Compact lens with circular spot profile for square die LEDs in multi-LED projectors.
In the stage illumination industry, LED technology is promising both in terms of energy use and novel features, but it also has inherent issues. This paper presents a solution to the poor color homogeneity arising when multiple rectangular images formed from LED dies are combined into a circular spot profile. Using ray tracing, a nonrotationally symmetric collimating lens was optimized to round off such die images. The result is a high-output lens with an almost perfectly circular spot. In a simulated red green blue color mixing projector with seven LEDs, the lens reduced measurable color inhomogeneity by ≈24.1%, with a 5.3% luminous gain, compared to the best rotationally symmetric benchmark lens.


Use of quinocide in treatment and prophylaxis of vivax malaria.
The discovery of antimalarial properties of derivatives of 8-aminoquinolines which combine high activity against the tissue stages of the malaria parasite with satisfactory tolerance by man can be said to have marked the final stage in the search for a radical cure of vivax malaria. Since its synthesis in the USSR in 1952, quinocide-an 8-aminoquinoline drug-has been subjected by Soviet workers to intensive research, an outline of which is presented in this paper. The results of their investigations, which ranged from laboratory and clinical studies of tolerance to the drug, through small-scale trials of its parasiticidal activity, to large-scale studies on the effectiveness of its mass administration are very encouraging. Both for anti-relapse treatment and for pre-epidemic prophylaxis, a short (10- or 14-day) course of quinocide proved as effective as a lengthy course of acriquine with plasmocide. Side-effects were infrequent, and most of those that occurred were transient and did not necessitate the suspension of treatment. It is suggested that the mass administration of quinocide would, in certain cases, be a useful adjunct to insecticidal measures in the clearance of malaria foci.


Translocation and accumulation of exogeneous hepatitis B virus preS surface proteins in the cell nucleus.
Recurrent reports about protease-sensitive sites in the junction of the preS and S region of the hepatitis B virus large surface protein have raised the question about a possible biological role of S protein-depleted, independent preS protein fragments in the virus life cycle. In the present study, this question was addressed by exogenous introduction of fluorescence-labeled recombinant preS proteins into permeabilized HepG2 cells. While maltose-binding proteins (MBP) were evenly distributed throughout the cytoplasm, MBP-preS fusion proteins selectively accumulated in the nucleus. Using truncated preS proteins, the effective domain for this nuclear accumulation was localized around the preS2 region. The mode of this action differs from conventional nuclear translocation mechanism in its energy- and mediator-independency and in that it is not saturated regardless of the increase of preS protein concentration. The biological meaning of this phenomenon has to be further studied. However, in regard to hepatitis B virus infection, this observation might provide a clue for unveiling the still poorly characterized events after initial internalization of the virus, which might make use of the nuclear translocation effect of the preS2 region to facilitate the infection.


ADAMTS4 level in patients with stable coronary artery disease and acute coronary syndromes.
A recent study indicates that ADAMTS4 (a disintegrin and metalloprotease with thrombospondin motifs 4) was expressed in macrophage rich areas of human atherosclerotic carotid plaques and coronary unstable plaques suggesting a pathogenic role in the development of acute coronary syndromes (ACS). The aim of the study was to compare ADAMTS4 across the entire spectrum of coronary artery disease (CAD) and to investigate the temporal profiles of ADAMTS4. Plasma levels of ADAMTS4 were measured in patients with stable effort angina pectoris (SAP), ACS and in controls. Venous blood was sampled upon admission before angiography and drug administration. In patients with ACS who underwent medical treatment, serial blood samples were also collected on days 1, 2, 3, 5 and 7 after admission. ADAMTS4 was measured using an enzyme immunoassay. Plasma ADAMTS4 level in cases was significantly greater than in controls (P<0.001). Higher levels of ADAMTS4 were found with progression of CAD from SAP to unstable angina pectoris (UAP) to non-ST-segment elevation acute myocardial infarction (NSTEMI) and to ST-segment elevation acute myocardial infarction (STEMI) (P<0.001). Elevated ADAMTS4 level was associated with ACS with an area under receiver operating characteristic (ROC) curve of 0.753 (95% CI 0.654-0.851; P<0.001). The pattern of ADAMTS4 release observed was clearly different in various forms of ACS. ADAMTS4 showed a weak correlation with high-sensitivity C-reactive protein (hs-CRP); however, no significant correlation was found between ADAMTS4 and troponin T (TnT) in ACS patients. Serial changes in plasma ADAMTS4 were documented in patients with ACS and may serve as a marker of plaque destabilization.


Janus kinase inhibitors for the treatment of myeloproliferative neoplasms.
Disordered signaling through the JAK/STAT pathway is a hallmark of myeloproliferative neoplasms (MPNs). Targeted therapies that inhibit and regulate this pathway are reasonable strategies for disease management. Only one JAK1/JAK2 inhibitor has gained FDA approval for treatment of myelofibrosis. Despite significant reductions in splenomegaly and disease-associated symptoms, additional agents are necessary to manage disease in those that do not respond. A review of the currently available literature and meeting abstracts for JAK inhibitors in myeloproliferative neoplasms identified studies aimed at improving outcomes and establishing alternative therapies in MPNs. Development of specific JAK inhibitors and ongoing trials involving ruxolitinib, CYT387, SAR302503, CEP701, SB 1518, XL-019, LY2784544, BMS-911453, NS-018, AZD1480 and INCB039110 are reviewed. The identification of JAK2V617F mutation and its link to MPNs has revolutionized treatment options. Resultant research in targeting the JAK/STAT pathway led to the approval of ruxolitinib, a JAK1/JAK2 inhibitor with activity in MPNs. While ruxolitinib produces durable reductions in splenomegaly and improvement of symptoms, and prolongs survival, there is room for new and more specific agents to be developed. Minimizing toxicity and avoiding drug resistance are challenges that lie ahead. Combining agents with different mechanisms seems to be a rational strategy.


Pathways of Association Between Childhood Irritability and Adolescent Suicidality.
Childhood irritability predicts suicidal ideation/attempt (suicidality), but it is unclear whether irritability is an independent and direct risk factor for suicidality or a marker of intermediate mental health symptoms associated with suicidality. This study aimed to identify developmental patterns of childhood irritability and to test whether childhood irritability is directly associated with suicidality or indirectly associated with intermediate mental health symptoms. One thousand three hundred ninety-three participants from the Québec Longitudinal Study of Child Development were followed from birth to 17 years. Teachers assessed irritability yearly (at 6-12 years) and children self-reported intermediate mental health symptoms (depression, anxiety, disruptiveness, and hyperactivity-impulsivity; at 13 years) and suicidality (at 15 and 17 years). Four irritability trajectories were identified: low (74.7%), rising (13.0%), declining (7.4%), and persistent (5.0%). Children following a rising irritability trajectory (versus a low trajectory) were at higher suicidality risk. A large proportion of this association was direct (odds ratio 2.11, 95% CI 1.30-3.43) and a small proportion was indirect by depressive symptoms (accounting for 23% of the association; odds ratio 1.17, 95% CI 1.03-1.34). Children on a persistent irritability trajectory (versus a low trajectory) were at higher risk of suicidality and this association was uniquely indirect by depressive symptoms (accounting for 73% of the association; odds ratio 1.51, 95% CI 1.16-1.97). The declining trajectory was not related to suicidality; no association with anxiety, disruptiveness, and hyperactivity-impulsivity was found. Rising irritability across childhood represents a direct risk for suicidality. Persistent irritability appears to be a distal marker of suicidality acting through more proximal depressive symptoms.


Effects of acute brainstem compression on auditory brainstem response in the guinea pig.
The purpose of this study was to establish the norm for parameters of auditory brainstem response (ABR) in the guinea pig and to investigate if acute brainstem compression results in significant changes to these parameters. Thirty-six guinea pigs with positive Preyer's reflex were anesthetized. A craniectomy was performed to remove the right occipital bone and the dura mater was opened to expose the brain, cerebellum and cerebellopontine angle (CPA). A small inflatable balloon was placed into the CPA precisely and slowly. ABR was recorded before incision of the skin as a baseline value, after placement and after inflation of the balloon with water at 0.1-ml intervals. Five stable peaks were recorded in 27 experimental animals. When the balloon was inflated with 0.1 ml water, the absolute latency (AL) of peaks IV and V and the interpeak latency (IPL) of peaks III and IV, and IV and V were prolonged. The amplitude ratios (AR) of peaks II, III, IV and V to peak I decreased. Inflation of the balloon with 0.2 ml of water caused further elongation of ALs of peaks IV and V and decreases in each AR. When the balloon volume increased to 0.3 ml, peak V became unrecognizable and peaks III and IV showed significant elongation of AL; peaks I and II did not show significant change in ALs. Further increase of the balloon volume to 0.4 ml resulted in disappearance of peaks III, IV and V; AL of peak II was also elongated. However, the amplitude and AL of peak I remained unchanged. Similar changes were observed in IPLs. This study establishes the norm of parameters of ABR in guinea pigs and demonstrates that acute brainstem compression causes elongation of ALs and IPLs of peaks II, III, IV and V. This suggests that peaks II, III, IV and V come from the brainstem and that peak I is not generated from the brainstem in the guinea pig.


Delaying or delivering: identification of novel NAM-1 alleles that delay senescence to extend wheat grain fill duration.
Senescence is a complex trait under genetic and environmental control, in which resources are remobilized from vegetative tissue into grain. Delayed senescence, or 'staygreen' traits, can confer stress tolerance, with extended photosynthetic activity hypothetically sustaining grain filling. The genetics of senescence regulation are largely unknown, with senescence variation often correlated with phenological traits. Here, we confirm staygreen phenotypes of two Triticum aestivum cv. Paragon ethyl methane sulfonate mutants previously identified during a forward genetic screen and selected for their agronomic performance, similar phenology, and differential senescence phenotypes. Grain filling experiments confirmed a positive relationship between onset of senescence and grain fill duration, reporting an associated ~14% increase in final dry grain weight for one mutant (P<0.05). Recombinant inbred line (RIL) populations segregating for the timing of senescence were developed for trait mapping purposes and phenotyped over multiple years under field conditions. Quantification and comparison of senescence metrics aided RIL selection, facilitating exome capture-enabled bulk segregant analysis (BSA). Using BSA we mapped our two staygreen traits to two independent, dominant, loci of 4.8 and 16.7 Mb in size encompassing 56 and 142 genes, respectively. Combining association analysis with variant effect prediction, we identified single nucleotide polymorphisms encoding self-validating mutations located in NAM-1 homoeologues, which we propose as gene candidates.


Schistosomiasis in the Senegal River Basin: before and after the construction of the dams at Diama, Senegal and Manantali, Mali and future prospects.
Ecological changes in the Senegal River Basin (SRB) resulting from the construction of a barrage at Diama, Senegal on the Senegal River to prevent the intrusion of sea water into the river, and a dam at Manantali, Mali on the Bafing River to control the flow of water and to generate electricity, have been responsible for changes in the epidemiology of human schistosomiasis. The introduction of Schistosoma mansoni into the Lower and Middle Valleys of the SRB and subsequent spread of the parasite in the human population is recorded with regard to prevalence and intensity. New foci of S. haematobium are described. The reduction in salinity and change from an acidic to an alkaline environment in the water are beneficial to both the fecundity and growth of freshwater snails and transmission of the parasite. The creation of new irrigation canals and expansion of the rice fields have provided new habitats for intermediate hosts to colonize. The evidence for praziquantel resistance/tolerance by populations of S. mansoni and the possibilities of the development, production and testing of a vaccine against human schistosomiasis are discussed. Future studies will monitor the spread of human urinary and mesenteric schistosomiasis in the SRB, will evaluate further the presence of praziquantel resistance/tolerance in S. mansoni, will examine the heavily infected human population for pathological symptoms and determine the most appropriate methods to control this severe outbreak of human schistosomiasis.


Research on the Influence of Bed Joint Reinforcement on Strength and Deformability of Masonry Shear Walls.
The areas of Central and Eastern Europe and, thus, Poland are not exposed to the effects of seismic actions. Any possible tremors can be caused by coal or copper mining. Wind, rheological effects, the impact of other objects, or a nonuniform substrate are the predominant types of loading included in the calculations for stiffening walls. The majority of buildings in Poland, as in most other European countries, are low, medium-high brick buildings. Some traditional materials, like solid brick (> 10% of construction materials market) are still used, but autoclaved aerated concrete (AAC) and cement-sand calcium-silicate (Ca-Si) elements with thin joints are prevailing (> 70% of the market) on the Polish market. Adding reinforcement only to bed joints in a wall is a satisfactory solution (in addition to confining) for seismic actions occurring in Poland that improves ULS (ultimate limit state) and SLS (serviceability limit state). This paper presents results from our own tests on testing horizontal shear walls without reinforcement and with different types of reinforcement. This discussion includes 51 walls made of solid brick (CB) reinforced with steel bars and steel trusses and results from tests on 15 walls made of calcium-silicate (Ca-Si) and AAC masonry units reinforced with steel trusses and plastic meshes. Taking into account our own tests and those conducted by other authors, empirical relationships were determined on the basis of more than 90 walls. They are applicable to the design and construction phases to determine the likely effect of reinforcements on cracking stress that damage shear deformation and wall stiffness.


Treatment options for sexual dysfunction in patients with chronic kidney disease: a systematic review of randomized controlled trials.
Sexual dysfunction is very common in patients with chronic kidney disease (CKD), but treatment options are limited. The benefits and harms of existing interventions for treatment of sexual dysfunction were assessed in patients with CKD. MEDLINE (1966 to December 2008), EMBASE (1980 to December 2008), and the Cochrane Trial Registry (Issue 4 2008) were searched for parallel and crossover randomized and quasi-randomized trials. Treatment effects were summarized as mean differences (MD) or standardized mean difference (SMD) with 95% confidence intervals (CI) using a random effects model. Fourteen trials (328 patients) were included. Phosphodiesterase-5 inhibitors (PDE5i) compared with placebo significantly increased the overall International Index of Erectile Function-5 (IIEF-5) score (three trials, 101 patients, MD 1.81, 95% CI 1.51 to 2.10), all of its individual domains, and the complete 15-item IIEF-5 (two trials, 80 patients, MD 10.64, 95% CI 5.32 to 15.96). End-of-treatment testosterone levels were not significantly increased by addition of zinc to dialysate (two trials, 22 patients, SMD 0.19 ng/dl, 95% CI -2.12 to 2.50), but oral zinc improved end-of-treatment testosterone levels. There was no difference in plasma luteinizing and follicle-stimulating hormone level at the end of the study period with zinc therapy. PDE5i and zinc are promising interventions for treating sexual dysfunction in CKD. Evidence supporting their routine use in CKD patients is limited. There is an unmet need for studying interventions for male and female sexual dysfunction in CKD considering the significant disease burden.


Laparoscopic versus open peritoneal dialysis catheter insertion, the LOCI-trial: a study protocol.
Peritoneal dialysis (PD) is an effective treatment for end-stage renal disease. It allows patients more freedom to perform daily activities compared to haemodialysis. Key to successful PD is the presence of a well-functioning dialysis catheter. Several complications, such as in- and outflow obstruction, peritonitis, exit-site infections, leakage and migration, can lead to catheter removal and loss of peritoneal access. Currently, different surgical techniques are in practice for PD-catheter placement. The type of insertion technique used may greatly influence the occurrence of complications. In the literature, up to 35% catheter failure has been described when using the open technique and only 13% for the laparoscopic technique. However, a well-designed randomized controlled trial is lacking. The LOCI-trial is a multi-center randomized controlled, single-blind trial (pilot). The study compares the laparoscopic with the open technique for PD catheter insertion. The primary objective is to determine the optimum placement technique in order to minimize the incidence of catheter malfunction at 6 weeks postoperatively. Secondary objectives are to determine the best approach to optimize catheter function and to study the quality of life at 6 months postoperatively comparing the two operative techniques. This study will generate evidence on any benefits of laparoscopic versus open PD catheter insertion. Dutch Trial Register NTR2878.


Sexual differentiation and hormonal regulation of the laryngeal synapse in Xenopus laevis.
In Xenopus laevis frogs, sex differences in adult laryngeal synapses contribute to sex differences in vocal behavior. This study explores the development of sex differences in types of neuromuscular synapses and the development and hormone regulation of sex differences in transmitter release. Synapses in the juvenile larynx have characteristics not found in adults: juvenile muscle fibers can produce subthreshold or suprathreshold potentials in response to the same strength of nerve stimulation and can also produce multiple spikes to a single nerve stimulus. Juvenile laryngeal muscle also contains the same synapse types (I, II, and III) as are found in adult laryngeal muscle. The distribution of laryngeal synapse types in juveniles is less sexually dimorphic than the distribution in adults. Analysis of quantal content indicates that laryngeal synapses characteristically release low amounts of transmitter prior to sexual differentiation. Quantal content values from male and female juveniles are similar to values for adult males and are lower than values for adult females. When juveniles are gonadectomized and treated with exogenous estrogen, quantal content values increase significantly, suggesting that this hormone may increase transmitter release at laryngeal synapses during development. Gonadectomy alone does not affect quantal content of laryngeal synapses in either sex. Androgen treatment decreases quantal content in juvenile females but not males; the effect is opposite to and smaller than that of estrogen. Thus, muscle fiber responses to nerve stimulation and transmitter release are not sexually dimorphic in juvenile larynges. Transmitter release is strengthened, or feminized, by the administration of estradiol, an ovarian steroid hormone.


Pre-transplant mycophenolate mofetil pharmacokinetics in Mexican children.
Mycophenolate mofetil is an immunosuppressive pro-drug frequently used to prevent renal graft rejection. It is hydrolyzed by esterases to obtain the active drug mycophenolic acid (MPA). There is high inter-patient variation in mycophenolic acid pharmacokinetics. Area under the concentration versus time curve (AUC) is used for therapeutic drug monitoring and recommended levels are 30-60 microg x hr/L. The aim of this study was to determine mycophenolic acid pharmacokinetics in children awaiting renal allograft in order to predict mycophenolate mofetil dose requirements. Children with end-stage renal disease on the waiting list for renal allograft transplantation were invited to participate in the study. A nine-point pharmacokinetic profile was performed. All patients received a single dose (600 mg/m2, subcutaneously) of mycophenolate mofetil at time zero. Mycophenolic acid was measured by HPLC. The AUC0-12h was estimated by the trapezoidal rule. Ten children were included in the study. Mean age was 13.5 +/- 3.5 years. The median AUC0-12h was 20.3 microg x hr/L, median Cmax = 0.7 microg/mL. Two children (20%) had no detectable levels of mycophenolic acid after a single mycophenolate mofetil dose, other two patients had AUC > 60 microg x hr/L. One patient had abdominal pain 1 hr after the mycophenolate mofetil dose. Twenty percent of our patients had AUC0-12h higher than the recommended value after a single mycophenolate mofetil dose, those patients should receive lower mycophenolate mofetil dose since the beginning of the transplant to avoid adverse events, and another 20% of patients had no detectable mycophenolic acid levels after a single mycophenolate mofetil dose. UGT1A9 gene polymorphisms remain to be studied in our patients, since they could explain the differences in bioavailability.


Diagnosis and treatment of disseminated intravascular coagulation in COVID-19 patients: a scoping review.
Disseminated intravascular coagulation (DIC) is noted in severe cases of coronavirus disease 2019 (COVID-19). Recently, a number of studies evaluating the diagnosis and treatment of DIC in COVID-19 patients have been reported. The aim of this study is to identify existing gaps where further research is needed on the diagnosis and treatment of DIC complicated by COVID-19. We used the PRISMA Extension for Scoping Reviews. MEDLINE, CENTRAL, WHO-ICTRP, ClinicalTrial.gov and PROSPERO were searched from their inception to 6 October 2020. Seven studies were selected; five were already published and two are ongoing. DIC was diagnosed using the International Society on Thrombosis and Hemostasis (ISTH) DIC score (n = 4) and the sepsis-induced coagulopathy (SIC) DIC score (n = 5). Seven studies examined the effectiveness of low molecular weight heparin (LMWH); of these, four studies used a prophylactic dose and five used a therapeutic dose of LMWH. A prophylactic dose of unfractionated heparin (UFH) was investigated in two studies. Studies on DIC diagnostic criteria and anticoagulants were limited to the ISTH or SIC scores and heparinoids, particularly LMWH. Further studies are needed to compare these with other available DIC scoring systems and anticoagulants.


Activation of multiple apoptotic pathways in human nasopharyngeal carcinoma cells by the prenylated isoflavone, osajin.
Osajin is a prenylated isoflavone showing antitumor activity in different tumor cell lines. The underlying mechanism of osajin-induced cancer cell death is not clearly understood. In the present study, the mechanisms of osajin-induced cell death of human nasopharyngeal carcinoma (NPC) cells were explored. Osajin was found to significantly induce apoptosis of NPC cells in a dose- and time-dependent manner. Multiple molecular effects were observed during osajin treatment including a significant loss of mitochondrial transmembrane potential, release of cytochrome c into the cytosol, enhanced expression of Fas ligand (FasL), suppression of glucose-regulated protein 78 kDa (GRP78), and activation of caspases-9, -8, -4 and -3. In addition, up-regulation of proapoptotic Bax protein and down-regulation of antiapoptotic Bcl-2 protein were also observed. Taken together, osajin induces apoptosis in human NPC cells through multiple apoptotic pathways, including the extrinsic death receptor pathway, and intrinsic pathways relying on mitochondria and endoplasmic reticulum stress. Thus, osajin could be developed as a new effective and chemopreventive compound for human NPC.


Mpox vaccination for men who have sex with men and their differential risk of exposure and infection.
Following the post-COVID-19 reopening of the society with enhanced traveling between countries, people at risk of mpox infection, notably men who have sex with men (MSM) and people living with HIV, are facing increasing threat of virus exposure. Mpox vaccination is an important public health strategy which is provided free in Hong Kong to people at higher risk of infection. Between October 2022 and January 2023, 326 and 184 MSM vaccinees from vaccination sites and HIV specialist clinics in Hong Kong, respectively, were recruited for assessing their infection risks. Apart from the urge to protect one's significant others (68%), 45% were worried about the stigmatizing mpox symptoms if infected. Compared with MSM vaccinees at vaccination site, a lower proportion of MSM vaccinees in HIV care were sexually active in the past 6 months (88% vs 97%), but a higher proportion had recent sexually transmitted infection diagnoses (19% vs 10%) and perceived considerable exposure risk in the following 6 months (40% vs 22%). There were no differences in the perceived effectiveness of mpox vaccination. If optimal supplies of mpox vaccines can be secured, a low threshold approach at vaccination site could enable MSM with different levels of behavioral risks to become protected.


Sick leaves by mental disorders:case study with public servants at an educational institution in Ceará, Brazil.
Mental disorders are one of the main causes of absenteeism in Brazil. The aim of the present study was to describe the occurrence of mental and behavioral disorders (MBD) among federal civil servants, present the data to managers and suggest measures to reduce absenteeism in this population. In the present cross-sectional study performed from January through December 2016 we analyzed medical records of employees at a public institution in the state of Ceará, Northeastern Brazil, who were granted sick leaves for MBD. The data were obtained from the Integrated Subsystem of Workers' Health Care (Subsistema Integrado de Atenção à Saúde do Servidor - SIASS) platform and the Federal Government's Transparency Portal. Mental disorders were the main cause of sick leaves along the analyzed period. Ninety-two employees were away from work for this reason, corresponding to 3% of the institution's employees and accounting for 5,081 working days lost. Mood and stress-related disorders were the most frequent causes of sick leaves. Mental disorders due to psychoactive substance use and physiological disturbances accounted for longest average number of sick leave days per employee. The results reinforce the notion that mental health and work are indissociable in regard to productivity and efficiency within federal public service. The institution's management backed the creation of a multidisciplinary service of psychological support for employees on sick leave.


The value of point-of-care tests for the detection of SARS-CoV-2 RNA or antigen in bronchoalveolar lavage fluid.
Transmission of SARS-CoV-2 from donor to recipient is a clinically relevant risk for developing severe COVID-19 after lung transplantation (LTx). This risk of iatrogenic transmission can be reduced by timely detection of viral RNA or antigen in samples of bronchoalveolar lavage (BAL) fluid obtained at the time of lung procurement. We aimed to retrospectively evaluate the detection of SARS-CoV-2 RNA or antigen in BAL fluid samples using three point-of-care tests (POCTs). BAL fluid samples came from patients hospitalized in an intensive care unit during the COVID-19 pandemic. These pandemic samples were scored as positive or negative for SARS-CoV-2 by a RT-qPCR comparator assay for orf1ab. Three commercially available POCTs were then evaluated: cobas SARS-CoV-2 & Influenza A/B assay with the cobas Liat RT-qPCR system (Roche Diagnostics), ID NOW COVID-19 and COVID-19 2.0 (Abbott), and SARS-CoV-2 Rapid Antigen Test (RAT) (Roche Diagnostics). Samples from the pre-pandemic era served as negative controls. We analyzed a total of 98 BAL fluid samples, each from a different patient: 58 positive pandemic samples (orf1ab Ct<38), 20 putatively negative pandemic samples (orf1ab Ct≥38), and 20 pre-pandemic samples. Univariate logistic regression shows that the probability of detection was highest for cobas Liat, followed by ID NOW, and then RAT. Of clinical relevance, cobas Liat detected SARS-CoV-2 RNA in 30 of the 31 positive pandemic samples that were collected within 10 days after RT-qPCR diagnosis of SARS-CoV-2 infection. None of the 20 pre-pandemic samples had a false-positive result for any POCT. POCTs enable the detection of SARS-CoV-2 RNA or antigen in BAL fluid samples and may provide additional information to decide if donor lungs are suitable for transplantation. Detection of respiratory pathogens with POCTs at the time of donor lung procurement is a potential strategy to increase safety in LTx by preventing iatrogenic transmission and severe postoperative infections.


Chronic Atmospheric Reactive Nitrogen Deposition Suppresses Biological Nitrogen Fixation in Peatlands.
Biological nitrogen fixation (BNF) represents the natural pathway by which mosses meet their demands for bioavailable/reactive nitrogen (Nr) in peatlands. However, following intensification of nitrogen fertilizer and fossil fuel use, atmospheric Nr deposition has increased exposing peatlands to Nr loading often above the ecological threshold. As BNF is energy intensive, therefore, it is unclear whether BNF shuts down when Nr availability is no longer a rarity. We studied the response of BNF under a gradient of Nr deposition extending over decades in three peatlands in the U.K., and at a background deposition peatland in Sweden. Experimental nitrogen fertilization plots in the Swedish site were also evaluated for BNF activity. In situ BNF activity of peatlands receiving Nr deposition of 6, 17, and 27 kg N ha-1 yr-1 was not shut down but rather suppressed by 54, 69, and 74%, respectively, compared to the rates under background Nr deposition of ∼2 kg N ha-1 yr-1. These findings were corroborated by similar BNF suppression at the fertilization plots in Sweden. Therefore, contribution of BNF in peatlands exposed to chronic Nr deposition needs accounting when modeling peatland's nitrogen pools, given that nitrogen availability exerts a key control on the carbon capture of peatlands, globally.


Bombyx mori nucleopolyhedrovirus-based surface display system for recombinant proteins.
We describe here the development of a 'eukaryotic display system' for heterologous proteins on the viral and host cell surfaces using Bombyx mori nucleopolyhedrovirus (BmNPV). The reporter gene gfp (green fluorescent protein) was fused to either the gp64 gene encoding the full-length BmNPV envelope protein GP64 or to its 5' region encoding only the N-terminal domain harbouring the signal sequence, and recombinant viruses expressing the corresponding fusion proteins under the strong viral polyhedrin promoter were generated. On infection of the host insect B. mori or the host-derived BmN cells with the full-length GP64-GFP virus, abundant expression of the recombinant protein and its display on the cell surface were achieved. The fusion protein was also a component of the budded virions. Thus, the BmNPV-based display system provides an alternative to the previously established Autographa californica multinucleocapsid nucleopolyhedrovirus display system. The recombinant virus expressing GFP has also been used in preliminary pathological investigations on virus infection in B. mori and provides a simple method for screening for antiviral agents.


Three-dimensional optical storage memory.
A novel three-dimensional (3-D) optical memory device is presented that allows fast random access of the information and extremely high bit densities. This device is based on two-photon writing, reading, and erasing of the information in a photochromic material embedded in a polymer matrix. Absorption and emission data show that two-photon writing and reading of information is feasible. The advantages and properties of such a 3-D optical memory are discussed.


Photodynamic therapy as an adjunct to non-surgical periodontal treatment: a randomized, controlled clinical trial.
Recent preclinical and clinical data have suggested a potential benefit of photodynamic therapy (PDT) in the treatment of periodontitis. However, there are very limited data from controlled clinical trials evaluating the effect of PDT in the treatment of periodontitis. The aim of this study was to evaluate the clinical and microbiologic effects of the adjunctive use of PDT to non-surgical periodontal treatment. Twenty-four subjects with chronic periodontitis were randomly treated with scaling and root planing followed by a single episode of PDT (test) or scaling and root planing alone (control). Full-mouth plaque score (FMPS), full-mouth bleeding score (FMBS), probing depth (PD), gingival recession, and clinical attachment level (CAL) were measured at baseline and 3 and 6 months after therapy. Primary outcome variables were changes in PD and CAL. Microbiologic evaluation of Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans), Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia (previously T. forsythensis), Treponema denticola, Parvimonas micra (previously Peptostreptococcus micros or Micromonas micros), Fusobacterium nucleatum, Campylobacter rectus, Eubacterium nodatum, Eikenella corrodens, and Capnocytophaga spp. was performed at baseline and 3 and 6 months following therapy by using a commercially available polymerase chain reaction test. At 3 and 6 months after treatment, there were no statistically significant differences between the groups with regard to CAL, PD, FMPS, or microbiologic changes. At 3 and 6 months, a statistically significantly greater improvement in FMBS was found in the test group. The additional application of a single episode of PDT to scaling and root planing failed to result in an additional improvement in terms of PD reduction and CAL gain, but it resulted in a significantly higher reduction in bleeding scores compared to scaling and root planing alone.


A role for protein kinase CbetaI in the regulation of Ca2+ entry in Jurkat T cells.
T cell activation leading to cytokine production and cellular proliferation involves a regulated increase and subsequent decrease in the intracellular concentration of Ca2+ ([Ca2+]i). While much is understood about agonist-induced increases in [Ca2+]i, less is known about down-regulation of this pathway. Understanding the mechanism of this down-regulation is critical to the prevention of cell death that can be the consequence of a sustained elevation in [Ca2+]i. Protein kinase C (PKC), activated by the diacylglycerol produced as a consequence of T cell receptor engagement, has long been presumed to be involved in this down-regulation, although the precise mechanism is not wholly clear. In this report we demonstrate that activation of PKC by phorbol esters slightly decreases the rate of Ca2+ efflux from the cytosol of Jurkat T cells following stimulation through the T cell receptor or stimulation in a receptor-independent manner by thapsigargin. On the other hand, phorbol ester treatment dramatically reduces the rate of Ca2+ influx following stimulation. Phorbol ester treatment is without an effect on Ca2+ influx in a different T cell line, HSB. Down-regulation of PKCbetaI expression by 18-h phorbol ester treatment is associated with a loss of the response to acute phorbol ester treatment in Jurkat cells, suggesting that PKCbetaI may be the isozyme responsible for the effects on Ca2+ influx. Electroporation of an anti-PKCbetaI antibody, but not antibodies against PKCalpha or PKCgamma, led to an increase in the rate of Ca2+ influx following stimulation. Taken together, these data suggest that PKCbetaI may be a component of the down-regulation of increases in [Ca2+]i associated with Jurkat T cell activation.


The diagnosis of multiple sclerosis and the clinical subtypes.
The diagnosis of multiple sclerosis (MS) requires objective findings referable to the central nervous system. A wide differential diagnosis often has to be considered. Magnetic resonance imaging and electrophysiologic and cerebrospinal fluid studies can all contribute to an early definitive diagnosis. The McDonald diagnostic criteria for MS (2005) are the currently recognized MS diagnostic criteria. The clinical subtypes of MS and their diagnosis are discussed in this article. Being informed of the diagnosis may be a stressful experience for the patient and this is also dealt with.


The structure of abelsonite.
Abelsonite, a C(31) nickel-porphyrin of the deoxophylloerythroetioporphyrin type, is shown to have methyl groups in the 2, 3, 7, 12, and 18 positions and ethyl groups in the 8 and 17 positions by high-resolution, high-field (1)H nuclear magnetic resonance and nuclear Overhauser effect studies. Removal of the nickel by treatment with methanesulfonic acid permitted confirmation of the structure on the free base porphyrin and demonstrated structural integrity under the conditions required for demetallation. The structure is best accounted for geochemically by the hypothesis that abelsonite is derived from a chlorophyll.


Objective and subjective sleep quality in premenopausal, perimenopausal, and postmenopausal women in the Wisconsin Sleep Cohort Study.
Assess objectively measured sleep quality in premenopausal, perimenopausal, and postmenopausal women. Observational epidemiology study. Community-based. Probability sample of 589 premenopausal, perimenopausal, and postmenopausal women recruited from state employee records. None. Menopausal status was determined by menstrual history, surgical history, and use of hormone replacement therapy. Sleep quality was objectively measured by full in-laboratory polysomnography and by self-reported sleep problems. Linear and logistic regression were used to estimate associations adjusted for potential confounding factors. Sleep quality was not worse in perimenopausal or postmenopausal women, compared with premenopausal women. To the contrary, postmenopausal woman had more deep sleep (16% vs 13% stages 3/4, P < 0.001) and significantly longer total sleep time (388 minutes vs 374 minutes, P = 0.05). Menopausal status was moderately related to self-reported dissatisfaction with sleep but was not consistently associated with symptoms of insomnia or sleepiness. Menopause is not associated with diminished sleep quality measured by polysomnography. Although perimenopausal and postmenopausal women, relative to premenopausal women, were less satisfied with their sleep, menopause was not a strong predictor of specific sleep-disorder symptoms. Symptoms and signs of sleep abnormalities in midlife women should not be attributed primarily to menopause before ruling out underlying sleep disorders.


Photosensitivity associated with fluorouracil, prochlorperazine, and topical tretinoin.
A woman newly diagnosed with colon cancer began chemotherapy with fluorouracil and leucovorin. Chemotherapy was given daily for 5 days with prochlorperazine premedication and was well tolerated. The patient continued her previous drug regimen during and after chemotherapy, which consisted of hormone replacement therapy, chloroquine, insulin, multivitamin, and tretinoin topical cream. Several days after the end of the first cycle of chemotherapy she experienced a dramatic photosensitivity reaction. Tretinoin application was discontinued, and she recovered. All other drugs remained unchanged. The patient was treated with five additional cycles of chemotherapy. She did not experience the reaction with any potentially photosensitizing agents again; only when the specific sequence and drug combination was administered in the first cycle.


[Alternative therapy. Chances in Bechterew disease?].
The Bechterew disease is inherited but the illness is triggered by outer influences. We are therefore not able to do causal treatment. In consequence a lot of alternative remedies like the extract of Thymus and Vitamin E have been tried. If the Bechterew disease shows more or less an ossifying progress they do not show any effect. If the issue is inflammatory Vitamin E could act as radicalintercepter. The extract of Thymus is only a placebo.


Evaluation of recent very efficient wide-pore stationary phases for the reversed-phase separation of proteins.
In the present contribution, columns packed with fully porous widepore 1.7μm particles (Acquity BEH300) and widepore core-shell 3.6μm particles (Aeris WP) were evaluated for the separation of model and therapeutic proteins of varying sizes, hydrophobicity and isoelectric points. Two types of bonding were compared, namely C4 and C18 in a systematic way. The kinetic performance of these stationary phases was evaluated in a previous paper hence this new work focuses on their retention behaviour, loading capacity and selectivity. Using the Tanaka tests, model proteins, and other confirmatory experiments, it is highly probable that with proteins, strong interaction mechanisms were predominant on the Aeris WP while the hydrophobic interaction was the driving force of the retention on the Acquity BEH300 material. This explained why, despite the lower pore volume of the Aeris WP material, the apparent retention factors of proteins possessing both hydrophobic and charged amino acids residues were very close on the four investigated columns. In terms of peak widths, values for proteins were similar for all the tested stationary phases, despite the probable strong ion exchange mechanisms of Aeris WP column. This could be explained by the excellent mass transfer characteristics afforded by the thin porous layer (∼0.2μm) at the surface of the particle which probably compensates for the slow secondary ionic interaction kinetics. The loading capacity was also evaluated on all the four widepore columns, using model proteins. On average, approximately 2-4 times higher amount of proteins can be injected on the fully porous BEH300 compared to the core-shell Aeris WP columns when avoiding 10% change in peak width or in tailing. However, this result could be strongly influenced by the nature and shape of the protein, its hydrophobicity, folding, size and number of charges. Finally, all of these columns were employed for the highly efficient separation of a therapeutic protein (interferon-α-2A) and some closely related proteins and showed excellent performance and selectivity. This result confirms that RPLC gained interest in the biopharmaceutical field as it provides significantly better peak widths than size-exclusion or ion-exchange and inherent compatibility with MS.


Generalizable Deep Learning Method for Suppressing Unseen and Multiple MRI Artifacts Using Meta-learning.
Magnetic Resonance (MR) images suffer from various types of artifacts due to motion, spatial resolution, and under-sampling. Conventional deep learning methods deal with removing a specific type of artifact, leading to separately trained models for each artifact type that lack the shared knowledge generalizable across artifacts. Moreover, training a model for each type and amount of artifact is a tedious process that consumes more training time and storage of models. On the other hand, the shared knowledge learned by jointly training the model on multiple artifacts might be inadequate to generalize under deviations in the types and amounts of artifacts. Model-agnostic meta-learning (MAML), a nested bi-level optimization framework is a promising technique to learn common knowledge across artifacts in the outer level of optimization, and artifact-specific restoration in the inner level. We propose curriculum-MAML (CMAML), a learning process that integrates MAML with curriculum learning to impart the knowledge of variable artifact complexity to adaptively learn restoration of multiple artifacts during training. Comparative studies against Stochastic Gradient Descent and MAML, using two cardiac datasets reveal that CMAML exhibits (i) better generalization with improved PSNR for 83% of unseen types and amounts of artifacts and improved SSIM in all cases, and (ii) better artifact suppression in 4 out of 5 cases of composite artifacts (scans with multiple artifacts).Clinical relevance- Our results show that CMAML has the potential to minimize the number of artifact-specific models; which is essential to deploy deep learning models for clinical use. Furthermore, we have also taken another practical scenario of an image affected by multiple artifacts and show that our method performs better in 80% of cases.


Bone sialoprotein mediates human endothelial cell attachment and migration and promotes angiogenesis.
Bone sialoprotein (BSP) is a secreted glycoprotein primarily found in sites of biomineralization. Recently, we demonstrated that BSP is strongly upregulated in osteotropic cancers and particularly those that exhibit microcalcifications. BSP contains an Arg-Gly-Asp (RGD) motif found in other adhesive molecules that interact with cellular integrins. In bone, BSP has been shown to mediate the attachment of osteoblasts and osteoclasts via alpha(v)beta(3) integrin receptors. Ligands for alpha(v)beta(3) integrin are considered to play a central role during angiogenesis. Therefore, we used human umbilical vein endothelial cells (HUVECs) to study the potential role of BSP in angiogenesis. We found that purified eukaryotic recombinant human BSP (rhBSP) is able to promote both adhesion and chemotactic migration of HUVECs in a dose-dependent manner. These interactions involve HUVEC alpha(v)beta(3) integrin receptors and the RGD domain of BSP. Indeed, HUVECs attach to a recombinant BSP fragment containing the RGD domain, whereas this response is not observed with the same fragment in which RGD has been mutated to Lys-Ala-Glu (KAE). A cyclic RGD BSP peptide inhibits both adhesion and migration of HUVECs to rhBSP. Moreover, anti-alpha(v)beta(3) but not anti-alpha(v)beta(5) monoclonal antibodies also prevent BSP-mediated adhesion and migration of HUVECs. We observed that both rhBSP and the RGD BSP recombinant fragment stimulated ongoing angiogenesis on the chorioallantoic chick membrane assay. BSP angiogenic activity was inhibited by anti-alpha(v)beta(3) antibody, and the KAE BSP fragment was inactive. Our findings represent the first report implicating BSP in angiogenesis. BSP could play a critical role in angiogenesis associated with bone formation and with tumor growth and metastatic dissemination.


Peripheral Nerve Stimulation for Refractory Trigeminal Pain: Recent Single-Institution Case Series With Long-Term Follow-Up and Review of the Literature.
Peripheral neurostimulation (PNS) for medically refractory trigeminal pain is an emerging alternative to traditional surgical approaches, with safety and efficacy demonstrated in several retrospective series and a prospective trial currently in progress. Many existing studies suffer from relatively small numbers and short or inconsistent follow-up, making balanced treatment assessment difficult. Consecutive cases of trial and permanent placement of trigeminal branch stimulation electrodes by a single surgeon from May 2014 through January 2019 were retrospectively reviewed from a prospectively collected database, following the PROCESS guidelines for surgical case series. Outcomes were assessed at six months and at last follow-up. Ninteen patients underwent trial electrode placement, with 15 patients undergoing permanent system placement. The most common diagnoses were idiopathic trigeminal neuralgia Type 2 (N = 8) and trigeminal neuropathic pain (N = 7). Median follow-up was 14 months (range 6-58 months). At last follow-up, 12 of 15 implanted patients (80%) were still receiving stimulation, with mean (median) pain reduction of 52.3% (47.5%). Infection and revision rates were high, although erosion and migration, which have typically plagued trigeminal PNS surgery, did not occur. Implanted systems were well-tolerated, with excellent cosmetic outcomes and high patient satisfaction that proved durable over long follow-up. We present a single-institution series of PNS for complex craniofacial pain involving the trigeminal nerve. The procedure is safe, effective and durable over at least one year in the large majority of a well-selected patient population.


[Frequency of decreased renal function between patients treated with brand and generic products of vancomycin hydrochloride injection].
The frequency of decreased renal function was compared between patients treated with brand and generic products of vancomycin injection (VCM) in a retrospective manner based on the clinical examination records archived in Okayama University Hospital. A total of 122 patients were found to have been solely treated with vancomycin injection for MRSA infection, and their examination records were analyzed. The renal function of those patients was evaluated based on the serum creatinine concentration (SCr), and patients whose SCr was maximally elevated above the defined upper limit of the normal range (1.20 mg/dl for males and 0.96 mg/dl for females) were considered to show decreased renal function. Although the amount of VCM administered to patients was larger in the case of generic rather than brand products, the percentage of patients whose renal function was decreased during VCM treatment was not significantly different between the VCM products, in which 2 among 62 patients receiving the brand product and 4 among 60 receiving the generic product were reported to show decreased renal function. It was additionally revealed that 3 of those 4 patients with a decreased renal function related to the generic product were not treated as instructed by the package insert, and their trough VCM concentration exceeded the recommended level of 10 microg/ml. With these findings, the brand and generic VCM products are considered to be similar regarding the adverse effect of decreasing renal function.


Inhibition of fatty acid metabolism by etomoxir or TOFA suppresses murine dendritic cell activation without affecting viability.
Objective: Dendritic cells (DCs) are important players in immunity against pathogens, but overactive DCs have been implicated in autoimmune diseases, like lupus, in which a paucity of targeted therapies remains. Recent research shows that DCs upregulate their immunometabolism when activating. We explored whether modulating fatty acid (FA) metabolism needed for oxidative phosphorylation can affect the activation of two main DC subsets. Material and methods: Sorted murine plasmacytoid DCs (pDCs) and conventional DCs (cDCs), generated in FLT3-L medium, were treated with etomoxir, an inhibitor of FA oxidation, or TOFA, an inhibitor of FA synthesis, then stimulated with TLR9 agonist CpGA. Surface activation markers and viability were analyzed by flow cytometry, cytokine, and chemokine production and were measured by ELISA. Results: Modulation of FA metabolism suppressed the upregulation of costimulatory molecules and the production of proinflammatory cytokine IL-6 and type I Interferon-dependent chemokine CXCL10 by both subsets of DCs, without affecting DC viability, neither of resting DCs or upon activation. Etomoxir inhibited pDCs at lower doses than cDCs, suggesting that pDCs may be more susceptible to FA metabolic modulation. Conclusions: Both cDCs, the primary antigen presenting cell, and pDCs, the primary type I IFN producer, exhibit a suppressed ability to activate but normal viability when their FA metabolism is inhibited by etomoxir or TOFA. Our findings indicate that FA metabolism plays an important role in the activation of both pDCs and cDCs and suggest that its modulation is an exploitable therapeutic target to suppress DC activation in inflammation or autoimmunity.


[Immune and nonimmune variants of acute pancreatitis].
The article gives an analysis of humoral immunity to structural and secretory components of the pancreas in acute pancreatitis. Based on the distinctions revealed the authors determined two variants of the disease--the immune and nonimmune variants which is of great significance in diagnostics and treatment of acute pancreatitis, for the administration of immunocorrecting medicines in particular.


Design rules for charge-transport efficient host materials for phosphorescent organic light-emitting diodes.
The use of blue phosphorescent emitters in organic light-emitting diodes (OLEDs) imposes demanding requirements on a host material. Among these are large triplet energies, the alignment of levels with respect to the emitter, the ability to form and sustain amorphous order, material processability, and an adequate charge carrier mobility. A possible design strategy is to choose a π-conjugated core with a high triplet level and to fulfill the other requirements by using suitable substituents. Bulky substituents, however, induce large spatial separations between conjugated cores, can substantially reduce intermolecular electronic couplings, and decrease the charge mobility of the host. In this work we analyze charge transport in amorphous 2,8-bis(triphenylsilyl)dibenzofuran, an electron-transporting material synthesized to serve as a host in deep-blue OLEDs. We show that mesomeric effects delocalize the frontier orbitals over the substituents recovering strong electronic couplings and lowering reorganization energies, especially for electrons, while keeping energetic disorder small. Admittance spectroscopy measurements reveal that the material has indeed a high electron mobility and a small Poole-Frenkel slope, supporting our conclusions. By linking electronic structure, molecular packing, and mobility, we provide a pathway to the rational design of hosts with high charge mobilities.


Family practice referral patterns in a health maintenance organization.
In one year, 3.85 percent of the 12,228 patient visits to a family practice clinic resulted in referral. The members of the health maintenance organization (HMO) had a referral rate of 4.46 percent, while fee-for-service patients had a referral rate of 3.19 percent. The fee-for-service patient population was similar to the HMO group, except for the significantly different rate of referral. Comparison of the referral patterns suggests that this difference is influenced by economic factors.


B cell antigen receptor-evoked calcium influx is enhanced in CD22-deficient B cell lines.
CD22 is a B cell membrane glycoprotein that, upon Ag receptor engagement, becomes rapidly tyrosyl phosphorylated and associates with several signaling molecules including Lyn, Syk, PLCgamma1, and the protein-tyrosine phosphatase, SHP-1. Two allelic forms of murine CD22 exist: CD22.1 is expressed in strains such as NZB and DBA/2, whereas CD22.2 is expressed in BALB/c and most other strains. WEHI-231 cells, which derive from a (BALB/c x NZB)F1 mouse, express one copy of each allele. Previous studies have proposed both positive and negative functions for CD22. We explored the role of CD22 in surface IgM Ag receptor signal transduction by examining signaling in three clonally independent WEHI-231 variants that have lost expression of the CD22.2 allele. This experimental design allowed us to assess the signaling functions of CD22 independent of its developmental role. These variants, which exhibit a 50% reduction of total surface CD22, are hyper-responsive to Ag receptor stimulation: several cellular proteins are hyperphosphorylated on tyrosyl residues and surface IgM-mediated calcium flux is markedly increased. Interestingly, the increased calcium response observed in CD22-deficient cells is due largely to enhanced calcium influx. Reconstitution of CD22 expression reduces these changes. The SHP-1/CD22 association is reduced in CD22-deficient cell lines and is restored by re-expression of CD22. Our results demonstrate that CD22 is a cell autonomous negative regulator of B cell Ag receptor signaling, and suggest that it regulates calcium entry via a mechanism downstream from or independent of calcium release from intracellular stores.


Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized trials.
Recent reports suggest altered antithrombotic efficacy and higher risk of bleeding with new oral anticoagulants (NOACs) in patients with renal insufficiency. A meta-analysis was performed to evaluate the efficacy and safety with recommended doses of NOAC compared with conventional treatment in patients with renal insufficiency. PubMed, Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases were searched from January 1, 2001 through March 23, 2014. Randomized controlled trials that compared NOACs (rivaroxaban, apixaban, and dabigatran) with comparators (vitamin K antagonist/warfarin, low molecular weight heparin, aspirin, placebo) were selected. We defined moderate renal insufficiency as creatinine clearance (estimated glomerular filtration rate [eGFR]) of 30-49 mL/min, and mild renal insufficiency as eGFR 50-79 mL/min. There were 40,693 patients with renal insufficiency in 10 trials. Compared with other anticoagulants in patients with mild renal insufficiency there was significantly less major or clinically relevant nonmajor bleeding (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.72-0.90) and stroke or systemic embolism (OR, 0.70; 95% CI, 0.54-0.92) with NOACs. Using random effects meta-analysis, there was significantly less stroke or systemic embolism (OR, 0.72; 95% CI, 0.57-0.92) and a trend toward less major or clinically relevant nonmajor bleeding (OR, 0.82; 95% CI, 0.59-1.14) with the NOACs among patients with moderate renal insufficiency, and this became statistically significant when evaluated using a fixed effects model. NOACs showed efficiency comparable with conventional anticoagulants for prevention of venous thromboembolism or related mortality. In patients with renal insufficiency, recommended doses of novel anticoagulants are noninferior and relatively safe compared with conventional anticoagulants.


Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer's disease: prelude to a clinical trial.
The Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aβ peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aβ antibodies failed to slow cognitive decline in mild to moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. Using an AD mouse model (Tg2576), we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. We found that Lu AF20513 induces robust "non-self" T-cell responses and the production of anti-Aβ antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or cerebral amyloid angiopathy. A single immunization with Lu AF20513 induced strong humoral immunity in mice with preexisting memory T-helper cells. In addition, Lu AF20513 induced strong humoral responses in guinea pigs and monkeys. These data support the translation of Lu AF20513 to the clinical setting with the aims of: (1) inducing therapeutically potent anti-Aβ antibody responses in patients with mild AD, particularly if they have memory T-helper cells generated after immunizations with conventional tetanus toxoid vaccine, and (2) preventing pathological autoreactive T-cell responses.


Comparison of the distribution patterns of tenascin and alkaline phosphatase in developing teeth, cartilage, and bone of rats and mice.
Tenascin is a glycoprotein of the extracellular matrix, which has been associated with differentiation of hard tissue forming cells. Alkaline phosphatase (AP) is involved in calcification, and it has also been suggested to function in cell differentiation. We have compared the distributions of tenascin and AP in the developing skull and teeth of embryonic and growing rats and mice. Tenascin was localized by immuno-Peroxidase and AP by enzyme histochemical staining of tissue sections. Both tenascin and AP were largely restricted to bone, cartilage, and teeth. In cartilage, tenascin was expressed in the perichondrium, whereas AP activity was detected only in the hypertrophic cartilage. In growing intramembranous bone, tenascin and AP were expressed in the periosteum and endosteum. AP activity was restricted to the inner layer of the periosteum, whereas tenascin expression extended to the more superficial layers. In bud-staged teeth tenascin but no AP activity was localized in the condensing mesenchymal cells around the epithelial bud. At the bell stage both tenascin and AP activity were localized in the cuspal mesenchyme, and the intensity of staining decreased towards the cervical region. In summary, tenascin was present at all sites of AP activity except in the epithelial cells of the enamel organ and the hypertrophic cartilage of the mandibular condyle. In mesenchymal tissues tenascin was more widely distributed than AP. It can be suggested that tenascin has functions at earlier stages of hard tissue formation than AP.


The potential for measles transmission in England.
Since the schools vaccination campaign in 1994, measles has been eliminated from England. Maintaining elimination requires low susceptibility levels to keep the effective reproduction number R below 1. Since 1995, however, MMR coverage in two year old children has decreased by more than 10%. Quarterly MMR coverage data for children aged two and five years resident in each district health authority in England were used to estimate susceptibility to measles by age. The effective reproduction numbers for each district and strategic health authority were calculated and possible outbreak sizes estimated. In 2004/05, about 1.9 million school children and 300,000 pre-school children were recorded as incompletely vaccinated against measles in England, including more than 800,000 children completely unvaccinated. Based on this, approximately 1.3 million children aged 2-17 years were susceptible to measles. In 14 of the 99 districts, the level of susceptibility is sufficiently high for R to exceed 1, indicating the potential for sustained measles transmission. Eleven of these districts are in London. Our model suggests that the potential exists for an outbreak of up to 100,000 cases. These results are sensitive to the accuracy of reported vaccination coverage data. Our analysis identified several districts with the potential for sustaining measles transmission. Many London areas remain at high risk even allowing for considerable under-reporting of coverage. Primary care trusts should ensure that accurate systems are in place to identify unimmunised children and to offer catch-up immunisation for those not up to date for MMR.


Multiplex-Polymerase Chain Reaction for Detecting Microdeletions in The Azoospermia Factor Region of Y Chromosome in Iranian Couples with Non-Obstructive Infertility and Recurrent Pregnancy Loss.
Approximately 15% of couples are infertile with the male factor explaining approximately 50% of the cases. One of the main genetic factors playing a role in male infertility is Y chromosomal microdeletions within the proximal long arm of the Y chromosome (Yq11), named the azoospermia factor (AZF) region. Recent studies have shown there is a potential connection between deletions of the AZF region and recurrent pregnancy loss (RPL). The aim of this study is to examine this association by characterizing AZF microdeletions in two infertile groups: in men with non-obstructive infertility and in men with wives displaying RPL. In this is a case-control study, genomic DNA was extracted from 80 male samples including 40 non-obstructive infertile men, 20 males from couples with RPL and 20 fertile males as controls. Multiplex polymerase chain reaction was used to amplify 19 sequence tagged sites (STS) to detect AZF microdeletions. Differences between the case and control groups were evaluated by two-tailed unpaired t test. P<0.05 were considered statistically significant. Only one subject was detected to have Y chromosome microdeletions in SY254, SY157 and SY255 among the 40 men with non-obstructive infertility. No microdeletion was detected in the males with wives displaying RPL and in 20 control males. Y chromosome microdeletion was neither significantly associated with non-obstructive infertility (P=0.48) nor with recurrent pregnancy loss. Performing Testing for Y chromosome microdeletions in men with non-obstructive infertility and couples with RPL remains inconclusive in this study.


Estrogen, androgen, glucocorticoid, and progesterone receptors in progestin-induced regression of human breast cancer.
A study was made of basic mechanisms involved in regression of breast cancer exposed to high levels of synthetic progestins. The possibility that progestins act on breast cancer by way of the progesterone receptor mechanism and subsequent increase of estradiol 17 beta-dehydrogenase activity could not be confirmed in this investigation. It is demonstrated that the progestins megestrol acetate and medroxyprogesterone acetate are strong competitors for steroids which bind specifically to androgen, glucocorticoid, and progesterone receptors, indicating that the progestins are able to bind to these receptors with high affinity. In contrast, these progestins do not compete with estradiol for estrogen receptor binding. In 34 patients with progressive metastatic breast cancer, results of receptor studies have been correlated with clinical response during treatment with megestrol acetate. Statistically, regressions were significantly associated with tumors containing large amounts of androgen receptors. Clinical correlation with the quantities of glucocorticoid receptor was weak, while such correlations with estrogen and progesterone receptors were absent. However, we did demonstrate relationships between the quantities of the various receptors in breast cancer. Tumors containing a large amount of androgen receptors also generally contain estrogen receptors. It might be that a favorable response to progestins is confined to the group of patients with hormone-responsive breast cancers, as such characterized by the presence of estrogen receptors, and that within this group the actual androgen receptor levels determine response.


Prophylactic irradiation in bronchogenic small cell anaplastic carcinoma. A comparative trial of localized versus extensive radiotherapy including prophylactic brain irradiation in patients receiving combination chemotherapy.
A total of 114 patients with bronchogenic small cell anaplastic carcinoma and staged as having regional disease all underwent combination chemotherapy consisting of CCNU, cyclophosphamide, and methotrexate. They were randomized to receive either radiotherapy to the primary tumor and regional lymph nodes (4000 rad) or extensive radiotherapy, which included the brain, adrenals, and upper retroperitoneal lymph nodes. Fifteen patients were free of disease after 18 months of chemotherapy and the treatment was discontinued. Only 3 patients subsequently relapsed. No difference was observed between the two groups of patients in median survival time, response rate, duration of response or relapse pattern, including the frequency of brain metastasis.


Optimizing the Rigid or Compliant Behavior of a Novel Parallel-Actuated Architecture for Exoskeleton Robot Applications.
The purpose of this work is to optimize the rigid or compliant behavior of a new type of parallel-actuated robot architecture developed for exoskeleton robot applications. This is done in an effort to provide those that utilize the architecture with the means to maximize, minimize, or simply adjust its stiffness property so as to optimize it for particular tasks, such as augmented lifting or impact absorption. This research even provides the means to produce non-homogeneous stiffness properties for applications that may require non-homogeneous dynamic behavior. In this work, the new architecture is demonstrated in the form of a shoulder exoskeleton. An analytical stiffness model for the shoulder exoskeleton is created and validated experimentally. The model is then used, along with a method of bounded nonlinear multi-objective optimization to configure the parallel substructures for desired rigidity, compliance or nonhomogeneous stiffness behavior. The stiffness model and its optimization can be applied beyond the shoulder to any embodiment of the new parallel architecture, including hip, wrist and ankle robot applications. In order to exemplify this, we present the rigidity optimization for a theoretical hip exoskeleton.


Structural Cerebral Network Differences in Prodromal Alzheimer's Disease and Prodromal Dementia with Lewy Bodies.
Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) have long prodromal phases without dementia. However, the patterns of cerebral network alteration in this early stage of the disease remain to be clarified. Participants were 48 patients with mild cognitive impairment (MCI) due to AD (MCI-AD), 18 patients with MCI with DLB (MCI with Lewy bodies: MCI-LB), and 23 healthy controls who underwent a 1.5-Tesla magnetic resonance imaging scan. Cerebral networks were extracted from individual T1-weighted images based on the intracortical similarity, and we estimated the differences of network metrics among the three diagnostic groups. Whole-brain analyses for degree, betweenness centrality, and clustering coefficient images were performed using SPM8 software. The patients with MCI-LB showed significant reduction of degree in right putamen, compared with healthy subjects. The MCI-AD patients showed significant lower degree in left insula and bilateral posterior cingulate cortices compared with healthy subjects. There were no significant differences in small-world properties and in regional gray matter volume among the three groups. We found the change of degree in the patients with MCI-AD and with MCI-LB, compared with healthy controls. These findings were consistent with the past single-photon emission computed tomography studies focusing on AD and DLB. The disease-related difference in the cerebral neural network might provide an adjunct biomarker for the early detection of AD and DLB.


Prediction of R5, X4, and R5X4 HIV-1 coreceptor usage with evolved neural networks.
The HIV-1 genome is highly heterogeneous. This variation affords the virus a wide range of molecular properties, including the ability to infect cell types, such as macrophages and lymphocytes, expressing different chemokine receptors on the cell surface. In particular, R5 HIV-1 viruses use CCR5 as co-receptor for viral entry, X4 viruses use CXCR4, whereas some viral strains, known as R5X4 or D-tropic, have the ability to utilize both co-receptors. X4 and R5X4 viruses are associated with rapid disease progression to AIDS. R5X4 viruses differ in that they have yet to be characterized by the examination of the genetic sequence of HIV-1 alone. In this study, a series of experiments was performed to evaluate different strategies of feature selection and neural network optimization. We demonstrate the use of artificial neural networks trained via evolutionary computation to predict viral co-receptor usage. The results indicate identification of R5X4 viruses with predictive accuracy of 75.5%.


Piloting a new method to estimate action thresholds in medicine through intuitive weighing.
In clinical decision-making, physicians take actions such as prescribing treatment only when the probability of disease is sufficiently high. The lowest probability at which the action will be considered, is the action threshold. Such thresholds play an important role whenever decisions have to be taken under uncertainty. However, while several methods to estimate action thresholds exist, few methods give satisfactory results or have been adopted in clinical practice. We piloted the adapted nominal group technique (aNGT), a new prescriptive method based on a formal consensus technique adapted for use in clinical decision-making. We applied this method in groups of postgraduate students using three scenarios: treat for rifampicin-resistant tuberculosis (RR-TB), switch to second-line HIV treatment and isolate for SARS-CoV-2 infection. The participants first summarise all harms of wrongly taking action when none is required and wrongly not taking action when it would have been useful. Then they rate the statements on these harms, discuss their importance in the decision-making process, and finally weigh the statements against each other. The resulting consensus threshold is estimated as the relative weights of the harms of the false positives divided by the total harm, and averaged out over participants. In some applications, the thresholds are compared with an existing method based on clinical vignettes. The resulting action thresholds were just over 50% for RR-TB treatment, between 20% and 50% for switching HIV treatment and 43% for COVID-19 isolation. These results were considered acceptable to all participants. Between sessions variation was low for RR-TB and moderate for HIV. Threshold estimates were moderately lower with the method based on clinical vignettes. The aNGT gives sensible results in our pilot and has the potential to estimate action thresholds, in an efficient manner, while involving all relevant stakeholders. Further research is needed to study the value of the method in clinical decision-making and its ability to generate acceptable thresholds that stakeholders can agree on.


HIV-infected children in rural Zambia achieve good immunologic and virologic outcomes two years after initiating antiretroviral therapy.
Many HIV-infected children in sub-Saharan Africa reside in rural areas, yet most research on treatment outcomes has been conducted in urban centers. Rural clinics and residents may face unique barriers to care and treatment. A prospective cohort study of HIV-infected children was conducted between September 2007 and September 2010 at the rural HIV clinic in Macha, Zambia. HIV-infected children younger than 16 years of age at study enrollment who received antiretroviral therapy (ART) during the study were eligible. Treatment outcomes during the first two years of ART, including mortality, immunologic status, and virologic suppression, were assessed and risk factors for mortality and virologic suppression were evaluated. A total of 69 children entered the study receiving ART and 198 initiated ART after study enrollment. The cumulative probabilities of death among children starting ART after study enrollment were 9.0% and 14.4% at 6 and 24 months after ART initiation. Younger age, higher viral load, lower CD4+ T-cell percentage and lower weight-for-age z-scores at ART initiation were associated with higher risk of mortality. The mean CD4(+) T-cell percentage increased from 16.3% at treatment initiation to 29.3% and 35.0% at 6 and 24 months. The proportion of children with undetectable viral load increased to 88.5% and 77.8% at 6 and 24 months. Children with longer travel times (≥ 5 hours) and those taking nevirapine at ART initiation, as well as children who were non-adherent, were less likely to achieve virologic suppression after 6 months of ART. HIV-infected children receiving treatment in a rural clinic experienced sustained immunologic and virologic improvements. Children with longer travel times were less likely to achieve virologic suppression, supporting the need for decentralized models of ART delivery.


Multifocus confocal Raman microspectroscopy for fast multimode vibrational imaging of living cells.
We have developed a multifocus confocal Raman microspectroscopic system for the fast multimode vibrational imaging of living cells. It consists of an inverted microscope equipped with a microlens array, a pinhole array, a fiber bundle, and a multichannel Raman spectrometer. Forty-eight Raman spectra from 48 foci under the microscope are simultaneously obtained by using multifocus excitation and image-compression techniques. The multifocus confocal configuration suppresses the background generated from the cover glass and the cell culturing medium so that high-contrast images are obtainable with a short accumulation time. The system enables us to obtain multimode (10 different vibrational modes) vibrational images of living cells in tens of seconds with only 1 mW laser power at one focal point. This image acquisition time is more than 10 times faster than that in conventional single-focus Raman microspectroscopy.


Qigong Effects on Heart Rate Variability and Peripheral Vasomotor Responses.
Population aging is occurring worldwide, and preventing cardiovascular event in older people is a unique challenge. The aim of this study was to examine the effects of a 12-week qigong (eight-form moving meditation) training program on the heart rate variability and peripheral vasomotor response of middle-aged and elderly people in the community. This was a quasi-experimental study that included the pre-test, post-test, and nonequivalent control group designs. Seventy-seven participants (experimental group = 47; control group = 30) were recruited. The experimental group performed 30 min of eight-form moving meditation 3 times per week for 12 weeks, and the control group continued their normal daily activities. After 12 weeks, the interaction effects indicated that compared with the control group, the experimental group exhibited significantly improved heart rate variability and peripheral vasomotor responses.


Male vole urine changes luteinizing hormone-releasing hormone and norepinephrine in female olfactory bulb.
Female prairie voles (Microtus ochrogaster) exposed to a single drop of male urine on the upper lip showed changes in concentrations of luteinizing hormone-releasing hormone (LHRH) and norepinephrine in olfactory bulb tissue; no such changes occurred in dopamine concentration. The changes were measured in the posterior but not the anterior olfactory bulb tissue of females within 1 hour after they were exposed to urine. These females also showed rapid increases in serum concentrations of luteinizing hormone. Females exposed to water on the upper lip showed none of these changes. These results suggest that in this species LHRH and norepinephrine in the olfactory bulb may mediate luteinizing hormone release in response to external (pheromonal) chemical cues.


Human serum Paraoxonase/Arylesterase's retained hydrophobic N-terminal leader sequence associates with HDLs by binding phospholipids : apolipoprotein A-I stabilizes activity.
In serum, human paraoxonase/arylesterase (PON1) is found exclusively associated with high density lipoprotein (HDL) and contributes to its antiatherogenic properties by inhibiting low density lipoprotein (LDL) oxidation. Difficulties in purifying PON1 from apolipoprotein A-I (apoA-I) suggested that PON1's association with HDL may occur through a direct binding between these 2 proteins. An unusual property of PON1 is that the mature protein retains its hydrophobic N-terminal signal sequence. By expressing in vitro a mutant PON1 with a cleavable N-terminus, we demonstrate that PON1 associates with lipoproteins through its N-terminus by binding phospholipids directly rather than binding apoA-I. Nonetheless, apoA-I stabilized arylesterase activity more than did phospholipid alone, apoA-II, or apoE. Consequently, we studied the role of apoA-I in PON1 expression and HDL association in mice genetically deficient in apoA-I. Though present in HDL fractions at decreased levels, PON1 arylesterase activity was less stable than in control mice. Furthermore, PON1 could be competitively removed from HDL by phospholipids, suggesting that PON1's retained N-terminal peptide allows transfer of the enzyme between phospholipid surfaces. Thus, our data suggest that PON1 is stabilized by apoA-I, and its binding to HDL and physiological distribution are dependent on the direct binding of the retained hydrophobic N-terminus to phospholipids optimally presented in association with apoA-I.


Moral distress in midwifery practice: A concept analysis.
Research suggests that the incidence of moral distress experienced by health professionals is significant and increasing, yet the concept lacks clarity and remains largely misunderstood. Currently, there is limited understanding of moral distress in the context of midwifery practice. The term moral distress was first used to label the psychological distress experienced following complex ethical decision-making and moral constraint in nursing. The term is now used across multiple health professions including midwifery, nursing, pharmacy and medicine, yet is used cautiously due to confusion regarding its theoretical and contextual basis. The aim of this study is to understand the concept of moral distress in the context of midwifery practice, describing the attributes, antecedents and consequences. This concept analysis uses Rodgers' evolutionary framework and is the first stage of a sequential mixed-methods study. A literature search was conducted using multiple databases resulting in eight articles for review. Data were analysed using NVivo12©. Three core attributes were identified: moral actions and inactions, conflicting needs and negative feelings/emotions. The antecedents of clinical situations, moral awareness, uncertainty and constraint were identified. Consequences of moral distress include adverse personal professional and organisational outcomes. A model case depicting these aspects is presented. A midwifery focused definition of moral distress is offered as 'a psychological suffering following clinical situations of moral uncertainty and/or constraint, which result in an experience of personal powerlessness where the midwife perceives an inability to preserve all competing moral commitments'. This concept analysis affirms the presence of moral distress in midwifery practice and provides evidence to move towards a consistent definition of moral distress.


An induction heating diamond anvil cell for high pressure and temperature micro-Raman spectroscopic measurements.
A new external heating configuration is presented for high-temperature diamond anvil cell instruments. The supporting rockers are thermally excited by induction from an externally mounted copper coil passing a 30 kHz alternating current. The inductive heating configuration therefore avoids the use of breakable wires, yet is capable of cell temperatures of 1100 K or higher. The diamond anvil cell has no resistive heaters, but uses a single-turn induction coil for elevating the temperature. The induction coil is placed near the diamonds and directly heats the tungsten carbide rockers that support the diamond. The temperature in the cell is determined from a temperature-power curve calibrated by the ratio between the intensities of the Stokes and anti-Stokes Raman lines of silicon. The high-pressure transformation of quartz to coesite is successfully observed by micro-Raman spectroscopy using this apparatus. The induction heating diamond anvil cell is thus a useful alternative to resistively heated diamond anvil cells.


Global gene expression analysis of the heat shock response in the phytopathogen Xylella fastidiosa.
Xylella fastidiosa is a phytopathogenic bacterium that is responsible for diseases in many economically important crops. Although different strains have been studied, little is known about X. fastidiosa stress responses. One of the better characterized stress responses in bacteria is the heat shock response, which induces the expression of specific genes to prevent protein misfolding and aggregation and to promote degradation of the irreversibly denatured polypeptides. To investigate X. fastidiosa genes involved in the heat shock response, we performed a whole-genome microarray analysis in a time course experiment. Globally, 261 genes were induced (9.7%) and 222 genes were repressed (8.3%). The expression profiles of the differentially expressed genes were grouped, and their expression patterns were validated by quantitative reverse transcription-PCR experiments. We determined the transcription start sites of six heat shock-inducible genes and analyzed their promoter regions, which allowed us to propose a putative consensus for sigma(32) promoters in Xylella and to suggest additional genes as putative members of this regulon. Besides the induction of classical heat shock protein genes, we observed the up-regulation of virulence-associated genes such as vapD and of genes for hemagglutinins, hemolysin, and xylan-degrading enzymes, which may indicate the importance of heat stress to bacterial pathogenesis. In addition, we observed the repression of genes related to fimbriae, aerobic respiration, and protein biosynthesis and the induction of genes related to the extracytoplasmic stress response and some phage-related genes, revealing the complex network of genes that work together in response to heat shock.


[Pelvic fractures: role of imaging methods in the diagnosis of isolated pelvic fractures and multi-trauma].
The authors evaluate the role of imaging methods used in the diagnostics of pelvic fractures with the aim to suggest the most effective way of their use. The exact diagnosis of an injury is achieved most quickly if, in hemodynamically stable patients, CT scan is the initial examination and, based on the findings, conservative, invasive (laparotomy) or miniinvasive (angiography with bleeding artery embolization) procedures are used. In hemodynamically unstable patients, the diagnostic procedure always begins with plain X-ray and FAST (ultrasound) examination of the pelvis. When large hemoperitoneum is diagnosed, laparotomy is indicated. When only a small amount of hemoperitoneum is detected, a primary, minimally invasive procedure (angiography with bleeding artery embolization) can be carried out by an experienced interventional radiologist. If this fails to result in stabilization of the circulation, laparotomy should follow. Key words: pelvic ring injury, diagnosis, plain radiography, FAST, MDCT, angiography, embolization.


Effect of the glial envelope on extracellular K(+) diffusion in olfactory glomeruli.
In many species, including vertebrates and invertebrates, first-order olfactory neuropils are organized into spherical glomeruli, partially enveloped by glial borders. The effect of this characteristic organization on olfactory information processing is poorly understood. The extracellular concentration of potassium ions ([K(+)]) must rise around olfactory receptor axons in specific glomeruli following odor-induced activation. To explore the time course and magnitude of K(+) accumulation and possible effects of such accumulation on neural activity within and among glomeruli, we developed a theoretical model to simulate the diffusion of K(+) in extracellular spaces of the glomeruli of the moth Manduca sexta. K(+) released by activated axons was assumed to diffuse through the extracellular spaces in glomeruli and the glial borders that surround them. The time-dependent diffusion equations were solved in spherical coordinates using a finite-difference method. The results indicate that the glial envelope forms a significant barrier to the spread of K(+) between neighboring glomeruli, thus reducing the likelihood of cross-talk between glomeruli, and may cause elevation of extracellular [K(+)] to levels that influence neural activity within the activated glomerulus for many seconds. Such effects could enhance olfactory discrimination and sensitivity, respectively.


Clinical Outcomes of First-line Therapies for Advanced Non-Small Cell Lung Cancer: A Systematic Review of Trials Published Between 2010 and 2020.
To analyze the evolution of clinical outcomes derived from clinical trials on first-line therapies for advanced or metastatic non-small cell lung cancer (NSCLC) published between 2010 and 2020, focusing on how these outcomes impact survival rates and management of patients. A systematic review of phase III and pivotal phase II clinical trials was conducted by a structured search on Medline and Embase. A comprehensive set of variables was collected to assess their influence on survival rates. We also estimated the clinical benefit by applying the ESMO-MCBS v1.1 and extracted the authors' conclusions. Sixty-six studies involving 34,951 patients were included. Best survival outcomes were found for nonsquamous non-small cell lung cancer (OS and progression-free survival medians: 19.4 and 10.2 mo) and for those expressing molecular targets (OS and progression-free survival medians: 23.8 and 11.0 mo). No significant influence on survival rates was observed for industry funding and disease stage (IIIB/IV vs. IV). ESMO-MCBS v1.1 was applied in 45 positive studies and resulted in a meaningful clinical benefit score in 37.8%. Quality of life (QoL) was reported in 57.6% of the original publications and showed statistical significance favoring the experimental arm in 33.3%. Positive authors' conclusions (75.7% of trials) were based on OS and/or QoL in 34% and on surrogate endpoints in 66%. Extended survival times and a steady improvement in QoL have been observed. However, there were more than twice as many studies reporting positive authors' conclusions as studies meeting the ESMO threshold for meaningful clinical benefit.


Switching of alternative electrochemical charging mechanism inside single-walled carbon nanotubes: a quartz crystal microbalance study.
We probed electrochemical ion storage in single-walled carbon nanotubes (SWCNTs) of different diameters in two different organic electrolytes using electrochemical quartz crystal microbalance (EQCM) tracking. The measurements showed that charge storage probed by cyclic voltammetry did not deteriorate when steric effects seemed to hinder the accessibility of counter-ions into SWCNTs, and instead proceeded predominantly by co-ion desorption, as was shown by the decrease in the electrode mass probed by EQCM. The dominant mechanism correlated with the SWCNT diameter/ion size ratio; counter-ion adsorption dominated in the whole potential range when the diameter of SWCNTs was comparable to the size of the largest ion, whereas for larger diameters the charge increase coincided with a decrease in the electrode mass, indicating the dominance of co-ion desorption. The dominance of co-ion desorption was not observed in activated carbon, nor was it previously reported for other carbon materials, and is likely switched on because the carrier density of SWCNT increases with applied potential, and maintains the electrode capacity by co-ion desorption to overcome the steric hindrances to counter-ion adsorption.


Drug recognition and stabilisation of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat.
The NMR structure of the parallel-stranded DNA quadruplex d(TTAGGGT)(4), containing the human telomeric repeat, has been determined in solution in complex with a fluorinated pentacyclic quino[4,3,2-kl]acridinium cation (RHPS4). RHPS4 has been identified as a potent inhibitor of telomerase at submicromolar levels (IC(50) value of 0.33(+/-0.13)microM), exhibiting a wide differential between telomerase inhibition and acute cellular toxicity. All of the data point to RHPS4 exerting its chemotherapeutic potency through interaction with, and stabilisation of, four-stranded G-quadruplex structures. RHPS4 forms a dynamic interaction with d(TTAGGGT)(4), as evident from 1H and 19F linewidths, with fast exchange between binding sites induced at 318 K. Perturbations to DNA chemical shifts and 24 intermolecular nuclear Overhauser effects (NOEs) identify the 5'-ApG and 5'-GpT steps as the principle intercalation sites; a structural model has been refined using NOE-restrained molecular dynamics. The central G-tetrad core remains intact, with drug molecules stacking at the ends of the G-quadruplex. The partial positive charge on position 13-N of the acridine ring appears to act as a "pseudo" potassium ion and is positioned above the centre of the G-tetrad in the region of high negative charge density. In both ApG and GpT intercalation sites, the drug is seen to converge to the same orientation in which the pi-system of the drug overlaps primarily with two bases of each G-tetrad. The drug is held in place by stacking interactions with the G-tetrads; however, there is some evidence for a more dynamic, weakly stabilised A-tetrad that stacks partially on top of the drug at the 5'-end of the sequence. Together, the interactions of RHPS4 increase the t(m) of the quadruplex by approximately 20 degrees C. There is no evidence for drug intercalation within the G-quadruplex; however, the structural model strongly supports end-stacking interactions with the terminal G-tetrads.


Infundibulopelvic stenosis, multicystic kidney, and calyectasis in a kindred: clinical observations and genetic analysis.
Congenital obstructive anomalies of the urinary tract usually occur sporadically. We describe inheritance in a three-generation kindred of a spectrum of kidney anomalies consistent with an autosomal-dominant mode of transmission, with incomplete penetrance, calyectasis (maternal grandmother), infundibulopelvic stenosis (uncle), and multicystic kidney (male proband, age 4 years). The proband's mother, father and half sister had normal renal imaging studies. Inheritance of informative polymorphic markers (3'-HVR, GGG1, GGG9, SM-7, KG8, and CW3) mapping close to the adult polycystic kidney disease type 1 (PKD-1) and tuberous sclerosis (TSC-2) loci on chromosome 16p was evaluated by Southern blot studies and by PCR-based, fluorescent genotyping for linkage to phenotype. The 3 affected individuals, as well as the unaffected mother (obligate carrier) and unaffected half-sister, inherit a common chromosome haplotype linked to the PKD1 locus. Our findings support the hypothesis that these anomalies may be part of a spectrum of obstructive renal dysplasia which are inherited as a simple Mendelian trait exhibiting an autosomal-dominant mode of transmission with variable expression and incomplete penetrance.


Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence.
There is a growing body of literature demonstrating the importance of T cell exhaustion in regulating and shaping immune responses to pathogens and cancer. Simultaneously, the parallel development of therapeutic antibodies targeting inhibitory molecules associated with immune exhaustion (such as PD-1, but also TIGIT, and LAG-3) has led to a revolution in oncology with dramatic benefits in a growing list of solid and hematologic malignancies. Given this success in reinvigorating exhausted T cells and the related anti-tumor effects, there are increasing efforts to apply immune checkpoint blockade to other exhausted immune cells beyond T cells. One approach involves the reinvigoration of "exhausted" NK cells, a non-T, non-B lymphoid cell of the innate immune system. However, in contrast to the more well-defined and established molecular, genetic, and immunophenotypic characteristics of T cell exhaustion, a consensus on the defining functional and phenotypic features of NK "exhaustion" is less clear. As is well-known from T cell biology, separate and distinct molecular and cellular processes including senescence, anergy and exhaustion can lead to diminished immune effector function with different implications for immune regulation and recovery. For NK cells, it is unclear if exhaustion, anergy, and senescence entail separate and distinct entities of dysfunction, though all are typically characterized by decreased effector function or proliferation. In this review, we seek to define these distinct spheres of NK cell dysfunction, analyzing how they have been shown to impact NK biology and clinical applications, and ultimately highlight key characteristics in NK cell function, particularly in relation to the role of "exhaustion."


Bromination of olefins with HBr and DMSO.
A simple and inexpensive methodology is reported for the conversion of alkenes to 1,2-dibromo alkanes via oxidative bromination using HBr paired with dimethyl sulfoxide, which serves as the oxidant as well as cosolvent. The substrate scope includes 21 olefins brominated in good to excellent yields. Three of six styrene derivatives yielded bromohydrins under the reaction conditions.