hospitalized patients for a 28 month period was performed in a large, urban university medical center. Location, patient type and age, activation trigger, interventions performed, duration of event and disposition were recorded. Admission diagnosis and length of stay were also recorded for patients admitted to the hospital. Academic medical center. Non-hospitalized persons requiring evaluation by the medical emergency team. None. There were a total of 1778 RRS activations during the study period. 232 (13%) of activations were for non-hospitalized patients. The patient cohort consisted of outpatients, visitors, and staff. Triggers for RRS activation were neurologic change (42%), cardiac (27%), respiratory (16%), and staff concerns (16%). The mean duration of the response was 38 min. The most common interventions performed included administration of oxygen (46%), intravenous fluids (13%) and dextrose (6%). 82% of patients were taken to the emergency department and 32% of the ED cohort were admitted to the hospital. Perceived emergencies in non-hospitalized patients occur commonly but require minimal emergent intervention. Restriction of critical care physician involvement to inpatient deteriorations should be considered when designing a RRS. Future studies are needed to evaluate the utility of non-physician provider led rapid response teams with protocol-driven interventions for similar populations.


Function of bovine CD46 as a cellular receptor for bovine viral diarrhea virus is determined by complement control protein 1.
The pestivirus bovine viral diarrhea virus (BVDV) was shown to bind to the bovine CD46 molecule, which subsequently promotes entry of the virus. To assess the receptor usage of BVDV type 1 (BVDV-1) and BVDV-2, 30 BVDV isolates including clinical samples were assayed for their sensitivity to anti-CD46 antibodies. With a single exception the infectivity of all tested strains of BVDV-1 and BVDV-2 was inhibited by anti-CD46 antibodies, which indicates the general usage of CD46 as a BVDV receptor. Molecular analysis of the interaction between CD46 and the BVD virion was performed by mapping the virus binding site on the CD46 molecule. Single complement control protein modules (CCPs) within the bovine CD46 were either deleted or replaced by analogous CCPs of porcine CD46, which does not bind BVDV. While the epitopes recognized by anti-CD46 monoclonal antibodies which block BVDV infection were attributed to CCP1 and CCP2, in functional assays only CCP1 turned out to be essential for BVDV binding and infection. Within CCP1 two short peptides on antiparallel beta strands were identified as crucial for the binding of BVDV. Exchanges of these two peptide sequences were sufficient for a loss of function in bovine CD46 as well as a gain of function in porcine CD46. Determination of the size constraints of CD46 revealed that a minimum length of four CCPs is essential for receptor function. An increase of the distance between the virus binding domain and the plasma membrane by insertion of one to six CCPs of bovine C4 binding protein exhibited only a minor influence on susceptibility to BVDV.


Evaluating the structure of psychopathic personality traits: A meta-analysis of the Psychopathic Personality Inventory.
Which core traits exemplify psychopathic personality disorder is a hotly debated question within psychology, particularly regarding the role of ostensibly adaptive traits such as stress immunity, social potency, and fearlessness. Much of the research on the interrelationships among putatively adaptive and more maladaptive traits of psychopathy has focused on the factor structure of the Psychopathic Personality Inventory (PPI) and its revision, the Psychopathic Personality Inventory-Revised (PPI-R). These instruments include content scales that have coalesced to form 2 higher order factors in some (but not all) prior studies: Fearless Dominance and Self-Centered Impulsivity. Given the inconsistencies in prior research, we performed a meta-analytic factor analysis of the 8 content scales from these instruments (total N > 18,000) and found general support for these 2 dimensions in community samples. The structure among offender samples (e.g., prisoners, forensic patients) supported a 3-factor model in which the Fearlessness content scale loaded onto Self-Centered Impulsivity (rather than Fearless Dominance). There were also indications that the Stress Immunity content scale had different relations to the other PPI scales in offender versus community samples. We discuss the theoretical and diagnostic implications of these differing factor structures for the field of psychopathy research. (PsycINFO Database Record


Temporal Trends in the Physical Fitness of Hong Kong Adolescents Between 1998 and 2015.
Low physical fitness in adolescence is linked with increased cardiometabolic risk and early all-cause mortality. This study aimed to estimate temporal trends in the physical fitness of Hong Kong adolescents aged 12-17 years between 1998 and 2015. Physical fitness (9-min run/walk, sit-ups, push-ups, and sit-and-reach) and body size data in a total of 28,059 adolescents tested across five population-representative surveys of Hong Kong secondary school pupils, were reported. Temporal trends in means were estimated at the gender-age level by best-fitting sample-weighted linear regression, with national trends estimated by a post-stratified population-weighting procedure. Overall, there were small declines in 9-min run/walk (effect size (ES)=-0.29 (95%CI: -0.32, -0.26)) and sit-ups performance (ES=-0.24 (95%CI: -0.27, -0.21)), with negligible changes in push-ups and sit-and-reach performance. There were small concurrent increases in both mean height and body mass, with a negligible increase in sum of skinfolds. Trends in mean physical fitness and body size/were not always uniform across the population distribution. The small declines in mean 9-min run/walk and sit-ups performance for Hong Kong adolescents are suggestive of corresponding declines in cardiorespiratory fitness and abdominal/core endurance, respectively. Increased national health promotion strategies are required to improve existing trends.


Comparison of changes in lung function measured by plethymography and IOS after bronchoprovocation.
Lung function tests are essential for the diagnosis and management of bronchial asthma. Impulse oscillation (IOS) system is an alternative way to measure lung mechanics for some patients. We investigated the relative sensitivities of IOS, body plethysmography and spirometry in detecting allergen- and methacholine-induced bronchoconstriction. Twenty-two subjects had single allergen inhalation and 8 subjects had 3 methacholine challenges. The tests were stopped when FEV1 fell by 20%. Lung function was measured using IOS (R5, R20, R5-R20, X5, AX, fres), plethysmography (sRaw, sGaw, FRC, lung volumes) and spirometry (FEV1, FVC, PEF, FEF50%) during inhalation challenges, and expressed as percent change from pre-challenge baseline. All subjects were non-smoking adults with mild allergic asthma. Following allergen challenges, the most sensitive IOS index was R5-R20 and the most sensitive plethysmography and spirometry measurements were sRaw, sGaw and FEF50%. Following methacholine challenge the most sensitive IOS index was AX, the most sensitive plethysmography measurement was sRaw. Overall, IOS (R5-R20, AX, X5Hz) proved to be more sensitive than plethysmography and spirometry measurements following allergen-induced and methacholine-induced bronchoconstriction. Our result shows that IOS is more sensitive than other lung function tests following allergen and methacholine challenge. In addition, IOS can act as an alternative measurement technique of airway resistance and obstruction in patients where manoeuvres involved in plethysmography and spirometry prove difficult to perform.


Molecular analysis of Oryza latifolia Desv. (CCDD genome)-derived introgression lines and identification of value-added traits for rice (O. sativa L.) improvement.
Oryza latifolia is a tetraploid wild Oryza species with a CCDD genome that has been reported to harbor resistance to bacterial blight (BB), brown planthopper, and whitebacked planthopper. Aside from these traits, O. latifolia is also being tapped as a new source of resistance to lodging and high biomass production. To explore the genetic potential of O. latifolia as a novel genetic resource for the improvement of existing O. sativa cultivars, 27 disomic derivatives of O. latifolia monosomic alien addition lines (MAAL) were characterized for alien chromosome segment introgressions and evaluated for yield components, BB resistance, and strong stem characteristics. A total of 167 simple sequence repeat, sequence tagged site, and single nucleotide polymorphism markers, along with newly developed indel markers that were specifically designed to detect O. latifolia chromosome segment introgressions in an O. sativa background, were used to define alien introgressions in 27 disomics derived from O. latifolia MAALs. Genotype data showed that 32 unique introgressions spanning 0.31-22.73 Mb were introgressed in different combinations in each of the 27 disomic derivatives. Evaluation of the disomic derivatives for agronomic traits identified lines with putative QTLs for resistance to Philippine races 3A, 4, 9A, and 9D of BB. Putative quantitative trait loci (QTLs) conferring strong stem in 19 out of the 27 disomic derivatives studied were also identified from O. latifolia introgressions on chromosome 6.


Troponin I, cardiac diastolic dysfunction and restrictive cardiomyopathy.
Cardiomyopathies are diseases of heart muscle that are associated with cardiac dysfunction. Molecular genetic studies performed to date have demonstrated that the damage or mutations in several sarcomeric contractile protein genes are associated with the development of the diseases. In this review, cardiac troponin I, one of the sarcomeric thin filament protein, will be discussed regarding its role in cardiac function, its deficiency-related diastolic dysfunction, and the mutation of this protein-mediated restrictive cardiomyopathy.


[Heterochromatinic segments in chromosomes of cultured human cells, sensitive and resistant to Coxsackie B viruses].
Comparative karyological studies of C-heterochromatin have been made on line J-96 of human cells, which are susceptible to enteroviruses, and on cell line J-41 derived from this culture and possessing highly specific resistance to Coxsackie B viruses. It was shown that the development of specific resistance to Coxsackie B viruses was accompanied by the loss of one of the chromosomes of pairs 1 and 9, and by the dissapearance of two marker chromosomes. There appeared new marker chromosomes with additional C-heterochromatain regions. The data obtained are discussed with respect to a possible interrelationship between these chromosomal alterations and the specific resistance to Coxsakie B viruses.


Cage-Confinement Pyrolysis Route to Ultrasmall Tungsten Carbide Nanoparticles for Efficient Electrocatalytic Hydrogen Evolution.
The size-controlled synthesis of ultrasmall metal-based catalysts is of vital importance for chemical conversion technologies. Here, a cage-confinement pyrolysis strategy is presented for the synthesis of ultrasmall tungsten carbide nanoclusters/nanoparticles. An RHO type zeolitic metal azolate framework MAF-6, possessing large nanocages and small apertures, is selected to confine the metal source W(CO)6. High temperature pyrolysis gives tungsten carbide nanoclusters/nanoparticles with sizes ca. 2 nm, which can serve as an excellent electrocatalyst for the hydrogen evolution reaction. In 0.5 M H2SO4, it exhibits very low overpotential of 51 mV at 10 mA cm-2 and Tafel slope of 49 mV per decade, as well as the highest exchange current density of 2.4 mA cm-2 among all tungsten/molybdenum-based catalysts. Moreover, it also shows excellent stability and antiaggregation behavior after long-term electrolytic process.


Synthetic gene complementation to determine off-target silencing.
RNA interference (RNAi) is a conserved mechanism in a wide range of eukaryotes. Introduction of synthetic dsRNA could specifically target suppression of a gene or could result in off-target silencing of another gene due to sequence similarity. To verify if the observed phenotype in an RNAi transgenic line is due to silencing of a specific gene or if it is due to another nontarget gene, a synthetic gene complementation approach could be used. Synthetic gene complementation described in this method uses the technology of synthesizing a variant of a native gene (used in RNAi silencing) to maximize the difference in DNA sequences while coding for the exact same amino acids as the original native gene. This is achieved through the use of alternate codons. The new variant gene is expressed in the original RNAi transgenic lines and analyzed for complementation of the RNAi phenotype. Complementation of the RNAi-induced phenotype will indicate gene-specific silencing and not off-target silencing.


[Current trends in the development of general pathology].
The author holds that the achievements of molecular biology and pathology should not contradict conventional concepts about the body as a whole system in which all particular processes are controlled by the regulatory systems at various levels of organization. Only such an approach may ensure a fruitful development of general pathology as a theoretical basis of medicine. Teaching general pathology as an independent discipline in the system of medical education is proposed.


Neuroanatomical substrates of arabic number processing, numerical comparison, and simple addition: a PET study.
Positron emission tomography was used to localize the cerebral networks specifically involved in three basic numerical processes: arabic numeral processing, numerical magnitude comparison, and retrieval of simple addition facts. Relative cerebral blood flow changes were measured while normal volunteers were resting with eyes closed, making physical judgment on nonnumerical characters or arabic digits, comparing, or adding the same digits. Processing arabic digits bilaterally produced a large nonspecific activation of occipito-parietal areas, as well as a specific activation of the right anterior insula. Comparison and simple addition fact retrieval revealed a fronto-parietal network involving mainly the left intraparietal sulcus, the superior parietal lobule and the precentral gyrus. Comparison also activated, but to a lesser extent, the right superior parietal lobe, whereas addition also activated the orbito-frontal areas and the anterior insula in the right hemisphere. Implications for current anatomo-functional models of numerical cognition are drawn.


Advantage of Fontana-Masson stain in capsule-deficient cryptococcal infection.
We describe light and electron microscopic findings in three cases of pulmonary infection caused by capsule-deficient Cryptococcus neoformans (CDCN) and emphasize the value of the Fontana-Masson silver (FMS) stain in diagnosing cryptococcosis. Capsule-deficient C neoformans infections, including coccidioidomycosis, histoplasmosis, typical cryptococcosis, blastomycosis, candidiasis, and pneumocystosis were used as controls. Several stains including mucicarmine, alcian blue, and FMS were done on tissue sections from all of the above mentioned infections. It was found that while the FMS stain was positive only in the organisms of CDCN and typical C neoformans, the mucicarmine was positive only in typical C neoformans. The negativity of the mucicarmine in the organisms of CDCN reflected the absence of capsular material as demonstrated by ultrastructural study. Therefore, when fungal cultures are not available or are negative, and tissue mucicarmine is negative, the FMS stain is a valuable alternative for use on tissue sections. It may be used, along with routine fungal stains, when a yeast-forming fungal infection is suspected.


The role of defective complement control in hemolytic uremic syndrome.
Atypical hemolytic uremic syndrome (HUS) is a severe disease that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Recent evidence has shown that defective complement activation and defective complement control is a cause of HUS. So far, mutations in single genes coding for the cofactor and complement regulator factor H, the membrane cofactor protein (MCP/CD46), the serine protease factor I, and autoantibodies to factor H have been linked to HUS. All of these proteins affect the same enzyme the alternative pathway convertase C3bBb. This article explains how alternative pathway activation proceeds and how defective control increases activation, which ultimately leads to endothelial cell damage.


Quantitative Imaging Flow Cytometry of Legionella-Infected Dictyostelium Amoebae Reveals the Impact of Retrograde Trafficking on Pathogen Vacuole Composition.
The ubiquitous environmental bacterium Legionella pneumophila survives and replicates within amoebae and human macrophages by forming a Legionella-containing vacuole (LCV). In an intricate process governed by the bacterial Icm/Dot type IV secretion system and a plethora of effector proteins, the nascent LCV interferes with a number of intracellular trafficking pathways, including retrograde transport from endosomes to the Golgi apparatus. Conserved retrograde trafficking components, such as the retromer coat complex or the phosphoinositide (PI) 5-phosphatase D. discoideum 5-phosphatase 4 (Dd5P4)/oculocerebrorenal syndrome of Lowe (OCRL), restrict intracellular replication of L. pneumophila by an unknown mechanism. Here, we established an imaging flow cytometry (IFC) approach to assess in a rapid, unbiased, and large-scale quantitative manner the role of retrograde-linked PI metabolism and actin dynamics in the LCV composition. Exploiting Dictyostelium discoideum genetics, we found that Dd5P4 modulates the acquisition of fluorescently labeled LCV markers, such as calnexin, the small GTPase Rab1 (but not Rab7 and Rab8), and retrograde trafficking components (Vps5, Vps26, Vps35). The actin-nucleating protein and retromer interactor WASH (Wiskott-Aldrich syndrome protein [WASP] and suppressor of cAMP receptor [SCAR] homologue) promotes the accumulation of Rab1 and Rab8 on LCVs. Collectively, our findings validate IFC for the quantitative and unbiased analysis of the pathogen vacuole composition and reveal the impact of retrograde-linked PI metabolism and actin dynamics on the LCV composition. The IFC approach employed here can be adapted for a molecular analysis of the pathogen vacuole composition of other amoeba-resistant pathogens.IMPORTANCELegionella pneumophila is an amoeba-resistant environmental bacterium which can cause a life-threatening pneumonia termed Legionnaires' disease. In order to replicate intracellularly, the opportunistic pathogen forms a protective compartment, the Legionella-containing vacuole (LCV). An in-depth analysis of the LCV composition and the complex process of pathogen vacuole formation is crucial for understanding the virulence of L. pneumophila Here, we established an imaging flow cytometry (IFC) approach to assess in a rapid, unbiased, and quantitative manner the accumulation of fluorescently labeled markers and probes on LCVs. Using IFC and L. pneumophila-infected Dictyostelium discoideum or defined mutant amoebae, a role for phosphoinositide (PI) metabolism, retrograde trafficking, and the actin cytoskeleton in the LCV composition was revealed. In principle, the powerful IFC approach can be used to analyze the molecular composition of any cellular compartment harboring bacterial pathogens.


The effect of QiangGuYin on osteoporosis through the AKT/mTOR/autophagy signaling pathway mediated by CKIP-1.
Osteoporosis is a systemic bone disease characterized by decreased bone mass and deterioration of bone microstructure, which leads to increased bone fragility and increased risk of fractures. Casein kinase 2 interacting protein 1 (CKIP-1, also known as PLEKHO1) is involved in the biological process of bone formation, differentiation and apoptosis, and is a negative regulator of bone formation. QiangGuYin (QGY) is a famous TCM formula that has been widely used in China for the clinical treatment of postmenopausal osteoporosis for decades, but the effect in regulating CKIP-1 on osteoporosis is not fully understood. This study aimed to explore the potential mechanism of CKIP-1 participating in autophagy in bone cells through the AKT/mTOR signaling pathway and the regulatory effect of QGY. The results in vivo showed that QGY treatment can significantly improve the bone quality of osteoporotic rats, down-regulate the expression of CKIP-1, LC3II/I and RANKL, and up-regulated the expression of p62, p-AKT/AKT, p-mTOR/mTOR, RUNX2 and OPG. It is worth noting that the results in vitro confirmed that CKIP-1 interacts with AKT. By up-regulating the expression of Atg5 and down-regulating the p62, the level of LC3 (autophagosome) is increased, and the cells osteogenesis and differentiation are inhibited. QGY inhibits the combination of CKIP-1 and AKT in osteoblasts, activates the AKT/mTOR signaling pathway, inhibits autophagy, and promotes cell differentiation, thereby exerting an anti-osteoporosis effect. Therefore, QGY targeting CKIP-1 to regulate the AKT/mTOR-autophagy signaling pathway may represent a promising drug candidate for the treatment of osteoporosis.


Booster, a Red-Shifted Genetically Encoded Förster Resonance Energy Transfer (FRET) Biosensor Compatible with Cyan Fluorescent Protein/Yellow Fluorescent Protein-Based FRET Biosensors and Blue Light-Responsive Optogenetic Tools.
Genetically encoded Förster resonance energy transfer (FRET)-based biosensors have been developed for the visualization of signaling molecule activities. Currently, most of them are comprised of cyan and yellow fluorescent proteins (CFP and YFP), precluding the use of multiple FRET biosensors within a single cell. Moreover, the FRET biosensors based on CFP and YFP are incompatible with the optogenetic tools that operate at blue light. To overcome these problems, here, we have developed FRET biosensors with red-shifted excitation and emission wavelengths. We chose mKOκ and mKate2 as the favorable donor and acceptor pair by calculating the Förster distance. By optimizing the order of fluorescent proteins and modulatory domains of the FRET biosensors, we developed a FRET biosensor backbone named "Booster". The performance of the protein kinase A (PKA) biosensor based on the Booster backbone (Booster-PKA) was comparable to that of AKAR3EV, a previously developed FRET biosensor comprising CFP and YFP. For the proof of concept, we first showed simultaneous monitoring of activities of two protein kinases with Booster-PKA and ERK FRET biosensors based on CFP and YFP. Second, we showed monitoring of PKA activation by Beggiatoa photoactivated adenylyl cyclase, an optogenetic generator of cyclic AMP. Finally, we presented PKA activity in living tissues of transgenic mice expressing Booster-PKA. Collectively, the results demonstrate the effectiveness and versatility of Booster biosensors as an imaging tool in vitro and in vivo.


A Multimodal Fusion Approach for Human Activity Recognition.
The problem of human activity recognition (HAR) has been increasingly attracting the efforts of the research community, having several applications. It consists of recognizing human motion and/or behavior within a given image or a video sequence, using as input raw sensor measurements. In this paper, a multimodal approach addressing the task of video-based HAR is proposed. It is based on 3D visual data that are collected using an RGB + depth camera, resulting to both raw video and 3D skeletal sequences. These data are transformed into six different 2D image representations; four of them are in the spectral domain, another is a pseudo-colored image. The aforementioned representations are based on skeletal data. The last representation is a "dynamic" image which is actually an artificially created image that summarizes RGB data of the whole video sequence, in a visually comprehensible way. In order to classify a given activity video, first, all the aforementioned 2D images are extracted and then six trained convolutional neural networks are used so as to extract visual features. The latter are fused so as to form a single feature vector and are fed into a support vector machine for classification into human activities. For evaluation purposes, a challenging motion activity recognition dataset is used, while single-view, cross-view and cross-subject experiments are performed. Moreover, the proposed approach is compared to three other state-of-the-art methods, demonstrating superior performance in most experiments.


[Gerontological aspects of cardiology].
The growing interest to problems of geriatric cardiology the author associates with considerable demographic shifts (an increased proportion of th elderly people within the structure of the population); a clearer idea as to the part played by age-specific changes in an ageing organism in the development of the circulatory pathology; and with the need to take account of clinical peculiarities common to diseases involving the cardiovascular system in persons of advanced and senile age, of features specific for their therapy and prevention. The research trends along which geriatric cardiology develops are analyzed; basic data on age-specific changes and their relation with developing pathology of the cardiovascular system, obtained in animal experiments and observations of practically healthy subjects of advanced and senile age are discussed.


Heterogeneous trends in burden of heart disease mortality by subtypes in the United States, 1999-2018: observational analysis of vital statistics.
To describe trends in the burden of mortality due to subtypes of heart disease from 1999 to 2018 to inform targeted prevention strategies and reduce disparities. Serial cross sectional analysis of cause specific heart disease mortality rates using national death certificate data in the overall population as well as stratified by race-sex, age, and geography. United States, 1999-2018. 12.9 million decedents from total heart disease (49% women, 12% black, and 19% <65 years old). Age adjusted mortality rates (AAMR) and years of potential life lost (YPLL) for each heart disease subtype, and respective mean annual percentage change. Deaths from total heart disease fell from 752 192 to 596 577 between 1999 and 2011, and then increased to 655 381 in 2018. From 1999 to 2018, the proportion of total deaths from heart disease attributed to ischemic heart disease decreased from 73% to 56%, while the proportion attributed to heart failure increased from 8% to 13% and the proportion attributed to hypertensive heart disease increased from 4% to 9%. Among heart disease subtypes, AAMR was consistently highest for ischemic heart disease in all subgroups (race-sex, age, and region). After 2011, AAMR for heart failure and hypertensive heart disease increased at a faster rate than for other subtypes. The fastest increases in heart failure mortality were in black men (mean annual percentage change 4.9%, 95% confidence interval 4.0% to 5.8%), whereas the fastest increases in hypertensive heart disease occurred in white men (6.3%, 4.9% to 9.4%). The burden of years of potential life lost was greatest from ischemic heart disease, but black-white disparities were driven by heart failure and hypertensive heart disease. Deaths from heart disease in 2018 resulted in approximately 3.8 million potential years of life lost. Trends in AAMR and years of potential life lost for ischemic heart disease have decelerated since 2011. For almost all other subtypes of heart disease, AAMR and years of potential life lost became stagnant or increased. Heart failure and hypertensive heart disease account for the greatest increases in premature deaths and the largest black-white disparities and have offset declines in ischemic heart disease. Early and targeted primary and secondary prevention and control of risk factors for heart disease, with a focus on groups at high risk, are needed to avoid these suboptimal trends beginning earlier in life.


Design and rationale of an intervention to improve cancer prevention using clinical decision support and shared decision making: A clinic-randomized trial.
Despite decades of research the gap in primary and secondary cancer prevention services in the U. S. remains unacceptably wide. Innovative interventions are needed to address this persistent challenge. Electronic health records linked with Web-based clinical decision support may close this gap, especially if delivered to both patients and their providers. The Cancer Prevention Wizard (CPW) study is an implementation, clinic-randomized trial designed to achieve these aims: 1) assess impact of the Cancer Prevention Wizard-Clinical Decision Support (CPW-CDS) alone and CPW-CDS plus Shared Decision Making Tools (CPW + SDMTs) compared to usual care (UC) on tobacco cessation counseling and drugs, HPV vaccinations, and screening tests for breast, cervical, colorectal, or lung cancer; 2) assess cost of the CPW-CDS intervention; and 3) describe critical facilitators and barriers for CPW-CDS implementation, use, and clinical impact using a mixed-methods approach supported by the CFIR and RE-AIM frameworks. 34 predominantly rural, primary care clinics were randomized to CPW-CDS, CPW + SMDTs, or UC. Between August 2018 and October 2020, primary care providers and their patients who met inclusion criteria in intervention clinics were exposed to the CPW-CDS with or without SDMTs. Study outcomes at 12 months post index visit include patients up to date on screening tests and HPV vaccinations, overall healthcare costs, and diagnostic codes and billing levels for cancer prevention services. We will test in rural primary care settings whether CPW-CDS with or without SDMTs can improve delivery of primary and secondary cancer prevention services. The trial and analyses are ongoing with results expected in 2021.


Cytologic diagnosis of medullary thyroid carcinoma in the Asia-Pacific region.
The accurate preoperative identification of medullary thyroid carcinoma (MTC) is challenging due to the rarity of tumor and variable cytologic appearance. The Asian experience with diagnosing MTC by fine-needle aspiration (FNA) was scarcely reported. Cases of MTC with available FNA slides were enrolled from 13 hospitals representing 8 Asia-Pacific countries. Clinicopathological information, including sample preparation technique, staining method, original cytologic diagnosis and review diagnosis were collected. Of a total of 145 MTC cases retrospectively recruited, 99 (68.3%) were initially interpreted as MTC/suspicious for MTC (S-MTC). The distribution of original FNA diagnostic categories was not associated with the staining method or sample preparation technique. The staining methods used were Papanicolaou, hematoxylin-eosin and Romanowsky stains. Liquid-based cytology (LBC) was used only in three countries. After reviewing all cases, the diagnostic rate of MTC/S-MTC increased to 91.7% (133/145). Cases with initially unrecognized MTC had either marked pleomorphism or cytology mimicking papillary carcinoma or follicular neoplasm. Although LBC provided certain benefits, there was no significant difference in diagnostic accuracy between conventional smear and LBC. Immunocytochemistry was available in 38 cases (26.2%), all of which were correctly recognized as MTC. Our report summarizes how MTC is handled in contemporary Asian thyroid FNA practice. Although the detection rate of MTC by cytology alone is less satisfactory, integration with ancillary tests could achieve an excellent performance. The recognition of constitutive cytomorphologic features is needed for each cytopreparatory method, which may result in a lower threshold to initiate further workup for MTC.


Matched hemiresection interposition arthroplasty of the distal radioulnar joint.
Since 1986 the senior author has performed a matched hemiresection with retinacular/capsular interposition for patients with painful disorders of the distal radioulnar joint. A retrospective review of 55 wrists was performed by an independent hand surgeon and hand therapist. Forty-nine of 54 wrists in the surviving patients were clinically and radiographically reviewed with an average follow-up interval of 36 months. Subjective assessment included a visual analog rating of pain improvement and satisfaction with treatment. Objective assessment included examination of range of motion, strength, stability, and standardized functional testing with the Jebsen and Minnesota Rate of Manipulation tests. Thirty-five patients reported pain improvement and 41 patients were satisfied. The range of supination and pronation increased from 54 degrees and 67 degrees, respectively, to 72 degrees and 72 degrees. Functional ability as measured by the Jebsen test was similar to the contralateral wrist. Patients had most difficulty turning large objects. The clinical, objective, functional, and x-ray films results correlated poorly with pain improvement and patient satisfaction. Complications included one infection, one reflex sympathetic dystrophy, one neuroma of the dorsal sensory branch of the ulnar nerve, and four cases of ulnar-carpal impaction. Pain relief was the primary determinant of patient satisfaction and should be considered the indication for surgery.


Missed opportunities: Reducing zero dose children amongthe urban poor after COVID, Mumbai India, 2022.
Reaching urban poor populations poses challenges for equitable immunization coverage. Furthermore, COVID disrupted routine immunization services. In Mumbai, India, first dose diphtheria tetanus pertussis containing vaccine (DTPCV1)coverage dropped from 88% (2019) to 76% (2021). We identified and characterized 125 zero-dose (those withoutDTPCV1)migrant children in urban Mumbai in October 2022. Almost half were born elsewhere than Mumbai; 53% resided at their present location for less than a year. More than half were 12-59 months of age, well-beyond the age for first routine childhood immunizations.Three of four zero dose children had received birth dose vaccination in the hospital; but failed to receive DTPCV1. Vaccine hesitancy, awareness gaps and operational issues were common reasons for non-vaccination. Despite frequent visits to health facilities for illness,only a third of facility staff asked or advised parents about vaccination.Missed opportunities were much more common in private than government facilities.For the vast majority (88%), residential sites were included in local routine immunization micro-plans and distances to immunization sites were short (less than 1 km for 94 % of families).However, planned session frequency was inadequate half of the time. Expanded efforts to reach migrant urban poor children are needed to ensure vaccine equity.


The Ixodes scapularis Symbiont Rickettsia buchneri Inhibits Growth of Pathogenic Rickettsiaceae in Tick Cells: Implications for Vector Competence.
Ixodes scapularis is the primary vector of tick-borne pathogens in North America but notably does not transmit pathogenic Rickettsia species. This tick harbors the transovarially transmitted endosymbiont Rickettsia buchneri, which is widespread in I. scapularis populations, suggesting that it confers a selective advantage for tick survival such as providing essential nutrients. The R. buchneri genome includes genes with similarity to those involved in antibiotic synthesis. There are two gene clusters not found in other Rickettsiaceae, raising the possibility that these may be involved in excluding pathogenic bacteria from the tick. This study explored whether the R. buchneri antibiotic genes might exert antibiotic effects on pathogens associated with I. scapularis. Markedly reduced infectivity and replication of the tick-borne pathogens Anaplasma phagocytophilum, R. monacensis, and R. parkeri were observed in IRE11 tick cells hosting R. buchneri. Using a fluorescent plate reader assay to follow infection dynamics revealed that the presence of R. buchneri in tick cells, even at low infection rates, inhibited the growth of R. parkeri by 86-100% relative to R. buchneri-free cells. In contrast, presence of the low-pathogenic species R. amblyommatis or the endosymbiont R. peacockii only partially reduced the infection and replication of R. parkeri. Addition of host-cell free R. buchneri, cell lysate of R. buchneri-infected IRE11, or supernatant from R. buchneri-infected IRE11 cultures had no effect on R. parkeri infection and replication in IRE11, nor did these treatments show any antibiotic effect against non-obligate intracellular bacteria E. coli and S. aureus. However, lysate from R. buchneri-infected IRE11 challenged with R. parkeri showed some inhibitory effect on R. parkeri infection of treated IRE11, suggesting that challenge by pathogenic rickettsiae may induce the antibiotic effect of R. buchneri. This research suggests a potential role of the endosymbiont in preventing other rickettsiae from colonizing I. scapularis and/or being transmitted transovarially. The confirmation that the observed inhibition is linked to R. buchneri's antibiotic clusters requires further investigation but could have important implications for our understanding of rickettsial competition and vector competence of I. scapularis for rickettsiae.


AC-2020-12-1420.R1 - HIV care providers' familiarity, concerns, and attitudes about HIV PrEP in Colombia: insights from the PrEP-Col-Study.
In 2019, Colombia approved the combination of tenofovir disoproxil fumarate/emtricitabine for HIV Pre-Exposure Prophylaxis (PrEP). Therefore, we conducted a situational analysis in HIV-care providers to identify barriers and facilitators for PrEP implementation. A survey was applied to a non-probabilistic sample of health care workers of HIV-specialized clinics. We examined PrEP awareness and familiarity, comfort with PrEP-related activities, perceived barriers for PrEP implementation, concerns, and attitudes. Poisson regressions assessed the relationship between these factors and the variable "having a plan to offer PrEP". The participation rate was 41% and included physicians (42.6%) and other health professionals (57.4%). Fifty-one percent of the participants reported more than five years of experience caring for people living with HIV. Forty-two percent of non-physician health care workers were nurses. Most reported high familiarity/comfort with PrEP-relevant activities. Concerns about PrEP were prevalent (> 50%) and included causing more harm than good, reducing condom use, medication non-adherence, drug resistance, and healthcare system barriers. Physicians had a plan to offer PrEP (72.2%) more often than other health professionals (52.6). Having a plan to offer PrEP was related to PrEP knowledge and comfort assessing sexual behavior and providing HIV counseling. Overall, about half of HIV-care providers seemed ready to offer PrEP and constitute an asset for PrEP implementation efforts in Colombia. PrEP awareness among non-physicians, PrEP concerns, and negative attitudes need to be addressed to enhance implementation.


Protoporphyrin IX fluorescence induced in basal cell carcinoma by oral delta-aminolevulinic acid.
Limited depth of penetration significantly limits photodynamic therapy of nodular basal cell carcinoma (BCC) using topical delta (5)-aminolevulinic acid (ALA). To demonstrate safety and efficacy of orally administered ALA in inducing endogenous protoporphyrin IX (PpIX) production in BCC, 13 patients with BCC ingested ALA in a dose-escalation protocol. All dose ranges (10, 20 or 40 mg/kg single doses) resulted in formation of PpIX in human skin and BCC, measurable by in vivo fluorescence spectrophotometry. The PpIX fluorescence peaked in tumors before normal adjacent skin from 1 to 3 h after ALA ingestion. Gross fluorescence imaging of ex vivo specimens revealed greater PpIX fluorescence in tumor than normal skin only at the 40 mg/kg dose. Fluorescence microscopy confirmed this finding by showing distinct, full-thickness PpIX fluorescence in all subtypes of BCC only after ALA given at 40 mg/kg. Side effects were dose dependent and self limited. Photosensitivity lasting less than 24 h and nausea coinciding with peak skin PpIX fluorescence occurred at 20 and 40 mg/kg doses. After 40 mg/kg ALA, serum hepatic enzyme levels rose to a maximum within 24 h, then resolved over 1-3 weeks. Transient bilirubinuria occurred in two patients.


3D MAS NMR Experiment Utilizing Through-Space 15N-15N Correlations.
We demonstrate a novel 3D NNC magic angle spinning NMR experiment that generates 15N-15N internuclear contacts in protein systems using an optimized 15N-15N proton assisted recoupling (PAR) mixing period and a 13C dimension for improved resolution. The optimized PAR condition permits the acquisition of high signal-to-noise 3D data that enables backbone chemical shift assignments using a strategy that is complementary to current schemes. The spectra can also provide distance constraints. The utility of the experiment is demonstrated on an M0Aβ1-42 fibril sample that yields high-quality data that is readily assigned and interpreted. The 3D NNC experiment therefore provides a powerful platform for solid-state protein studies and is broadly applicable to a variety of systems and experimental conditions.


Do facial morphology, posture and function change following glossectomy? A systematic review.
To systematically investigate and critically appraise the quality of the currently available literature regarding the morphological, postural, and functional changes observed in individuals following glossectomy. A search without restrictions in eight databases (including grey literature) and hand searching from inception until March 2018 was performed. Data on morphological, postural, and functional changes after glossectomy were reviewed. Methodological quality was evaluated using the risk of bias in nonrandomized studies of intervention tool. Out of 835 initially identified unique records, only three articles following patients for 1 year after glossectomy fulfilled the selection criteria. Overall, no significant morphological, postural, and functional changes were observed. Only the distance between the dorsum and the nasal line increased and the freeway space decreased significantly. Overall, no significant differences were noted in the medium term, in terms of dentofacial structures adaptation and tongue function following glossectomy. Further research is warranted in order to elucidate the consequences of the altered oral environment.


In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson's Disease.
Parkinson's Disease (PD) is a long-term neurodegenerative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel antiparkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD. However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenomena) associated with long-term L-DOPA replacement therapy have limited its antiparkinsonian efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt to counteract the motor side effects associated with dopamine replacement therapy. Being one of the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a relevant target for drug discovery focused on a wide range of therapeutic areas, including Central Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD, excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR subclasses, including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors, metabotropic glutamate receptors, and 5-hydroxytryptamine receptors, on the pathophysiology of PD and the importance of structure- and ligand-based in silico approaches for the development of small molecules to target these receptors.


It's not all black and white: investigating colour polymorphism in manta rays across Indo-Pacific populations.
Intraspecific colour polymorphisms have been the focus of numerous studies, yet processes affecting melanism in the marine environment remain poorly understood. Arguably, the most prominent example of melanism in marine species occurs in manta rays (Mobula birostris and Mobula alfredi). Here, we use long-term photo identification catalogues to document the frequency variation of melanism across Indo-Pacific manta ray populations and test for evidence of selection by predation acting on colour morph variants. We use mark-recapture modelling to compare survivorship of typical and melanistic colour morphs in three M. alfredi populations and assess the relationship between frequency variation and geographical distance. While there were large differences in melanism frequencies among populations of both species (0-40.70%), apparent survival estimates revealed no difference in survivorship between colour morphs. We found a significant association between phenotypic and geographical distance in M. birostris, but not in M. alfredi. Our results suggest that melanism is not under selection by predation in the tested M. alfredi populations, and that frequency differences across populations of both species are a consequence of neutral genetic processes. As genetic colour polymorphisms are often subjected to complex selection mechanisms, our findings only begin to elucidate the underlying evolutionary processes responsible for the maintenance and frequency variation of melanism in manta ray populations.


Beyond Coronary Artery Disease: Assessing the Microcirculation.
Ischemic heart disease (IHD) affects more than 20 million adults in the United States. Although classically attributed to atherosclerosis of the epicardial coronary arteries, nearly half of patients with stable angina and IHD who undergo invasive coronary angiography do not have obstructive epicardial coronary artery disease. Ischemia with nonobstructive coronary arteries is frequently caused by microvascular angina with underlying coronary microvascular dysfunction (CMD). Greater understanding the pathophysiology, diagnosis, and treatment of CMD holds promise to improve clinical outcomes of patients with ischemic heart disease.


Convolutional neural networks trained with a developmental sequence of blurry to clear images reveal core differences between face and object processing.
Although convolutional neural networks (CNNs) provide a promising model for understanding human vision, most CNNs lack robustness to challenging viewing conditions, such as image blur, whereas human vision is much more reliable. Might robustness to blur be attributable to vision during infancy, given that acuity is initially poor but improves considerably over the first several months of life? Here, we evaluated the potential consequences of such early experiences by training CNN models on face and object recognition tasks while gradually reducing the amount of blur applied to the training images. For CNNs trained on blurry to clear faces, we observed sustained robustness to blur, consistent with a recent report by Vogelsang and colleagues (2018). By contrast, CNNs trained with blurry to clear objects failed to retain robustness to blur. Further analyses revealed that the spatial frequency tuning of the two CNNs was profoundly different. The blurry to clear face-trained network successfully retained a preference for low spatial frequencies, whereas the blurry to clear object-trained CNN exhibited a progressive shift toward higher spatial frequencies. Our findings provide novel computational evidence showing how face recognition, unlike object recognition, allows for more holistic processing. Moreover, our results suggest that blurry vision during infancy is insufficient to account for the robustness of adult vision to blurry objects.


Who shall live when not all can live? Intellectual property in accessing and benefit-sharing influenza viruses through the World Health Organisation.
This article addresses the development of the World Health Organisation's (WHO) arrangements for accessing viruses and the development of vaccines to respond to potential pandemics (and other lesser outbreaks). It examines the ongoing "conflict" between the United Nations' Convention on Biological Diversity (CBD) and the World Trade Organisation's Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS) in the context of the debates about the paramountcy of intellectual property, and the potential for other (equity and development) imperatives to over-ride respect for intellectual property and TRIPS. The article concludes that the same intellectual property fault lines are evident in the WHO forum as those apparent at the CBD and the WTO fora, and an ongoing failure to properly address questions of equity and development. This poses a challenge for the Australian Government in guaranteeing a satisfactory pandemic influenza preparation and response.


Lesson of the month 1: Large vessel vasculitis - a diagnostic challenge and the role of 18-fluorodeoxyglucose positron emission tomography.
Large vessel vasculitis can pose a significant diagnostic challenge. It may be insidious in onset with the only presenting symptoms consisting of constitutional compromise. It may mimic other pathologies and the only serological abnormalities may be abnormal inflammatory markers. Conventional imaging modalities may not be diagnostic. We present a case of large vessel vasculitis that proved a significant diagnostic challenge with diagnosis established on 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) computerised tomography (CT) imaging. This is one of five cases of large vessel vasculitis that were diagnosed in the rheumatology department at our trust over a 12-month period with diagnosis established with the use of 18F-FDG PET CT. We discuss the advantages of 18F-FDG PET CT over more conventional imaging modalities in diagnosing large vessel vasculitis.


A new image flux conduction model and its application to selective image smoothing.
A discrete image flux conduction equation which is completely new in this field is proposed. The new approach starts with formulating a discrete image flux conduction equation based on the concept of heat conduction theory. Based on this discrete equation, the status change at a time point can be directly computed from its spatial neighborhood. To more accurately estimate an image flux, we have used an orthogonal wavelet basis to approximate the gradient of the intensity at each point. Since the proposed approach is discrete by nature, it is not necessary to formulate a continuous PDE to fit the discrete image data set. Furthermore, introduction of different numerical methods to solve the PDE can also be avoided. Since the proposed approach does not require that a PDE be solved, it is therefore more efficient and accurate than the conventional methods. Experimental results obtained using both synthetic signals and real images have demonstrated that the proposed model could effectively handle the selective image smoothing problem.


Diagnostic and prognostic value of fibrin stabilising factor in Schönlein-Henoch syndrome.
Fibrin stabilising factor (FSF) was studied in the circulating blood of 196 children. These 196 children comprised three groups: 131 controls (group A), 20 children with diseases of potential repercussion on FSF determination (group B), and 45 children with Schönlein-Henoch syndrome (group C). Determinations from groups A and B produced normal values, but results from group C were significantly lower at the onset of the vasculitis. Seventeen children with Schönlein-Henoch syndrome have had complications, in 7 of whom these were severe. The decrease in FSF levels was correlated with the severity of such complications, and an increase in FSF was associated with recovery. Determination of FSF activity appears to help in the diagnosis of Schönlein-Henoch vasculitis, as well as helping to monitor the course of the disease and assessing the risks of complications.


Three dissimilar high fat diets differentially regulate lipid and glucose metabolism in obesity-resistant Slc:Wistar/ST rats.
Epidemiologic and ecologic studies suggest that dietary fat plays an important role in the development of obesity. Certain Wistar rat strains do not become obese when fed high-fat diets unlike others. In a preliminary study, we confirmed that Slc:Wistar/ST rats did not become obese when fed high-fat diets. The mechanisms governing the response of hepatic lipid-metabolizing enzymes to large quantities of dietary lipids consumed by obesity-resistant animals are unknown. The aim of the present study is to examine how obesity-resistant animals metabolize various types of high-fat diets and why they do not become obese. For this purpose, male Slc:Wistar/ST rats were fed a control low-fat diet (LS) or a high-fat diet containing fish oil (HF), soybean oil (HS), or lard (HL) for 4 weeks. We observed their phenotypes and determined lipid profiles in plasma and liver as well as mRNA expression levels in liver of genes related to lipid and glucose metabolism using DNA microarray and quantitative reverse transcriptase polymerase chain analyses. The body weights of all dietary groups were similar due to isocaloric intakes, whereas the weight of white adipose tissues in the LS group was significantly lower. The HF diet lowered plasma lipid levels by accelerated lipolysis in the peroxisomes and suppressed levels of very-low-density lipoprotein (VLDL) secretion. The HS diet promoted hepatic lipid accumulation by suppressed lipolysis in the peroxisomes and normal levels of VLDL secretion. The lipid profiles of rats fed the LS or HL diet were similar. The HL diet accelerated lipid and glucose metabolism.


Respiratory infections and coinfections: geographical and population patterns.
Acute respiratory infections are the second cause of mortality in children younger than five years, with 150.7 million episodes per year. Human orthopneumovirus (hOPV) and metapneumovirus (hMPV) are the first and second causes of bronchiolitis; type 2 human orthorubulavirus (hORUV) has been associated with pneumonia in immunocompromised patients. To define hOPV, hMPV and hORUV geographical distribution and circulation patterns. An observational, prospective cross-sectional pilot study was carried out. Two-hundred viral strains obtained from pediatric patients were genotyped by endpoint reverse transcription polymerase chain reaction (RT-PCR). One-hundred and eighty-six positive samples were typed: 84 hOPV, 43 hMPV, two hORUV and 57 co-infection specimens. Geographical distribution was plotted. hMPV, hOPV, and hORUV cumulative incidences were 0.215, 0.42, and 0.01, respectively. Cumulative incidence of hMPV-hORUV and hMPV-hOPV coinfection was 0.015 and 0.23; for hOPV-hMPV-hORUV, 0.035; and for hORUV-hOPV, 0.005. The largest number of positive cases of circulating or co-circulating viruses occurred between January and March. This study successfully identified circulation and geographical distribution patterns of the different viruses, as well as of viral co-infections.


Polypyrrole-coated cellulose nanofibers: influence of orientation, coverage and electrical stimulation on SH-SY5Y behavior.
In the field of tissue engineering, much research has been devoted to the surface topography of conductive materials. However, less work has been carried out on how the electrical stimulation of such materials influences nerve regeneration. Here, we investigated the effect of electrical stimulation on randomly- and uniaxially-aligned polypyrrole-coated cellulose acetate butyrate (PPy/CAB) nanofibers. First, SEM revealed that the conducting PPy coverage resulted in dramatic changes to the nanofiber morphology. In turn, these changes led to an increase in the sample wettability. Fourier transform spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) confirmed the presence of a PPy layer. Second, human neuroblastoma cells (SH-SY5Y) were seeded on the PPy/CAB nanofibers and stimulated by 100 mV mm-1 at 1 Hz pulses in vitro. We demonstrated that either with or without this electrical stimulation both nanofiber alignment and PPy coverage had a strong influence on cell morphology and attachment. Moreover, fluorescence microscopy revealed that the cells stimulated on PPy/CAB had longer neurite outgrowth. Collectively, our results shed light on the combined effect of scaffold morphology and external stimulation on neuronal cell behavior.


CRISPR Systems for COVID-19 Diagnosis.
The emergence of the new coronavirus 2019 (COVID-19) was first seen in December 2019, which has spread rapidly and become a global pandemic. The number of cases of COVID-19 and its associated mortality have raised serious concerns worldwide. Early diagnosis of viral infection undoubtedly allows rapid intervention, disease management, and substantial control of the rapid spread of the disease. Currently, the standard approach for COVID-19 diagnosis globally is the RT-qPCR test; however, the limited access to kits and associated reagents, the need for specialized lab equipment, and the need for highly skilled personnel has led to a detection slowdown. Recently, the development of clustered regularly interspaced short palindromic repeats (CRISPR)-based diagnostic systems has reshaped molecular diagnosis. The benefits of the CRISPR system such as speed, precision, specificity, strength, efficiency, and versatility have inspired researchers to develop CRISPR-based diagnostic and therapeutic methods. With the global COVID-19 outbreak, different groups have begun to design and develop diagnostic and therapeutic programs based on the efficient CRISPR system. CRISPR-based COVID-19 diagnostic systems have advantages such as a high detection speed (i.e., 30 min from raw sample to reach a result), high sensitivity and precision, portability, and no need for specialized laboratory equipment. Here, we review contemporary studies on the detection of COVID-19 based on the CRISPR system.


Association and clinical utility of NAT2 in the prediction of isoniazid-induced liver injury in Singaporean patients.
Isoniazid (INH) is part of the first-line-therapy for tuberculosis (TB) but can cause drug-induced liver injury (DILI). Several candidate single nucleotide polymorphisms (SNPs) have been previously identified but the clinical utility of these SNPs in the prediction of INH-DILI remains uncertain. The aim of this study was to assess the association between selected candidate SNPs and the risk of INH-DILI and to assess the clinical validity of associated variants in a Singaporean population. This was a case-control study where 24 INH-DILI cases and 79 controls were recruited from the TB control unit in a tertiary hospital. Logistic regression was used to test for the association between candidate SNPs and INH-DILI. NAT2 acetylator status was inferred from genotypes and tested for association with INH-DILI. Finally, clinical validity measures were estimated for significant variants. Two SNPs in NAT2 (rs1041983 and rs1495741) and NAT2 slow acetylators (SA) were significantly associated with INH-DILI (OR (95% CI) = 13.86 (4.30-44.70), 0.10 (0.03-0.33) and 9.98 (3.32-33.80), respectively). Based on an INH-DILI prevalence of 10%, the sensitivity, specificity, positive and negative predictive values of NAT2 SA were 75%, 78%, 28% and 97%, respectively. The population attributable fraction (PAF) and number needed to test (NNT) for NAT2 SA were estimated to be 0.67 and 4.08, respectively. A model with clinical and NAT2 acetylator status provided significantly better prediction for INH-DILI than a clinical model alone (area under receiver operating characteristic curve = 0.863 vs. 0.766, respectively, p = 0.027). We show the association between NAT2 SA and INH-DILI in a Singaporean population and demonstrated its clinical utility in the prediction of INH-DILI.


Translation of HDAC6 PET Imaging Using [18F]EKZ-001-cGMP Production and Measurement of HDAC6 Target Occupancy in Nonhuman Primates.
Histone deacetylase 6 (HDAC6) is a multifunctional cytoplasmic enzyme involved in diverse cellular processes such as intracellular transport and protein quality control. Inhibition of HDAC6 can alleviate defects in cell and rodent models of certain diseases, particularly neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. However, while HDAC6 represents a potentially powerful therapeutic target, development of effective brain-penetrant HDAC6 inhibitors remains challenging. Recently, [18F]EKZ-001 ([18F]Bavarostat), a brain-penetrant positron emission tomography (PET) radioligand with high affinity and selectivity toward HDAC6, was developed and evaluated preclinically for its ability to bind HDAC6. Herein, we describe the efficient and robust fully automated current Good Manufacturing Practices (cGMP) compliant production method. [18F]EKZ-001 quantification methods were validated in nonhuman primates (NHP) using full kinetic modeling, and [18F]EKZ-001 PET was applied to compare dose-occupancy relationships between two HDAC6 inhibitors, EKZ-317 and ACY-775. [18F]EKZ-001 is cGMP produced with an average decay-corrected radiochemical yield of 14% and an average molar activity of 204 GBq/μmol. We demonstrate that a two-tissue compartmental model and Logan graphical analysis are appropriate for [18F]EKZ-001 PET quantification in NHP brain. Blocking studies show that the novel compound EKZ-317 achieves higher target occupancy than ACY-775. This work supports the translation of [18F]EKZ-001 PET for first-in-human studies.


HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression.
Chronic inflammation can be a major risk factor for cancer development and may contribute to the high worldwide incidence of hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) is known to be an important mediator of inflammatory responses; however, its link to hepatitis B virus (HBV)-mediated inflammatory responses has not been established. Here, we demonstrate that the expression of COX-2 mRNA and protein was significantly elevated in cells transfected by HBV replicon but not in cells transfected by HBV genome lacking the HBx gene. Notably, COX-2 induction was correlated with HBx's ability to increase reactive oxygen species (ROS) levels. Consistently with this, antioxidant treatment and ectopic expression of manganese superoxide dismutase or catalase completely abolished COX-2 induction. Interestingly, a mitochondria localization-defective mutant of HBx (HBx(Delta 68-117)) neither increased intracellular ROS levels nor induced COX-2 expression. HBx(68-117), which encodes only amino acids 68-117 and is sufficient for mitochondria localization, increased ROS levels but did not induce COX-2 expression. Similarly, HBx targeting to the outer membrane of mitochondria (Mito-HBx) increased ROS but also failed to increase COX-2 expression, suggesting that other cytoplasmic signaling pathways are involved in HBx-mediated COX-2 induction. Indeed, inhibition of cytoplasmic calcium signaling by cyclosporine A, blocking mitochondrial permeability transition pore, and herbimycin, and inhibition of calcium-dependent tyrosine kinase suppressed HBV-mediated COX-2 induction. Thus, the data indicate that both mitochondrial ROS and cytoplasmic calcium signaling are necessary for the COX-2 induction. Our studies revealed a pathophysiological link between HBV infection and hepatic inflammation, and this chain of events might contribute to early steps in HBV-associated liver carcinogenesis.


The Ubiquitous Cognitive Assessment Tool for Smartwatches: Design, Implementation, and Evaluation Study.
Cognitive functioning plays a significant role in individuals' mental health, since fluctuations in memory, attention, and executive functions influence their daily task performance. Existing digital cognitive assessment tools cannot be administered in the wild and their test sets are not brief enough to capture frequent fluctuations throughout the day. The ubiquitous availability of mobile and wearable devices may allow their incorporation into a suitable platform for real-world cognitive assessment. The aims of this study were threefold: (1) to evaluate a smartwatch-based tool for the assessment of cognitive performance, (2) to investigate the usability of this tool, and (3) to understand participants' perceptions regarding the application of a smartwatch in cognitive assessment. We built the Ubiquitous Cognitive Assessment Tool (UbiCAT) on a smartwatch-based platform. UbiCAT implements three cognitive tests-an Arrow test, a Letter test, and a Color test-adapted from the two-choice reaction-time, N-back, and Stroop tests, respectively. These tests were designed together with domain experts. We evaluated the UbiCAT test measures against standard computer-based tests with 21 healthy adults by applying statistical analyses significant at the 95% level. Usability testing for each UbiCAT app was performed using the Mobile App Rating Scale (MARS) questionnaire. The NASA-TLX (Task Load Index) questionnaire was used to measure cognitive workload during the N-back test. Participants rated perceived discomfort of wearing a smartwatch during the tests using a 7-point Likert scale. Upon finishing the experiment, an interview was conducted with each participant. The interviews were transcribed and semantic analysis was performed to group the findings. Pearson correlation analysis between the total correct responses obtained from the UbiCAT and the computer-based tests revealed a significant strong correlation (r=.78, P<.001). One-way analysis of variance (ANOVA) showed a significant effect of the N-back difficulty level on the participants' performance measures. The study also demonstrated usability ratings above 4 out of 5 in terms of aesthetics, functionality, and information. Low discomfort (<3 out of 7) was reported by our participants after using the UbiCAT. Seven themes were extracted from the transcripts of the interviews conducted with our participants. UbiCAT is a smartwatch-based tool that assesses three key cognitive domains. Usability ratings showed that participants were engaged with the UbiCAT tests and did not feel any discomfort. The majority of the participants were interested in using the UbiCAT, although some preferred computer-based tests, which might be due to the widespread use of personal computers. The UbiCAT can be administered in the wild with mentally ill patients to assess their attention, working memory, and executive function.


Comparison of alendronate and raloxifene for the management of primary hyperparathyroidism.
To evaluate and compare the efficacy of alendronate sodium (ALN) and raloxifene (RLX) for the management of primary hyperparathyroidism (PHPT) in postmenopausal female patients (pts) with osteoporosis. Twenty-four postmenopausal women with osteoporosis who were diagnosed with PHPT, but refused the option of surgery, were enrolled. Participants were sequentially randomized into two groups: an ALN-group of 12 pts (70 mg/week) and a RLX-group of 12 pts (60 mg/day). The control group consisted of 10 pts with PHPT who did not have any indications for surgery. The decrease in ionized calcium levels was significantly more pronounced in the ALN group compared to the RLX and control groups (p<0.001). In terms of difference from baseline in bone mineral density (BMD) of the lumbar area in percentages over a period of 12 months, pts in the ALN and RLX groups both showed statistically significant improvements compared to pts in the control group (control vs ALN, p<0.001; control vs RLX, p<0.001). BMD measurements of the femoral and radial areas were comparable in all three groups. ALN and RLX may improve bone density in the lumbar area of osteoporotic post-menopausal women with PHPT. The more significant decrease in serum calcium levels which was observed in the ALN group compared to both RLX and control groups, suggests that ALN could be used for the short-term control of calcium levels in patients awaiting surgery.


Cholic acid synthesis as an index of the severity of liver disease in man.
Bile acid pool size and kinetics were determined in 17 patients with cirrhosis and 11 patients without liver disease and correlated with the severity of liver disease as determined by the usual clinical and laboratory criteria. In order to assess the severity of liver disease, a grading system was devised which assigned numerical values to various clinical signs and laboratory results. The total clinical score and the patients were divided into two groups of advanced (7-18 points) or mild (1-6 points) cirrhosis. The clinical rating was then correlated with the various aspects of bile acid metabolism. Cholic acid synthesis was markedly reduced in the early stages of cirrhosis and continued to decrease with the advancement of the liver disease. There was an inverse correlation between synthesis of cholic acid and the severity of cirrhosis. Nine of the 10 patients with advanced cirrhosis and a very low cholic acid synthetic rate (average 68 mg per day) died within one to 13 months from the start of the study. Patients with mild cirrhosis also had significantly reduced cholic acid synthesis (average 152 mg per day) but they all were well and alive three to 23 months after the study. In contrast, chenodeoxycholic acid synthesis was not markedly affected in either patients with mild or advanced cirrhosis. There was also a high degree of correlation between the fractional daily turnover rate of cholic acid and the severity of liver disease. The fractional daily turnover rate of cholic acid was greatly reduced (50%) in patients with advanced cirrhosis. Deoxycholic acid was reduced in patients with mild cirrhosis and virtually absent from the bile of patients with advanced cirrhosis. The findings of the present report provide evidence that cholic acid synthesis is a sensitive indicator of the hepatocellular damage, whereas chenodeoxycholic acid synthesis is relatively unaffected by cirrhosis. The selective alteration in cholic acid synthesis probably resides in a deficiency of one or more enzymes regulating the formation of the 3-keto, 7 alpha, 12 alpha-dihydroxy precursor of cholic acid.


Adenovirus-A Deadly Disease in the Solid Organ Transplant Population: Risk Factors and Outcomes.
The importance of adenoviruses (AdV) in the immunocompromised population has been more recognized in recent decades. We aimed to assess the risk factors and outcomes associated with AdV in solid organ transplant recipients. This was a retrospective cohort study of solid organ transplant recipients who tested positive for AdV between January 1, 2004, and March 12, 2014. The subjects were divided in 2 groups: AdV asymptomatic infection and AdV disease. The characteristics and outcomes of the groups were compared using Wilcoxon rank-sum and Fisher exact tests; logistic regression was performed to evaluate risk factors. A total of 125 patients were included with a mean (SD) age of 9.79 years (16.54); 49.6% were male, and 20.8% had AdV disease. No significant risk factors were found for AdV disease by univariate analyses. Comparing patients with disease and with asymptomatic infection, rejections during the first year after testing positive for AdV were 7 (26.92%) vs 17 (17.17%); mortality at 1 year post-transplantation was 26.92% vs 6.06% (P = .006), respectively, and at 1 year after testing positive for AdV was 38.46% vs 11.11% (P = .002), respectively. No independent risk factor for AdV disease was identified, but patients with AdV disease had a significantly higher mortality compared with those with asymptomatic infection.


Nanofiltration membranes for salt and dye filtration: effect of membrane properties on performances.
In this study, commercial nanofiltration membranes (Toray, NF 270, Desal 5 L) were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, optical profilometry, contact angle, mechanical strength and zeta potential measurements. Filtration performance tests were conducted with distilled water, MgSO4 solution and synthetic dye solutions, respectively. Among three commercial membranes, the Toray membrane was thought to be better choice. Additional experiments were carried out for a more detailed characterization of the selected membrane. Therefore, firstly, flux and removal efficiency was monitored by using dye solutions at different pH values, and then experiments were carried out to observe the effect of different temperatures. Also, another filtration test with NaCl solution was performed for the Toray membrane. As the main purpose of this study, we aimed to establish a significant correlation between the structural properties of membranes and their performances. In light of the results obtained, it was observed that the contact angle, mechanical strength and surface roughness values of the membrane significantly affected the membrane performance. It was concluded that the most important parameter in dye removal was the zeta potential. As a result of this work, a data set of commercial membranes was created and is available to all membrane users.


Hydration thermodynamics using the reference interaction site model: speed or accuracy?
We report a method to dramatically improve the accuracy of hydration free energies (HFE) calculated by the 1D and 3D reference interaction site models (RISM) of molecular integral equation theory. It is shown that the errors in HFEs calculated by RISM approaches using the Gaussian fluctuations (GF) free energy functional are not random, but can be decomposed into linear combination of contributions from different structural elements of molecules (number of double bonds, number of OH groups, etc.). Therefore, by combining RISM/GF with cheminformatics, one can develop an accurate method for HFE prediction. We call this approach the structural description correction model (SDC) ( Ratkova et al. J. Phys. Chem. B 2010 , 114 , 12068 ). In this work, we investigated the prediction quality of the SDC model combined with 1D and 3D RISM approaches. In parallel, we analyzed the computational performance of these two methods. The SDC model parameters were obtained by fitting against a training set of 53 simple organic molecules. To demonstrate that the values of these parameters were transferable between different classes of molecules, the models were tested against 98 more complex molecules (including 38 polyfragment compounds). The results show that the 3D RISM/SDC model predicts the HFEs with very good accuracy (RMSE of 0.47 kcal/mol), while the 1D RISM approach provides only moderate accuracy (RMSE of 1.96 kcal/mol). However, a single 1D RISM/SDC calculation takes only a few seconds on a PC, whereas a single 3D RISM/SDC HFE calculation is approximately 100 times more computationally expensive. Therefore, we suggest that one should use the 1D RISM/SDC model for large-scale high-throughput screening of molecular hydration properties, while further refinement of these properties for selected compounds should be carried out with the more computationally expensive but more accurate 3D RISM/SDC model.


Decadal oscillation provides skillful multiyear predictions of Antarctic sea ice.
Over the satellite era, Antarctic sea ice exhibited an overall long-term increasing trend, contrary to the Arctic reduction under global warming. However, the drastic decline of Antarctic sea ice in 2014-2018 raises questions about its interannual and decadal-scale variabilities, which are poorly understood and predicted. Here, we identify an Antarctic sea ice decadal oscillation, exhibiting a quasi-period of 8-16 years, that is anticorrelated with the Pacific Quasi-Decadal Oscillation (r = -0.90). By combining observations, Coupled Model Intercomparison Project historical simulations, and pacemaker climate model experiments, we find evidence that the synchrony between the sea ice decadal oscillation and Pacific Quasi-Decadal Oscillation is linked to atmospheric poleward-propagating Rossby wave trains excited by heating in the central tropical Pacific. These waves weaken the Amundsen Sea Low, melting sea ice due to enhanced shortwave radiation and warm advection. A Pacific Quasi-Decadal Oscillation-based regression model shows that this tropical-polar teleconnection carries multi-year predictability.


The Jieduan-Niwan (JDNW) Formula Ameliorates Hepatocyte Apoptosis: A Study of the Inhibition of E2F1-Mediated Apoptosis Signaling Pathways in Acute-on-Chronic Liver Failure (ACLF) Using Rats.
Acute-on-chronic liver failure (ACLF) is a severe, complicated human disease. E2F1-mediated apoptosis plays an important role in ACLF development. Jieduan-Niwan (JDNW) formula, a traditional Chinese medicine (TCM), has shown remarkable clinical efficacy in ACLF treatment. However, the hepatoprotective mechanisms of the formula are barely understood. This study aimed to investigate the mechanisms of JDNW formula in ACLF treatment by specifically regulating E2F1-mediated apoptotic signaling pathways in rats. The JDNW components were determined by high-performance liquid chromatography (HPLC) analysis. The ACLF rat model was established using human serum albumin immune-induced liver cirrhosis, followed by D-galactosamine and lipopolysaccharide joint acute attacks. The ACLF rat was treated with JDNW formula. Prothrombin time activity was measured to investigate the coagulation function. Liver pathological injury was observed by hematoxylin-eosin (HE) and reticular fiber staining. The hepatocyte apoptosis index and apoptosis rate were determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and flow cytometry, respectively. Additionally, the expression of key genes and proteins that regulate E2F1-mediated apoptosis was analyzed by quantitative real-time PCR and Western blot. Seven major components of JDNW formula were detected. The formula ameliorated the coagulation function, decreased the hepatocyte apoptosis index and apoptosis rate, and alleviated liver pathological damage in ACLF rats. The down-regulation of the expression of genes and proteins from p53-dependent and non-p53-dependent apoptosis pathways and the up-regulation of the expression of genes from blocking anti-apoptotic signaling pathways indicated that JDNW formula inhibited excessive hepatocyte apoptosis in ACLF rats via E2F1-mediated apoptosis signaling pathways. The findings indicate that JDNW formula protects livers of ACLF rats by inhibiting E2F1-mediated apoptotic signaling pathways, implying that these pathways might be a potential therapeutic target for ACLF treatment.


Hereditary C2 deficiency associated with cutaneous lupus erythematosus: clinical, laboratory, and genetic studies.
Selective congenital deficiency in the second component of complement has been described in association with lupus erythematosus (LE) and other connective tissue disorders. We identified a 59-year-old woman with a 13-year history of cutaneous LE and no detectable serum C2. The patient's photosensitivity, large polycyclic erosive cutaneous lesions, lack of renal disease, paucity of serological findings, and high incidence of bacterial infection is consistent with previously described patients with this association. Uniquely, the patient demonstrated secondary infection with Staphylococcus aureus and Trichophyton rubrum in the skin lesions themselves. Immunologic studies disclosed depression in both humoral and cellular immunity. Moderation in her clinical disease and immunologic measurements has been observed after treatment with levamisole hydrochloride. Immunogenetic studies of the patient's four-generation kindred was consistent with an autosomal recessive inheritance of C2 deficiency genetically linked to HLA, segregating with the B18 allele. Mixed lymphocyte culture determinations reinforce evidence for linkage between the HLA-D locus and the trait for C2 deficiency.