Feasibility and use of a transition process planning and communication tool among multiple subspecialties within a pediatric health system.
An emerging need to improve health care transition planning has developed worldwide as more youth with special health care needs are surviving to adulthood. Nurses have been instrumental in facilitating transition planning and supporting youth throughout this process. While various transition tools have been developed, health professionals' utilization and perception of these tools have yet to be explored. Furthermore, there are no universally-accepted documentation tools for transition planning. The purpose of this study was to develop and implement a transition process planning and communication tool to facilitate transition planning among multiple, pediatric subspecialties within a system-wide transition program. This project was a cross-sectional quality improvement initiative. Eligible encounters in the electronic medical record (N = 20,645) were obtained from 38 subspecialty clinics at a large, freestanding pediatric health system. Transition planning documentation was monitored for 8 months pre-implementation and 14 months post-implementation of the tool. Health professionals (N = 89) completed a survey to assess the tool's feasibility. Implementation of the tool was feasible and corresponded with increased transition planning documentation post-implementation. Nurses represented 33% of the sample that utilized the tool. Survey results revealed barriers to documentation and utilization of the tool, along with strategies for improvement. This study demonstrates that health professionals, especially pediatric nurses and nurse practitioners, are willing to adopt new, electronic documentation tools to enhance multidisciplinary transition planning consistent with best practices. Future studies should address identified barriers, assess the effectiveness of the tool on improving transition outcomes, and consider implications for integration into global health care models. System-wide implementation of such tools may improve multidisciplinary communication and coordination of care for youth with special health care needs.


Motif effects in Affymetrix GeneChips seriously affect probe intensities.
An Affymetrix GeneChip consists of an array of hundreds of thousands of probes (each a sequence of 25 bases) with the probe values being used to infer the extent to which genes are expressed in the biological material under investigation. In this article, we demonstrate that these probe values are also strongly influenced by their precise base sequence. We use data from >28 000 CEL files relating to 10 different Affymetrix GeneChip platforms and involving nearly 1000 experiments. Our results confirm known effects (those due to the T7-primer and the formation of G-quadruplexes) but reveal other effects. We show that there can be huge variations from one experiment to another, and that there may also be sizeable disparities between batches within an experiment and between CEL files within a batch.


Drug resistance mutations among virological failure HIV-1 infected patients in Malaysia.
The determination of HIV drug resistance mutations (DRMs) towards antiretroviral (ARV) drugs among HIV-1 treated patients with virological failure is crucial for further management of the patient. This study aimed to assess the most common genomic mutation and to analyse subtypes among the HIV-1 patients with viral load level > 1,000 copies/mL. A total of 101 virological failure HIV-1 patients from four different regions of Peninsular Malaysia with a viral load measurement facility were included in the study. Majority of patients (89.1%) have at least 1 mutation associated with clinical resistance to either protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs). Major resistance mutations among the patients towards NRTIs and NNRTIs were 70.3% and 18.8%, respectively. The most common mutation for NRTIs was M184V while K103N mutation was detected in the majority of patients who were treated with NNRTIs. The most commonly observed mutations for major PI and minor PI seen among the study population were V82A/T and L10V, respectively. In HIV-1 subtype analysis, CRF33_01B was the most predominant HIV-1 subtype in this study group. The vast detection of DRMs in this study emphasized the importance of genotypic resistance test in the management of HIV patients as DRMs can alter patient's susceptibility towards ARV drugs. Further study on larger number of samples is essential for the development of a database on HIV-1 DRMs among patients that experience virological failure in Malaysia.


Performing the unexplainable: implicit task performance reveals individually reliable sequence learning without explicit knowledge.
Memory-impaired patients express intact implicit perceptual-motor sequence learning, but it has been difficult to obtain a similarly clear dissociation in healthy participants. When explicit memory is intact, participants acquire some explicit knowledge and performance improvements from implicit learning may be subtle. Therefore, it is difficult to determine whether performance exceeds what could be expected on the basis of the concomitant explicit knowledge. Using a challenging new sequence-learning task, robust implicit learning was found in healthy participants with virtually no associated explicit knowledge. Participants trained on a repeating sequence that was selected randomly from a set of five. On a performance test of all five sequences, performance was best on the trained sequence, and two-thirds of the participants exhibited individually reliable improvement (by chi-square analysis). Participants could not reliably indicate which sequence had been trained by either recognition or recall. Only by expressing their knowledge via performance were participants able to indicate which sequence they had learned.


Family experience of palliative sedation therapy: proportional vs. continuous deep sedation.
Some patients experience intense symptoms refractory to intensive palliative care, and palliative sedation is sometimes used. Palliative sedation may be classified into proportional and continuous deep sedation (CDS). The primary aim of this study was to compare family experience between families of patients who received proportional or CDS. A multicenter questionnaire survey was conducted involving bereaved families of cancer patients who received proportional or CDS based on a sedation protocol. Overall evaluation of sedation (satisfaction, family-perceived distress, appropriateness of timing, and patient distress) and 13-item family concerns, good death, satisfaction with care, depression, quality of care, unfinished business, and balance between symptom relief and maintaining communication were measured. Among the 2120 patients who died, 222 patients received a continuous infusion of midazolam. A sedation protocol was used in 147 patients, and questionnaires were sent to 124 families. A total of 78 responses were finally returned (proportional, 58 vs. CDS, 20). There were no significant differences in the overall evaluation, family concerns, total score of good death, satisfaction, depression, or balance between symptom relief and maintaining communication. On the other hand, some quality of care items, i.e., relationship with medical staff (P < 0.01), physical care by nurses (P = 0.04), and coordination and consistency (P = 0.04), were significantly better in the CDS group than in the proportional sedation group. Family-reported unfinished business was also better in the CDS group, with marginal significance. Family experience of CDS was not less favorable than proportional sedation, and actually rated more favorably for some elements of quality of care and unfinished business.


Detection of lymph node metastasis in colon cancer by ectopically expressed fibroblast markers FOXQ1 and THBS2.
Approximately 25% of colon cancer (CC) patients having curative surgery will relapse. Therefore, it is crucial to identify patients with increased recurrence risk to offer them adjuvant chemotherapy. Three markers with prominent expression in fibroblasts: forkhead box Q1 (FOXQ1), matrix metalloproteinase-11 (MMP11), and thrombospondin-2 (THBS2), and the fibroblast expressed chemokine CXCL12 were selected for studies because of the critical role of fibroblasts in the microenvironment of the tumor. The expression levels of the biomarkers were assessed in primary CC tumors, lymph nodes of CC patients and controls, and CC cell lines at mRNA and protein levels by real-time qRT-PCR and immunohistochemistry, respectively. FOXQ1, MMP11, and THBS2 mRNAs were expressed at significantly higher levels in primary tumors compared to normal colon (P=0.002, P<0.0001, and P<0.0001, respectively). In contrast, CXCL12 mRNA levels were higher in normal colon tissue. FOXQ1, MMP11, and THBS2 levels were also expressed at significantly higher levels in metastasis-positive lymph nodes compared to both metastasis-negative- and control nodes (P<0.0001/P=0.002, P<0.0001/P<0.0001, and P<0.0001/P<0.0001, respectively). Immuno-morphometry revealed that 30-40% of the tumor cells expressed FOXQ1, MMP11, and THBS2. FOXQ1 and THBS2 were barely detected in normal colon epithelium (P<0.0001), while MMP11 was expressed in normal colon epithelium at high levels. We conclude that CC tumor cells show ectopic expression of FOXQ1 and THBS2 possibly making these tumor cells independent of fibroblast cell support. The high expression levels of these two biomarkers in metastatic lymph nodes suggest that they are potential indicators of patients at risk for recurrence.


Interventions to improve patient flow in emergency departments: an umbrella review.
Patient flow and crowding are two major issues in ED service improvement. A substantial amount of literature exists on the interventions to improve patient flow and crowding, making it difficult for policymakers, managers and clinicians to be familiar with all the available literature and identify which interventions are supported by the evidence. This umbrella review provides a comprehensive analysis of the evidence from existing quantitative systematic reviews on the interventions that improve patient flow in EDs. An umbrella review of systematic reviews published between 2000 and 2017 was undertaken. Included studies were systematic reviews and meta-analyses of quantitative primary studies assessing an intervention that aimed to improve ED throughput. The search strategy yielded 623 articles of which 13 were included in the umbrella review. The publication dates of the systematic reviews ranged from 2006 to 2016. The 13 systematic reviews evaluated 26 interventions: full capacity protocols, computerised provider order entry, scribes, streaming, fast track and triage. Interventions with similar characteristics were grouped together to produce the following categories: diagnostic services, assessment/short stay units, nurse-directed interventions, physician-directed interventions, administrative/organisational and miscellaneous. The statistical evidence from 14 primary randomised controlled trials (RCTs) was evaluated to determine if correlation or clustering of observations was considered. Only the fast track intervention had moderate evidence to support its use but the RCTs that assessed the intervention did not use statistical tests that considered correlation. Overall, the evidence supporting the interventions to improve patient flow is weak. Only the fast track intervention had moderate evidence to support its use but correlation/clustering was not taken into consideration in the RCTs examining the intervention. Failure to consider the correlation of the data in the primary studies could result in erroneous conclusions of effectiveness.


Effect of the self-monitoring approach on exercise maintenance during cardiac rehabilitation: a randomized, controlled trial.
To evaluate the effect of the self-monitoring approach (SMA) on self-efficacy for physical activity (SEPA), exercise maintenance, and objective physical activity level over a 6-mo period after a supervised 6-mo cardiac rehabilitation (CR) program. We conducted a randomized, controlled trial with 45 myocardial infarction patients (38 men, seven women; mean age, 64.2 yrs) recruited after completion of an acute-phase, exercise-based CR program. Patients were randomly assigned to an SMA group (n = 24) or control group (n = 21). Along with CR, the subjects in the SMA group self-monitored their weight and physical activity for 6 mos. The SMA used in this study was based on Bandura's self-efficacy theory and was designed to enhance confidence for exercise maintenance. The control group participated in CR only. All patients were evaluated with the SEPA assessment tool. Exercise maintenance, SEPA scores, and objective physical activity (average steps per week) as a caloric expenditure were assessed at baseline and during a 6-mo period after the supervised CR program. Mean period from myocardial infarction onset did not differ significantly between the SMA and control groups (12.1 +/- 1.3 vs. 12.2 +/- 1.2 mos, P = 0.692). All patients maintained their exercise routine in the SMA group. Mean SEPA score (90.5 vs. 72.7 points, P < 0.001) and mean objective physical activity (10,458.7 vs. 6922.5 steps/wk, P < 0.001) at 12 mos after myocardial infarction onset were significantly higher in the SMA than control group. SEPA showed significant positive correlation with objective physical activity (r = 0.642, P < 0.001). SMA during supervised CR may effectively increase exercise maintenance, SEPA, and objective physical activity at 12 mos after myocardial infarction onset.


APN1 is a functional receptor of Cry1Ac but not Cry2Ab in Helicoverpa zea.
Lepidopteran midgut aminopeptidases N (APNs) are phylogenetically divided into eight clusters, designated as APN1-8. Although APN1 has been implicated as one of the receptors for Cry1Ac in several species, its potential role in the mode of action of Cry2Ab has not been functionally determined so far. To test whether APN1 also acts as one of the receptors for Cry1Ac in Helicoverpa zea and even for Cry2Ab in this species, we conducted a gain of function analysis by heterologously expressing H. zea APN1 (HzAPN1) in the midgut and fat body cell lines of H. zea and the ovarian cell line of Spodoptera frugiperda (Sf9) and a loss of function analysis by RNAi (RNA interference) silencing of the endogenous APN1 in the three cell lines using the HzAPN1 double strand RNA (dsRNA). Heterologous expression of HzAPN1 significantly increased the susceptibility of the three cell lines to Cry1Ac, but had no effects on their susceptibility to Cry2Ab. Knocking down of the endogenous APN1 made the three cell lines resistant to Cry1Ac, but didn't change cell lines susceptibility to Cry2Ab. The findings from this study demonstrate that HzAPN1 is a functional receptor of Cry1Ac, but not Cry2Ab.


Microbial Surface Biofilm Responds to the Growth-Reproduction-Senescence Cycle of the Dominant Coral Reef Macroalgae Sargassum spp.
Macroalgae play an intricate role in microbial-mediated coral reef degradation processes due to the release of dissolved nutrients. However, temporal variabilities of macroalgal surface biofilms and their implication on the wider reef system remain poorly characterized. Here, we study the microbial biofilm of the dominant reef macroalgae Sargassum over a period of one year at an inshore Great Barrier Reef site (Magnetic Island, Australia). Monthly sampling of the Sargassum biofilm links the temporal taxonomic and putative functional metabolic microbiome changes, examined using 16S rRNA gene amplicon and metagenomic sequencing, to the pronounced growth-reproduction-senescence cycle of the host. Overall, the macroalgal biofilm was dominated by the heterotrophic phyla Firmicutes (35% ± 5.9% SD) and Bacteroidetes (12% ± 0.6% SD); their relative abundance ratio shifted significantly along the annual growth-reproduction-senescence cycle of Sargassum. For example, Firmicutes were 1.7 to 3.9 times more abundant during host growth and reproduction cycles than Bacteroidetes. Both phyla varied in their carbohydrate degradation capabilities; hence, temporal fluctuations in the carbohydrate availability are potentially linked to the observed shift. Dominant heterotrophic macroalgal biofilm members, such as Firmicutes and Bacteroidetes, are implicated in exacerbating or ameliorating the release of dissolved nutrients into the ambient environment, though their contribution to microbial-mediated reef degradation processes remains to be determined.


The greening of medical computing: federal policy and the information industry.
Some of the most valuable medical databases in existence are created and maintained by the federal government. Yet, in most cases, to access them the user must go through expensive commercial channels. In effect this forces the user to pay for them twice--once as a tax-payer and again as a user. It is argued that computerized medical information is no longer a novelty or a luxury item and is becoming fundamental to patient care, administration, education and research. As a result these data ought not be locked up by commercial vendors, but rather should be made widely and freely available to all--especially when the information was developed with public monies in the first place.


Platelet-derived growth factor induces chemotaxis of neuroepithelial stem cells.
The ability of differentiating cells to migrate within the developing central nervous system (CNS) depends on extrinsic guidance signals, some of which are growth factors. In this study we have investigated the chemotactic response of cultured stem cells from the embryonic rat cortex to platelet-derived growth factor (PDGF). Nestin-positive stem cells from the developing CNS can be maintained and expanded in vitro under serum-free conditions in the presence of basic fibroblast growth factor (bFGF). Northern blot analysis of PDGF receptor expression revealed both alpha- and beta-receptors on bFGF-treated neural stem cells. Both PDGF-AA and PDGF-BB readily induced directed migration of cultured neuroepithelial cells as measured in a microchemotaxis assay. Blocking of the migratory response was achieved by incubation with PDGF isoform-specific antibodies. More than 90% of the migrating cells were nestin-positive and incorporation of BrdU was also seen suggesting the cells to be immature and not yet committed to a specific cell lineage. These findings suggest a role for PDGF in cell migration in the developing cortex.


Multi-focal occurrence of cortical dysplasia in epilepsy patients.
This study describes the existence and the clinical and electrophysiological features of multi-focal cortical dysplasia in epilepsy patients. Five patients with intractable focal epilepsy are reported. All patients underwent invasive presurgical video-electroencephalography monitoring. Localization of dysplastic areas was based on high-resolution magnetic resonance scanning, surface and intracranial electroencephalography. Four patients underwent epilepsy surgery. Histological findings in focal cortical dysplasia (FCD) were classified according to Palmini. In addition, genetic examinations were performed in order to assess possible mutations in the genes for tuberous sclerosis complex. In four patients, FCDs were located in the same hemisphere. One case presented with bilateral FCDs. In three patients seizures arose from two separate dysplastic areas and in one patient, one lesion showed only interictal activity. In one further patient, seizures started exclusively from the hippocampus. In two of three patients with removal of the FCDs, the histological subtype was identical (Palmini type 2) and in one patient, histology differed between the lesions. All operated patients became seizure-free. In patients with FCD type 2, germ-line mutations in the tuberous sclerosis complex genes were not detectable. Dysplastic brain regions may not be restricted to a single brain region. Areas of FCD can have different degrees of epileptogenicity, ranging from electrographic silence to interictal epileptic discharges and initial involvement in seizure generation. Based on genetic analysis and clinical features, multi-FCD in this patient series was not likely to be related to tuberous sclerosis.


Preliminary evidence for a unique role of disgust-based conditioning in posttraumatic stress.
Independent lines of evidence have linked posttraumatic stress symptomatology to both peritraumatic disgust (i.e., disgust experienced during a traumatic event) and posttraumatic disgust reactivity in response to traumatic event cues among individuals exposed to traumatic events. Much of this work suggests disgust, defined as a rejection/revulsion response aimed at distancing oneself from a potential source of contamination, may be important in understanding the nature of posttraumatic stress reactions even after accounting for the more frequently studied affective states of fear and anxiety. The current investigation provided a preliminary test of a model of disgust in posttraumatic stress among a sample of 54 community-recruited women with a history sexual victimization. Both peritraumatic disgust (r = .31) and posttraumatic disgust reactivity (r = .42) in response to an idiographic traumatic event script were significantly associated with posttraumatic stress symptom severity. After accounting for variability-associated peritraumatic fear and posttraumatic anxious reactivity, an indirect effect of peritraumatic disgust through posttraumatic disgust reactivity also was found, suggesting that one mechanism through which peritraumatic disgust relates to posttraumatic stress is through its relation with increased posttraumatic disgust reactivity. These findings highlight the importance of further elucidating the nature of disgust in relation to traumatic events and subsequent posttraumatic stress reactions.


A novel perfusion bioreactor providing a homogenous milieu for tissue regeneration.
We developed a novel perfusion bioreactor that is capable of cultivating multiple 3-dimensional (3D) cellular constructs in one flow chamber with a total cross-section area of 20 cm(2). Two unique features integrated into the bioreactor provided a homogenous fluid flow along the bioreactor cross-section and maximal exposure of the cellular constructs to the perfusing medium. Mathematical modeling of the fluid flow regime in the perfusion bioreactor showed that integrating a flow-distributing mesh 1.5 cm upstream from the construct compartment imposed an equal medium flow and shear stress of 0.6 dynes /cm(2) along the entire cell construct cross-section area. The design of 95.8%open-pore-area fixing nets enabled the exposure of 99.88% of the cell construct volume to the perfusing medium. Cardiac cell constructs seeded with physiologically relevant cell density (0.7 x 10(8) cells/cm(3)) in alginate scaffolds developed into homogenous compacted cardiac tissue, as judged using cell staining with fluorescein diacetate and hematoxylin-eosin histology. The cell constructs maintained 80% viability for nearly 2 weeks, whereas in static-cultivated cell constructs, only 50% of the initial cells remained, as determined according to total DNA content and MTT viability assay. Medium perfusion resulted in better cell viability, presumably due to the convective-diffusive transport of oxygen, compared with oxygen diffusion within the static-cultivated cell constructs, as well as due to efficient removal of harmful cell secretions. It is envisioned that this bioreactor would be useful for 3D cultivation of different mammalian cells for purposes of tissue engineering or production of valuable biologicals.


Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model.
We tested the hypothesis that microtubule (MT)-binding drugs could be therapeutically beneficial in tauopathies by functionally substituting for the MT-binding protein tau, which is sequestered into inclusions of human tauopathies and transgenic mouse models thereof. Transgenic mice were treated for 12 weeks with weekly i.p. injections of 10 or 25 mg/m(2) paclitaxel (Paxceed). Both doses restored fast axonal transport in spinal axons, wherein MT numbers and stable (detyrosinated) tubulins were increased, compared with sham treatment, and only Paxceed ameliorated motor impairments in tau transgenic mice. Thus, MT-stabilizing drugs could have therapeutic potential for treating neurodegenerative tauopathies by offsetting losses of tau function that result from the sequestration of this MT-stabilizing protein into filamentous inclusions.


Raltegravir blocks the infectivity of red-fluorescent-protein (mCherry)-labeled HIV-1JR-FL in the setting of post-exposure prophylaxis in NOD/SCID/Jak3-/- mice transplanted with human PBMCs.
Employing NOD/SCID/Jak3-/- mice transplanted with human PBMCs (hNOJ mice) and replication-competent, red-fluorescent-protein (mCherry; mC)-labeled HIV-1JR-FL (HIVmC), we examined whether early antiretroviral treatment blocked the establishment of HIV-1 infection. The use of hNOJ mice and HIVmC enabled us to visually locate infection foci and to examine the early dynamics of HIVmC infection without using a large amount of antiretroviral unlike in non-human primate models. Although when raltegravir (RAL) administration was begun 1 day after intraperitoneal (ip) inoculation of HIVmC, no plasma p24 or plasma HIV-1-RNA (pRNA) were detected in 10 of 12 hNOJ (hNOJmCRAL+) mice as assessed on the last day of the 14-day continuous twice-daily RAL administration, all 10 untreated hNOJmC (hNOJmCRAL-) mice became positive for p24 and pRNA and had significantly swollen lymph nodes in peritoneal cavity and abundant p24+/mC+/CD3+/CD4+ T cells and p24+/mC+/CD68+ monocytes/macrophages were identified in their omenta and mesenteric lymphoid tissues/lymph nodes upon necropsy of the mice on day 14. In 12 hNOJmCRAL+ mice, no significantly swollen lymph nodes were seen compared to hNOJmCRAL- mice; however, in the omentum of the 2 hNOJmCRAL+ mice that were positive for pRNA and in site RNA, mC+/p24+/CD3+/CD83+ cells were identified, suggesting that viral breakthrough occurred later in the observation period. The present data suggest that the use of hNOJ mouse model and HIVmC may shed light on the study of early-phase dynamics of HIV-1 infection and cellular events in post-exposure/pre-exposure prophylaxis.


Diarrhoea treatments--fluid replacement and alternatives.
Treatments for diarrhoea in animals include antibiotics, antisecretory drugs, adsorbents and fluid therapy. Of these, antibiotics have a role in bacterial disease, but are probably often used in cases where they contribute little. Other drug approaches (antisecretory, adsorbents, etc.) may in the future be useful, but those so far available do not appear very effective. Fluid therapy, especially by the oral route, is rational, is effective in both bacterial and viral diarrhoea, and should be the treatment of first choice.


[Nocturnal-diurnal changes of norepinephrine blood levels in patients with chronic cardiac insufficiency. Practical values].
The purpose of this study was to investigate circadian changes in noradrenaline (norepinephrine) levels in patients presenting with congestive heart failure. Eighteen patients were investigated with a group mean age of 66 years, 12 in NYHA class III and 6 in class IV. The cause of the heart failure was ischemia in 7 cases, valvular in 1 case and idiopathic in the other 10 cases. The mean follow-up time of the disease was 3.9 years. Six healthy volunteers were investigated following the same protocol. Blood samples were taken while the patient was lying down over a period of 24 hours, after installing a peripheral venous catheter. The assay was carried out by means of high performance liquid chromatography with electrochemical detection. In the controls, the mean noradrenaline level (norepinephrine) was 220 +/- 62 pg/ml, with daytime peaks. The heart failure patients showed a high mean level (230 +/- 404 pg/ml), with less daytime variability than the controls (92% vs 127%; p < 0.05). The 8 a.m. value was reproducible, and there was close correlation between this value and the mean value for the 24 hours (p < 0.001). Thus, the morning sample provides a good estimation of the levels over the 24 hours.


Effect of Recombinant Human Granulocyte Colony-Stimulating Factor for Patients With Coronavirus Disease 2019 (COVID-19) and Lymphopenia: A Randomized Clinical Trial.
Lymphopenia is common and correlates with poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19). To determine whether a therapy that increases peripheral blood leukocyte and lymphocyte cell counts leads to clinical improvement in patients with COVID-19. Between February 18 and April 10, 2020, we conducted an open-label, multicenter, randomized clinical trial at 3 participating centers in China. The main eligibility criteria were pneumonia, a blood lymphocyte cell count of 800 per μL (to convert to ×109/L, multiply by 0.001) or lower, and no comorbidities. Severe acute respiratory syndrome coronavirus 2 infection was confirmed with reverse-transcription polymerase chain reaction testing. Usual care alone, or usual care plus 3 doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF, 5 μg/kg, subcutaneously at days 0-2). The primary end point was the time from randomization to improvement of at least 1 point on a 7-category disease severity score. Of 200 participants, 112 (56%) were men and the median (interquartile range [IQR]) age was 45 (40-55) years. There was random assignment of 100 patients (50%) to the rhG-CSF group and 100 (50%) to the usual care group. Time to clinical improvement was similar between groups (rhG-CSF group median of 12 days (IQR, 10-16 days) vs usual care group median of 13 days (IQR, 11-17 days); hazard ratio, 1.28; 95% CI, 0.95-1.71; P = .06). For secondary end points, the proportion of patients progressing to acute respiratory distress syndrome, sepsis, or septic shock was lower in the rhG-CSF group (rhG-CSF group, 2% vs usual care group, 15%; difference, -13%; 95%CI, -21.4% to -5.4%). At 21 days, 2 patients (2%) had died in the rhG-CSF group compared with 10 patients (10%) in the usual care group (hazard ratio, 0.19; 95%CI, 0.04-0.88). At day 5, the lymphocyte cell count was higher in the rhG-CSF group (rhG-CSF group median of 1050/μL vs usual care group median of 620/μL; Hodges-Lehmann estimate of the difference in medians, 440; 95% CI, 380-490). Serious adverse events, such as sepsis or septic shock, respiratory failure, and acute respiratory distress syndrome, occurred in 29 patients (14.5%) in the rhG-CSF group and 42 patients (21%) in the usual care group. In preliminary findings from a randomized clinical trial, rhG-CSF treatment for patients with COVID-19 with lymphopenia but no comorbidities did not accelerate clinical improvement, but the number of patients developing critical illness or dying may have been reduced. Larger studies that include a broader range of patients with COVID-19 should be conducted. Chinese Clinical Trial Registry: ChiCTR2000030007.


Expression of calcipressin1, an inhibitor of the phosphatase calcineurin, is altered with aging and Alzheimer's disease.
Protein phosphatase 2B (calcineurin) activity has been shown to be decreased in Alzheimer's disease and is a possible mechanism(s) for the hyperphosphorylation of tau and subsequent neurofibrillary tangle formation. Recently, mRNA expression of Down's syndrome Critical Region 1 gene, which encodes the protein calcipressin (an endogenous inhibitor of calcineurin), was found to be upregulated in both Down's syndrome and Alzheimer's disease. Calcipressin is induced by oxidative stress and Abeta in vitro, further establishing a link in the pathology of both diseases. Using immunohistochemistry techniques, calcipressin protein expression in the pyramidal neurons of the temporal lobe was shown to increase with aging (r2=0.5658; p=0.0313), and also in moderate to severe Alzheimer's disease compared to control patients (t=3.872; p=0.0017). In addition, there was a positive correlation between the total number of calcipressin-positive pyramidal neurons and the number of neurofibrillary tangles in the temporal cortex (r2= 0.5955; p=0.0249). As there was an 88% increase in nuclear calcipressin in Alzheimer's disease (p=0.0001), the relationship between cellular localization of calcipressin and neurofibrillary tangle formation was investigated, which revealed a decrease in neurofibrillary tangle-bearing neurons that contain nuclear calcipressin (t=4.874; p=0.0028) and further demonstrates that the cellular regulation of calcipressin is altered in Alzheimer's disease.


IoT-Based COVID-19 Diagnosing and Monitoring Systems: A Survey.
To date, the novel Coronavirus (SARS-CoV-2) has infected millions and has caused the deaths of thousands of people around the world. At the moment, five antibodies, two from China, two from the U.S., and one from the UK, have already been widely utilized and numerous vaccines are under the trail process. In order to reach herd immunity, around 70% of the population would need to be inoculated. It may take several years to hinder the spread of SARS-CoV-2. Governments and concerned authorities have taken stringent measurements such as enforcing partial, complete, or smart lockdowns, building temporary medical facilities, advocating social distancing, and mandating masks in public as well as setting up awareness campaigns. Furthermore, there have been massive efforts in various research areas and a wide variety of tools, technologies and techniques have been explored and developed to combat the war against this pandemic. Interestingly, machine learning (ML) algorithms and internet of Things (IoTs) technology are the pioneers in this race. Up till now, several real-time and intelligent IoT-based COVID-19 diagnosing, and monitoring systems have been proposed to tackle the pandemic. In this article we have analyzed a wide range of IoTs technologies which can be used in diagnosing and monitoring the infected individuals and hotspot areas. Furthermore, we identify the challenges and also provide our vision about the future research on COVID-19.


Metal ion activation of phosphate transfer by bidentate coordination.
The hydrolysis of methyl phosphate bound to the triethylenetetramine-cobalt(III) ion is much faster than the hydrolysis of either dimethyl phosphate bound to the same cation or methyl phosphate bound to the pentamminecobalt-(III) ion. The rate enhancement is attributed to bidenate coordination of the methyl phosphate. This feature suggests a pseudorotation mechanism analogous to that proposed by Westheimer for the hydrolysis of ethylene methyl phosphate. Stabilization of bidentate coordination might play a role in metal ion activation of phosphate-transfer enzymes.


The efficacy of involuntary outpatient treatment in Massachusetts.
One means to address some of the unintended consequences of the shift of treatment for individuals with serious mental illness from hospitals to communities has been involuntary outpatient treatment (IOT). Using Massachusetts data, 19 patients with court orders for IOT were matched to all and to best fits on demographic and clinical variables, and then to individuals with the closest fit on utilization before the IOT date. Outcomes indicated the IOT group had significantly fewer admissions and hospital days after the court order. The full impact of IOT requires more study, particularly directed toward IOT's effects on insight and quality of life.


Treatment of primary chronic glomerulonephritis with Rehmannia glutinosa acteosides in combination with the angiotensin receptor blocker irbesartan: a randomized controlled trial.
This study aims to assess the efficacy and safety of Rehmannia glutinosa acteosides used in combination with the angiotensin receptor blocker irbesartan to treat primary chronic glomerulonephritis. A total of 479 patients diagnosed with primary chronic glomerulonephritis were recruited from outpatient clinics and were randomly assigned to the treatment group (Rehmannia glutinosa acteosides, two 200-mg capsules, bid; and irbesartan, one 150-mg tablet, qd) or the control group (irbesartan, one 150-mg tablet, qd). The primary outcome was 24-h urinary protein. Secondary outcome measures included blood pressure, estimated glomerular filtration rate, erythrocyturia, serum alanine aminotransferase, aspartate transaminase and electrolytes. After 8 weeks of treatment, the treatment group showed a mean reduction in 24-h proteinuria of 36.42% compared to baseline, which was significantly higher than the mean reduction from baseline of 27.97% in the control group (P = 0.0278).Adverse drug reactions occurred at a similarly low rate in the treatment group (0.4%) and control group (1.2%, P = 0.3724). In the treatment of chronic glomerulonephritis, the combination of Rehmannia glutinosa acteosides and irbesartan can reduce proteinuria more effectively than irbesartan alone.


Research of the relationship of pedestrian injury to collision speed, car-type, impact location and pedestrian sizes using human FE model (THUMS Version 4).
Injuries in car to pedestrian collisions are affected by various factors such as the vehicle body type, pedestrian body size and impact location as well as the collision speed. This study aimed to investigate the influence of such factors taking a Finite Element (FE) approach. A total of 72 collision cases were simulated using three different vehicle FE models (Sedan, SUV, Mini-Van), three different pedestrian FE models (AM50, AF05, AM95), assuming two different impact locations (center and the corner of the bumper) and at four different collision speeds (20, 30, 40 and 50 km/h). The impact kinematics and the responses of the pedestrian model were validated against those in the literature prior to the simulations. The relationship between the collision speed and the predicted occurrence of head and chest injuries was examined for each case, analyzing the impact kinematics of the pedestrian against the vehicle body and resultant loading to the head and the chest. Strain based indicators were used in the simulation model to estimate skeletal injury (bony fracture) and soft tissue (brain and internal organs) injury. The study results primarily showed that the injury risk became higher with the collision speed, but was also affected by the combination of the factors such as the pedestrian size and the impact location. The study also discussed the injury patterns and trends with respect to the factors examined. In all of the simulated conditions, the model did not predict any severe injury at a collision speed of 20 km/h.


Dietary protein shapes the profile and repertoire of intestinal CD4 + T cells.
The intestinal immune system must tolerate food antigens to avoid allergy, a process requiring CD4 + T cells. Combining antigenically defined diets with gnotobiotic models, we show that food and microbiota distinctly influence the profile and T cell receptor repertoire of intestinal CD4 + T cells. Independent of the microbiota, dietary proteins contributed to accumulation and clonal selection of antigen-experienced CD4 + T cells at the intestinal epithelium, imprinting a tissue specialized transcriptional program including cytotoxic genes on both conventional and regulatory CD4 + T cells (Tregs). This steady state CD4 + T cell response to food was disrupted by inflammatory challenge, and protection against food allergy in this context was associated with Treg clonal expansion and decreased pro-inflammatory gene expression. Finally, we identified both steady state epithelium-adapted CD4 + T cells and tolerance-induced Tregs that recognize dietary antigens, suggesting that both cell types may be critical for preventing inappropriate immune responses to food.


Reflectances from a supercontinuum laser-based instrument: hyperspectral, polarimetric and angular measurements.
Recent developments of active hyperspectral systems require optical characterization of man-made materials for instrument calibration. This work presents an original supercontinuum laser-based instrument designed by Onera, The French Aerospace Lab, for fast hyperspectral polarimetric and angular reflectances measurements. The spectral range is from 480 nm to 1000 nm with a 1 nm spectral resolution. Different polarization configurations are made possible in whole spectrum. This paper reviews the design and the calibration of the instrument. Hyper-spectral polarimetric and angular reflectances are measured for reference and man-made materials such as paint coatings. Physical properties of reflectances as positivity, energy conservation and Helmholtz reciprocity are retrieved from measurements.


Regression analysis and modelling of data acquisition for SELDI-TOF mass spectrometry.
Pre-processing of SELDI-TOF mass spectrometry data is currently performed on a largel y ad hoc basis. This makes comparison of results from independent analyses troublesome and does not provide a framework for distinguishing different sources of variation in data. In this article, we consider the task of pooling a large number of single-shot spectra, a task commonly performed automatically by the instrument software. By viewing the underlying statistical problem as one of heteroscedastic linear regression, we provide a framework for introducing robust methods and for dealing with missing data resulting from a limited span of recordable intensity values provided by the instrument. Our framework provides an interpretation of currently used methods as a maximum-likelihood estimator and allows theoretical derivation of its variance. We observe that this variance depends crucially on the total number of ionic species, which can vary considerably between different pooled spectra. This variation in variance can potentially invalidate the results from naive methods of discrimination/classification and we outline appropriate data transformations. Introducing methods from robust statistics did not improve the standard errors of the pooled samples. Imputing missing values however-using the EM algorithm-had a notable effect on the result; for our data, the pooled height of peaks which were frequently truncated increased by up to 30%.


A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects.
Dolutegravir (DTG; S/GSK1349572) is under clinical development as a once daily, unboosted integrase inhibitor for the treatment of HIV infection. The effect of DTG on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and creatinine clearance (CLcr ) was evaluated in 34 healthy volunteers. Subjects received DTG 50 mg (once daily or twice daily) or placebo for 14 days. GFR was measured by iohexol plasma clearance, ERPF was assessed by para-aminohippurate plasma clearance and CLcr was measured by 24 h urine collection. All treatments were generally well tolerated. A modest decrease (10-14%) in CLcr was observed, consistent with clinical study observations. DTG 50 mg once daily and twice daily had no significant effect on GFR or ERPF compared with placebo over 14 days in healthy subjects. These findings support in vitro data that DTG increases serum creatinine by the benign inhibition of the organic cation transporter 2, which is responsible for tubular secretion of creatinine.


Canadian Network and Centre for Trials Internationally (CANNeCTIN): a national network for Canadian-led trials in cardiovascular diseases and diabetes mellitus.
The Canadian Network and Centre for Trials INternationally (CANNeCTIN) was jointly funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation in April 2008 to provide infrastructure for clinical studies of cardiovascular diseases and diabetes mellitus. Its functional components include a national coordinating centre at the Population Health Research Institute (PHRI) in Hamilton (Ontario), a collaborative Canadian network and an affiliated international network of hospitals and clinics. The rationales for CANNeCTIN include the global health burden of cardiovascular diseases and diabetes, the strengths of randomized controlled trials - particularly large, multicentre and international - and the track record of success of the PHRI. CANNeCTIN will provide investigators from across Canada with opportunities to become the principal investigators of national and international trials coordinated by the PHRI. CANNeCTIN will support priority pilot studies, and successful investigators will be encouraged and assisted to apply for peer review and industrial funding for full studies to be conducted within the network and coordinated by the PHRI. An extensive education program offers hands-on experience in organizing and leading large national⁄international clinical trials led by accomplished researchers, distance learning courses in clinical research methodology, biostatistics and study coordination, and 'cutting-edge' workshops. A knowledge translation program seeks opportunities arising from clinical trials and encourages research into this paradigm for understanding how best to close the gaps between knowledge and effective practice. The five-year goals are to enhance the capacity of Canadian investigators to lead major clinical studies, facilitate knowledge translation and exchange, and augment Canada's capacity to train the next generation of leaders in cardiovascular and diabetes clinical research.


[Lab study of splinted teeth mobility with the help of periotestmetry].
Mobility of splinted teeth was determined with the help of the device Periotest, its meterage depended upon abutment fixation nature and their number. Critical for the device sensitivity was the weight of splinting construction equal to 12.71+/-0.81 g.


Gender differences in perceiving the portion size of meat when being observed.
Previous research has shown that being observed can influence people's behaviors, including their eating habits. In this study, we predicted that men and women would exhibit different reactions to the perception of portion size of meat when being observed. By utilizing a camera to create a sense of being observed during the act of eating meat, we revealed that men in the observed condition reported perceiving the portion size of the meat they ate to be smaller and the eating amount to be less than was reported by those in the non-observed condition. However, women did not show any differences in their perceptions of the portion size of the meat they ate. These findings demonstrate that gender identity plays a role in how people perceive the meat they eat when they are aware of being observed. The discussion highlights the effect of being observed on meat consumption and illustrates the influence of masculine identity.


Approach to machine learning for extraction of real-world data variables from electronic health records.
Background: As artificial intelligence (AI) continues to advance with breakthroughs in natural language processing (NLP) and machine learning (ML), such as the development of models like OpenAI's ChatGPT, new opportunities are emerging for efficient curation of electronic health records (EHR) into real-world data (RWD) for evidence generation in oncology. Our objective is to describe the research and development of industry methods to promote transparency and explainability. Methods: We applied NLP with ML techniques to train, validate, and test the extraction of information from unstructured documents (e.g., clinician notes, radiology reports, lab reports, etc.) to output a set of structured variables required for RWD analysis. This research used a nationwide electronic health record (EHR)-derived database. Models were selected based on performance. Variables curated with an approach using ML extraction are those where the value is determined solely based on an ML model (i.e. not confirmed by abstraction), which identifies key information from visit notes and documents. These models do not predict future events or infer missing information. Results: We developed an approach using NLP and ML for extraction of clinically meaningful information from unstructured EHR documents and found high performance of output variables compared with variables curated by manually abstracted data. These extraction methods resulted in research-ready variables including initial cancer diagnosis with date, advanced/metastatic diagnosis with date, disease stage, histology, smoking status, surgery status with date, biomarker test results with dates, and oral treatments with dates. Conclusion: NLP and ML enable the extraction of retrospective clinical data in EHR with speed and scalability to help researchers learn from the experience of every person with cancer.


Mitochondrial electron transport inhibition and viability of intraerythrocytic Plasmodium falciparum.
Although mitochondrial electron transport is a validated target of the antimalarial drug atovaquone, the molecular details underlying parasite demise are unclear. We have shown that a critical function of mitochondrial electron transport in blood-stage Plasmodium falciparum is to support pyrimidine biosynthesis. Here, we explore the effects of atovaquone, alone and in combination with proguanil, on P. falciparum viability. Our results suggest that the effects of inhibition depend upon the erythrocytic stage of the parasites and the duration of exposure. Ring- and schizont-stage parasites are most resilient to drug treatment and can survive for 48 h, with a fraction remaining viable even after 96 h. Survival of parasites does not appear to require nutrient uptake. Thus, intraerythrocytic parasites with inhibited mitochondrial electron transport and collapsed mitochondrial membrane potential do not undergo apoptosis but enter an apparent static state. These results have significant implications for desirable properties of antimalarials under development that target mitochondrial functions.


Consumption effect of a formula with extended release carbohydrates on the glycemic response and post prandial insulin in healthy individuals.
There are specific formulas of enteral nutrition to improve glycemic control in diabetic patients containing different types of carbohydrates which glycemic response should be investigated. The consumption effect of a formula with carbohydrates with extended release was determined on the glycemic response and postprandial insulin in 21 healthy individuals (11 men and 10 women) from 17 to 25 years old, who consumed in two different time the polymeric enteral formula for diabetics and the reference food (white bread) in a quantity of 50 g of available carbohydrates. The glycemia was measured at 0, 15, 30, 45, 60, 75, 90, 105 and 120 min and the insulin concentrations in fasting and within 120 min. The area in the glycemic curve was measured being the lowest the formula 11718.20. ± 1112.38 than in white bread 13269.18 ± 1351.05 (P<0.001). The glycemic index (GI) resulted to be intermediate (63.33±5.22) and lower when compared to the GT ranks published for the reference food (80-96). A lower concentration of glycemia occurred after the consumption of the formula, without increments in the insulin requirements; thus, assuming an adequate use in diabetic and a more extended feeling of fullness. This effect and the glycated hemoglobin should be studied after the extended consumption in people with diabetes.


The effect of secukinumab treatment on hematological parameters in ankylosing spondylitis and psoriatic arthritis.
Secukinumab, a new treatment agent, selectively neutralizes interleukin (IL)-17A. It is used in the treatment of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and psoriasis. It is known that the agents used in the treatment of rheumatic diseases have effects on hematological parameters. In this study, we aimed to determine whether hematological parameters are affected in secukinumab therapy in patients with AS and PsA. Thirty-six patients on secukinumab treatment were included in the study by scanning the database of our hospital. Data on patients' age, gender, complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), uric acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine values, and additional drug treatments were recorded from our database. The 0- and 6-month values of patients were analyzed. Sixteen males (44.4%) and 20 females (55.6%) were included in our study. The average age was calculated to be 39.8±8.9 years. Of these, 30 patients receiving secukinumab treatment were diagnosed with AS, and 6 patients were diagnosed with PsA. Twenty-three patients (63.9%) were continued with secukinumab treatment at the 6th month. When CBC, glucose, urea, creatine, AST, ALT, ESR, CRP, and uric acid values of the patients at 0 and 6 months were compared, there was no significant difference. In our study, no significant difference was found between 0 and 6 months in terms of CBC, AST, ALT, urea, creatinine, uric acid, glucose, CRP, and ESR levels in patients receiving secukinumab. However, an increase in hemoglobin values was observed in patients who continued the treatment. These results may suggest that secukinumab treatment has no negative effects on hematological parameters.


Hint1 Overexpression Inhibits the Cell Cycle and Induces Cell Apoptosis in Human Osteosarcoma Cells.
New evidence suggests that histidine triad nucleotide-binding protein 1 (Hint1) exerts a tumor suppressor effect in various human tumors, such as colorectal cancer and gastric cancer. However, it has not been reported whether Hint1 is involved in the occurrence and development of osteosarcoma (OS). The present study investigated the role of Hint1 in human OS cells by using cell lines, including 143B, U2OS, KHOS-240S, Saos-2 and MG-63. Cell proliferation and apoptosis were detected by flow cytometry. The present result revealed that Hint1 is downregulated in these cell lines. The overexpression of Hint1 by adenovirus transfection in 143B and MG63 cell lines suppressed the proliferation and cell cycle, and increased the cell apoptosis. Mechanically, it was found that Hint1 downregulated the cyclin D1 expression via FOXO1 inhibition. Furthermore, FOXO1 overexpression in the 143B and MG63 cell lines significantly blurred the effects of Hint1 on cellular proliferation and apoptosis. The present study indicates that Hint1 inhibits the development of OS by regulating FoxO1-cyclin D1, suggesting that Hint1 may be a new method for the treatment of OS.


A Type IV-A CRISPR-Cas System in Pseudomonas aeruginosa Mediates RNA-Guided Plasmid Interference In Vivo.
Bacteria and archaea use CRISPR-Cas adaptive immune systems to destroy complementary nucleic acids using RNAs derived from CRISPR loci. Here, we provide the first functional evidence for type IV CRISPR-Cas, demonstrating that the system from Pseudomonas aeruginosa strain PA83 mediates RNA-guided interference against a plasmid in vivo, both clearing the plasmid and inhibiting its uptake. This interference depends on the putative NTP-dependent helicase activity of Csf4/DinG.


Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation.
We quantified urinary levels of two metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in people who had stopped smoking: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its O-glucuronide, 4-[(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-beta-O-D-glucosiduronic acid (NNAL-Gluc). Twenty-seven people completed the study. Thirteen used the nicotine patch starting at the quit date, whereas the others used no patch. Two 24-h urine samples were collected on 2 consecutive days before smoking cessation; blood was also obtained. Beginning at their quit date, subjects provided 24-h urine samples on days 7, 21, 42, 70, 98, and 126, and some subjects also provided samples at later times. The urine was analyzed for NNAL, NNAL-Gluc, nicotine plus nicotine-N-glucuronide, and cotinine plus cotinine-N-glucuronide. Some blood samples were also analyzed for NNAL. The decline of urinary NNAL and NNAL-Gluc after smoking cessation was much slower than expected. This was clearly demonstrated by comparison with cotinine and nicotine levels in urine. One week after smoking cessation, 34.5% of baseline NNAL plus NNAL-Gluc was detected in urine, whereas the corresponding values for cotinine and nicotine were 1.1 and 0.5%, respectively. Even 6 weeks after cessation, 7.6% of the original levels of NNAL plus NNAL-Gluc remained. In some subjects, NNAL plus NNAL-Gluc were detected 281 days after cessation. The distribution half-life for NNAL and NNAL-Gluc was 3-4 days, whereas the elimination half-life was 40-45 days. Total body clearance of NNAL was estimated to be 61.4 +/- 35.4 ml/min, and volume of distribution in the beta-phase was estimated to be 3800 +/- 2100 liters, indicating substantial distribution into the tissues. Parallel studies in rats treated chronically or acutely with NNK in the drinking water support the conclusion that NNAL has a large volume of distribution. There was no effect of the nicotine patch on levels of NNAL plus NNAL-Gluc, indicating that NNK is not formed endogenously from nicotine. The results of this study demonstrate that NNAL and NNAL-Gluc are slowly cleared from the body after smoking cessation, indicating the presence of a high-affinity compartment where NNK, NNAL, and/or NNAL-Gluc are retained or sequestered and slowly released.


Evaluation of knowledge, awareness, and attitude toward emergency dental trauma management among the school teachers of Kolkata.
Traumatic dental injuries (TDIs) are very common in childhood. Majority of TDI occur at home followed by schools. The prognosis of TDIs to a great extent is dependent on prompt emergency measures taken at the site of accident. Hence, it is of paramount importance to assess the knowledge of people present at the site of accident that generally includes parents, teachers, and sports coaches. The aim of the study was to assess the knowledge, attitude, and awareness of school teachers of Kolkata regarding management of TDIs. A cross-sectional survey was conducted on 400 school teachers of Kolkata over a period of 2 months using a pretested close-ended questionnaire. The questionnaire had three parts: Part 1 contained questions on personal information, Part 2 contained questions based on two imaginary cases of trauma, and Part 3 related to their attitude toward dental trauma education. Chi-square test was done to describe the strength of the associations. The overall knowledge of school teachers regarding management of TDIs was not found to be satisfactory. It was observed that most of the teachers were in favor of taking immediate professional consultation for the emergency management, but most of them were unaware of the steps to be taken on their part to minimize complications and improve prognosis. Despite the lack of knowledge and awareness regarding management of dental trauma, school teachers of Kolkata had a good attitude toward management of dental trauma and its education.


Cancer Among Adolescents and Young Adults Between 2000 and 2016 in France: Incidence and Improved Survival.
Purpose: This study was undertaken to determine cancer survival and describe the spectrum of cancers diagnosed among French adolescent and young adult (AYA) population. Methods: All cases of cancer diagnosed in 15-24 years, recorded by all French population-based registries (18% of the French population), over the 2000-2016 period, were included. Age-standardized incidence rates, conventional annual percentage change (cAPC) of incidence over time, and 5-year overall survival (5yOS) were calculated. Results: We analyzed 2734 cancer diagnoses in adolescents and 4199 in young adults. Overall incidence rates were 231.9/106 in 15-19 year olds and 354.0/106 in 20-24 year olds. The most frequently diagnosed cancers in male AYA were malignant gonadal germ-cell tumors (GCT), Hodgkin lymphoma (HL), and malignant melanoma and were HL, thyroid carcinoma, and malignant melanoma in females. Cancer incidence was stable over time with a cAPC of 0.8% (p = 0.72). For all cancers combined, 5yOS was 86.6% (95% CI: 85.8-87.4), >85% for HL, non-Hodgkin lymphomas (NHL), GCT, thyroid carcinomas, and malignant melanomas, and around 60% and lower for osteosarcomas, Ewing tumors, hepatic carcinomas, and rhabdomyosarcomas. The 5yOS has significantly improved from 2000-2007 to 2008-2015 for all cancers pooled, with a substantial gain of 4% for 15-19 year olds and 3% for 20-24 year olds. Conclusion: Notwithstanding the encouraging results for some cancers, and overall, persistent poorer survivals in AYA were shown compared to children for acute lymphoblastic leukemia, osteosarcoma, Ewing tumor, rhabdomyosarcoma, and malignant hepatic tumors. These disparities require further investigation to identify and address the causes of these inferior outcomes.


The Implantable Pediatric Artificial Lung: Interim Report on the Development of an End-Stage Lung Failure Model.
An implantable pediatric artificial lung (PAL) may serve as a bridge to lung transplantation for children with end-stage lung failure (ESLF); however, an animal model of pediatric lung failure is needed to evaluate the efficacy of PAL before it can enter clinical trials. The objective of this study was to assess ligation of the right pulmonary artery (rPA) as a model for pediatric ESLF. Seven lambs weighing 20-30 kg underwent rPA ligation and were recovered and monitored for up to 4 days. Intraoperatively, rPA ligation significantly increased physiologic dead space fraction (Vd/Vt; baseline = 48.6 ± 5.7%, rPA ligation = 60.1 ± 5.2%, p = 0.012), mean pulmonary arterial pressure (mPPA; baseline = 17.4 ± 2.2 mm Hg, rPA ligation = 28.5 ± 5.2 mm Hg, p < 0.001), and arterial partial pressure of carbon dioxide (baseline = 40.4 ± 9.3 mm Hg, rPA ligation = 57.3 ± 12.7 mm Hg, p = 0.026). Of the seven lambs, three were unable to be weaned from mechanical ventilation postoperatively, three were successfully weaned but suffered cardiorespiratory failure within 4 days, and one survived all 4 days. All four animals that were successfully weaned from mechanical ventilation had persistent pulmonary hypertension (mPPA = 28.6 ± 2.2 mm Hg) and remained tachypneic (respiratory rate = 63 ± 21 min). Three of the four recovered lambs required supplemental oxygen. We conclude that rPA ligation creates the physiologic derangements commonly seen in pediatric ESLF and may be suitable for testing and implanting a PAL.


Sonochemically Prepared BSA Microspheres as Adsorbents for the Removal of Organic Pollutants from Water.
This work investigates, for the first time, the application of sonochemically prepared bovine serum albumin (BSA) microspheres (BSAMS) as adsorbents of industrial organic pollutant dyes, such as rhodamine B (RhB), rhodamine 6G (Rh6G), and methylene blue (MB). These dyes also serve as model compounds for other organic pollutants such as bisphenol A and 2-nitrophenol. Adsorption kinetics of the dyes by the BSAMS was studied using pseudo-first-order (PFO) and pseudo-second-order (PSO) kinetic models. It was found that RhB follows PFO, with an adsorption capacity, qe,cal, of 7.9 mg/g, which was closer to the experimental adsorption capacity of qe,exp. of 7.6 mg/g. However, MB and Rh6G were controlled by PSO kinetics, with a qe,cal of 5.6 mg/g for MB and 6.6 mg/g for Rh6G, closer to the experimental adsorption capacity of 5.7 and 6.4 mg/g, respectively. The intraparticle diffusion (ID) model applied to the three dyes indicated multi-linearity with ID as the rate-limiting step in the adsorption process. Furthermore, the adsorption equilibria for each of the organic pollutants were studied through various isotherm models such as Langmuir, Freundlich, Temkin, and Halsey, which indicated physical interaction between the BSAMS and the dye pollutants, thus suggesting the applicability of the BSAMS as pollutant adsorbent materials. It was found that the BSAMS can effectively remove RhB, MB, and Rh6G from wastewater with efficiencies of 95.5, 83.3, and 97.9%, respectively.


Musical training orchestrates coordinated neuroplasticity in auditory brainstem and cortex to counteract age-related declines in categorical vowel perception.
Musicianship in early life is associated with pervasive changes in brain function and enhanced speech-language skills. Whether these neuroplastic benefits extend to older individuals more susceptible to cognitive decline, and for whom plasticity is weaker, has yet to be established. Here, we show that musical training offsets declines in auditory brain processing that accompanying normal aging in humans, preserving robust speech recognition late into life. We recorded both brainstem and cortical neuroelectric responses in older adults with and without modest musical training as they classified speech sounds along an acoustic-phonetic continuum. Results reveal higher temporal precision in speech-evoked responses at multiple levels of the auditory system in older musicians who were also better at differentiating phonetic categories. Older musicians also showed a closer correspondence between neural activity and perceptual performance. This suggests that musicianship strengthens brain-behavior coupling in the aging auditory system. Last, "neurometric" functions derived from unsupervised classification of neural activity established that early cortical responses could accurately predict listeners' psychometric speech identification and, more critically, that neurometric profiles were organized more categorically in older musicians. We propose that musicianship offsets age-related declines in speech listening by refining the hierarchical interplay between subcortical/cortical auditory brain representations, allowing more behaviorally relevant information carried within the neural code, and supplying more faithful templates to the brain mechanisms subserving phonetic computations. Our findings imply that robust neuroplasticity conferred by musical training is not restricted by age and may serve as an effective means to bolster speech listening skills that decline across the lifespan.


Positive margin length and highest Gleason grade of tumor at the margin predict for biochemical recurrence after radical prostatectomy in patients with organ-confined prostate cancer.
To evaluate the pathologic features after radical prostatectomy to determine if the length of positive surgical margin (PSM) and the highest Gleason grade within the tumor at the PSM could risk stratify patients for biochemical recurrence (BCR). We performed a retrospective, matched, cohort study to identify patients with pathologically organ-confined (pT2) tumors and negative nodes (pN0/Nx), receiving no adjuvant therapy. Specimens underwent single pathologist review. BCR-free survival was estimated using the Kaplan-Meier method and compared between subgroups using two-sided log-rank test. Using Classification and Regression Tree analysis (CART), we identified an optimal cutoff for the PSM length which differentiated risk for BCR. Cox proportional hazards regression models were fit to assess the association between variables and BCR-free survival. Two-hundred PSM patients were matched to 200 patients with negative surgical margins (NSM). Median follow-up was 64 months. 5 year BCR-free survival was 90% (95% CI 84-97%) in the NSM group and 70% (95% CI 63-79%) in the PSM group. There was an increased risk of BCR with any PSM. Multivariable analysis demonstrated an association with length of PSM ( > 1 mm vs. ≤ 1 mm, HR 2.29; 95% CI 1.2-4.5) and having a highest Gleason grade of the cancer focus at the margin ≥ 4 (HR 6.8; 95% CI 1.6-29). We demonstrated that patients with pathologic T2 tumors with PSM > 1 mm or a Gleason grade of tumor focus at the margin ≥ 4 are at elevated risk for BCR. However, this study suggests that patients with pT2 tumors with positive surgical margins have a relatively low risk of biochemical recurrence and adjuvant radiation may be over treating this sub population. The subsets at greatest risk for BCR may benefit from more frequent PSA monitoring to direct salvage therapies.


Experimental coronary artery stenosis accelerates kidney damage in renovascular hypertensive swine.
The impact of coronary artery stenosis (CAS) on renal injury is unknown. Here we tested whether the existence of CAS, regardless of concurrent atherosclerosis, would induce kidney injury and magnify its susceptibility to damage from coexisting hypertension (HT). Pigs (seven each) were assigned to sham, left-circumflex CAS, renovascular HT, and CAS plus HT groups. Cardiac and nonstenotic kidney functions, circulating and renal inflammatory and oxidative markers, and renal and microvascular remodeling were assessed 10 weeks later. Myocardial perfusion declined distal to CAS. Systemic levels of PGF2-α isoprostane, a marker of oxidative stress, increased in CAS and CAS plus HT, whereas single-kidney blood flow responses to acetylcholine were significantly blunted only in CAS plus HT compared with sham, HT, and CAS, indicating renovascular endothelial dysfunction. Tissue expression of inflammatory and oxidative markers were elevated in the CAS pig kidney, and further magnified in CAS plus HT, whereas angiogenic factor expression was decreased. Bendavia, a mitochondria-targeted peptide, decreased oxidative stress and improved renal function and structure in CAS. Furthermore, CAS and HT synergistically amplified glomerulosclerosis and renal fibrosis. Thus, mild myocardial ischemia, independent of systemic atherosclerosis, induced renal injury, possibly mediated by increased oxidative stress. Superimposed HT aggravates renal inflammation and endothelial dysfunction caused by CAS, and synergistically promotes kidney fibrosis, providing impetus to preserve cardiac integrity in order to protect the kidney.


Trends in total laryngectomy in the era of organ preservation: a population-based study.
To describe time trends in total laryngectomy health services utilization across the United States, such as rates of surgery, cost, length of stay, and insurance payer, and to compare this to important milestones in recommendations for laryngeal cancer treatment. Population-based cohort study. Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) 1997-2008: stratified sample of all US hospital discharges. All patients with the principal procedure of complete laryngectomy. The unit of analysis was the discharge. Between 1997 and 2008, the number of laryngectomies done in the United States decreased by 48%. New cases of laryngeal cancer decreased 33% during the same time. The proportion of patients older than 65 years decreased from 48% to 43%. Mortality for the procedure was 1.4% in 1997 and 1.1% in 2008. Mean length of stay over the study period increased from 13 days to 14 days. Mean hospital charges rose from $58,000 in 1997 to $109,000 in 2008, consistent with the overall rise in US health care costs. Medicare was the dominant insurer throughout. Home health was ordered in 50% of 2008 discharges but only 32% in 1997. The rate of total laryngectomy has dropped more than the incidence of laryngeal cancer has dropped, consistent with the trend toward nonsurgical treatment. Lower surgical volumes and/or salvage laryngectomy surgeries are hypothesized to play a role in longer length of stay, stable mortality rates despite younger patient age, and increased need for home services after discharge.


Effects of melatonin on cytokine release and healing of colonic anastomoses in an experimental sepsis model.
The present objective was to identify effects of early melatonin application on healing of anastomotic wound and inflammation in an experimental sepsis model. A total of 60 Wistar albino rats were divided into 2 groups. Cecal ligation puncture (CLP) and colonic resection anastomosis were performed on both the control group and the melatonin treatment group. Both groups were divided into 3 subgroups consisting of 10 rats each. One subgroup from each group underwent re-laparotomy at the 16th hour, the next on the 3rd day, and the final subgroup on the 7th day. Presently evaluated were effects of melatonin treatment of early sepsis on interleukin-6 (IL-6), interleukin-10 (IL-10), interferon gamma (INF-γ), and C-reactive protein (CRP) levels, as well as burst pressures (BPs), collagen and hydroxyproline (OHP) content of the anastomotic segments, histopathologic healing, immunohistochemical expressions, CD34, and transforming growth factor beta (TGF-ß). IL-6 and INF-γ levels of the treatment group showed a significant decrease at the 16th hour and an increase on the 3rd and 7th postoperative days. IL-10 levels were significantly higher at the 16th hour and significantly lower on the 3rd and 7th postoperative days in the control group (p<0.001 for each). The treatment group also showed significantly higher capillary permeability, fibroblast proliferation, and collagen deposits (p<0.001 for each). CD34 expression was significantly increased in the treatment group on the 7th postoperative day (p=0.005). Application of melatonin in early sepsis significantly improved colonic anastomotic healing in a rat model.


Is MS an auto-immune disease or a chronic gammaherpesvirus infection?
The geographical-epidemiological findings of MS over the past 75 years are reviewed. Evidence concerning PR latitude-gradients, clusters, migration patterns, and enhancement-protective factors are critically reviewed and analyzed. The evidence in genetics, twin-studies and auto-immune theories are also thoroughly scrutinized as to their possible involvement as causative factors in MS- and found to be somewhat lacking. Environmental discoveries in the Faroes and Key West clusters are reviewed for possible similar environmental causes by a deadly agent. Exogenous-environmental candidate agents over the past 35 years from measles to Marek's are reviewed and analyzed. The undisputed positive laboratory findings of MDV are discussed in relation to Bray's unusually high positive findings with EBV antigen and MS serums. The important discovery of HHV-6 in oligodendrocytes of MS brains but not controls is considered and how this might relate to MDV. The conclusion is that genetics are indeed important in the natural resistance of individual immune systems to invading infectious agents (especially herpesviruses) but genetics in general have little to do with the pathogenesis of multiple sclerosis (but HHV-6, EBV, and MDV do).


Biomarkers in the diagnosis of pleural diseases: a 2018 update.
The use of biomarkers on pleural fluid (PF) specimens may assist the decision-making process and enhance clinical diagnostic pathways. Three paradigmatic examples are heart failure, tuberculosis and, particularly, malignancy. An elevated PF concentration of the amino-terminal fragment of probrain natriuretic peptide (>1500 pg/ml) is a hallmark of acute decompensated heart failure. Adenosine deaminase, interferon-γ and interleukin-27 are three valuable biomarkers for diagnosing tuberculous pleurisy, yet only the first has been firmly established in clinical practice. Diagnostic PF biomarkers for malignancy can be classified as soluble-protein based, immunocytochemical and nucleic-acid based. Soluble markers (e.g. carcinoembryonic antigen (CEA), carbohydrate antigen 15-3, mesothelin) are only indicative of cancer, but not confirmatory. Immunocytochemical studies on PF cell blocks allow: (a) to distinguish mesothelioma from reactive mesothelial proliferations (e.g. loss of BAP1 nuclear expression, complemented by the demonstration of p16 deletion using fluorescence in situ hybridization, indicate mesothelioma); (b) to separate mesothelioma from adenocarcinoma (e.g. calretinin, CK 5/6, WT-1 and D2-40 are markers of mesothelioma, whereas CEA, EPCAM, TTF-1, napsin A, and claudin 4 are markers of carcinoma); and (c) to reveal tumor origin in pleural metastases of an unknown primary site (e.g. TTF-1 and napsin A for lung adenocarcinoma, p40 for squamous lung cancer, GATA3 and mammaglobin for breast cancer, or synaptophysin and chromogranin A for neuroendocrine tumors). Finally, PF may provide an adequate sample for analysis of molecular markers to guide patients with non-small cell lung cancer to appropriate targeted therapies. Molecular testing must include, at least, mutations of epidermal growth-factor receptor and BRAF V600E, translocations of rat osteosarcoma and anaplastic lymphoma kinase, and expression of programmed death ligand 1.


Oscillation of gas molecules in carbon nanotubes.
The dynamics of N(2) molecules blocked in open single-walled carbon nanotubes is investigated using molecular dynamics simulations. It is found that periodic axial and radial oscillations with extremely high frequency exist widely among these molecules. Between the two nanotube ends, N(2) molecules oscillate along or parallel to the nanotube axis, and their frequencies show an inverse length dependence in the range of 22 to 64 GHz. Accompanying the axial oscillation, the molecules oscillate radially with small amplitudes in the lateral potential well. The corresponding frequencies have a magnitude of several hundred gigahertz, and the maximum exceeds 1800 GHz. These periodic oscillations contribute to the molecular blockage in nanotubes.


Anti-inflammatory effects of a topical preparation containing nicotinamide, retinol, and 7-dehydrocholesterol in patients with acne: a gene expression study.
Acne vulgaris is a skin disorder of the sebaceous follicles, involving hyperkeratinization and perifollicular inflammation. Aberrant extracellular matrix remodeling due to matrix metalloproteinases (MMPs) has been associated with the presence of acne conditions. Given the complex pathophysiology of acne, novel topical therapies should include combination products that target multiple pathogenetic mechanisms. In this pilot study we investigated the changes in gene expression of extracellular MMPs, the tissue inhibitors of metalloproteinases, and proinflammatory molecules after 45 days of topical application of a combination product containing nicotinamide, retinol, and 7-dehydrocholesterol in 16 patients with inflammatory acne on their back. Skin biopsies were obtained before and after treatment for gene expression studies. Quantitative real-time polymerase chain reaction revealed a significant downregulation of MMP-1, MMP-2, MMP-9, MMP-14, interleukin-6, monocyte chemoattractant protein-1, and macrophage migration inhibitory factor. In contrast, the tissue inhibitors of metalloproteinases and transforming growth factor-β1 were significantly upregulated. The gene expression findings correlated well with the clinical treatment response. The combination of nicotinamide, retinol, and 7-dehydrocholesterol appears to be effective for acne treatment from both clinical and molecular standpoints.


Encouraging sun safety for children and adolescents.
The rise in the number of cases of skin cancers, both melanomas and nonmelanomas, has prompted increased awareness and educational efforts to limit sun exposure. Because 80% of lifetime sun exposure occurs before the age of 18, educating parents and adolescents to incorporate sun-protective behaviors into daily routines is particularly important. Education of parents is essential to establishing healthy behavior patterns in children. Educational interventions are recommended that encourage the following: using sunscreen, wearing hats with wide brims and clothing that blocks or absorbs ultraviolet rays, using sunglasses that block ultraviolet radiation, and seeking shade. Continued efforts are important through adolescence to maintain the established behaviors. School nurses are in a position to affect the health education curriculum, as well as school policies that promote sun safety behaviors.


Calcitonin and bipolar disorder: a hypothesis revisited.
Double-blind trials conducted in the early 1980s showed that subcutaneous injections of salmon calcitonin in patients suffering from mania resulted in significant decreases in irritability, euphoria and hyperactivity. Although these results were promising, there were no follow-up studies in this area. A MEDLINE search into the effect of calcitonin on neuronal tissues revealed that calcitonin affects neuronal tissues in a manner similar to that of the currently accepted mood-stabilizing agents--namely by modulating intracellular second messenger signalling mechanisms, stabilizing neuronal membranes and inhibiting neuronal calcium influx. We suggest that these effects of calcitonin on neuronal tissues, combined with earlier clinical research showing its efficacy in treating the acute symptoms of mania, make calcitonin a candidate for further research in the treatment of bipolar disorder.


Evolutionary history and stress regulation of the lectin superfamily in higher plants.
Lectins are a class of carbohydrate-binding proteins. They play roles in various biological processes. However, little is known about their evolutionary history and their functions in plant stress regulation. The availability of full genome sequences from various plant species makes it possible to perform a whole-genome exploration for further understanding their biological functions. Higher plant genomes encode large numbers of lectin proteins. Based on their domain structures and phylogenetic analyses, a new classification system has been proposed. In this system, 12 different families have been classified and four of them consist of recently identified plant lectin members. Further analyses show that some of lectin families exhibit species-specific expansion and rapid birth-and-death evolution. Tandem and segmental duplications have been regarded as the major mechanisms to drive lectin expansion although retrogenes also significantly contributed to the birth of new lectin genes in soybean and rice. Evidence shows that lectin genes have been involved in biotic/abiotic stress regulations and tandem/segmental duplications may be regarded as drivers for plants to adapt various environmental stresses through duplication followed by expression divergence. Each member of this gene superfamily may play specialized roles in a specific stress condition and function as a regulator of various environmental factors such as cold, drought and high salinity as well as biotic stresses. Our studies provide a new outline of the plant lectin gene superfamily and advance the understanding of plant lectin genes in lineage-specific expansion and their functions in biotic/abiotic stress-related developmental processes.


Thymol-Induced Chemical Leukoderma Successfully Treated with 308-Nanometer Excimer Laser.
Chemical leukoderma (CL) is an acquired depigmenting disorder caused by repeated exposure to chemical compounds. Thymol is a phenol derivative used as a preservative or antiseptic in many commercially available products. Here, we present the second reported case of CL caused by a thymol-containing compound. A 48-year-old woman presented with a 4-month history of depigmentation of the nail folds of all ten fingers. This occurred after 1 month of twice-daily application of a thymol-containing compound intended for the removal of gel nails. No improvement was noted after the product was discontinued. There was no family history of vitiligo or other autoimmune disorders. On physical exam, depigmentation of all ten proximal and lateral nail folds was seen, with accentuation on Wood's lamp exam. Partial re-pigmentation was achieved after 32 treatments with 308-nm excimer laser. A thorough history and physical exam are instrumental in differentiating CL from other causes of depigmentation. Avoidance of the offending agent is an essential part of management. It is important to note that many cosmetic products are not tightly regulated by the FDA. Excimer laser is an effective treatment for CL with a favorable side-effect profile.


Health promotion model for childhood violence prevention and exposure.
To discuss the Health Promotion Model for Violence Prevention and Exposure and intervention strategies for implementation. Violence causes physical and psychosocial harm to children. Because little collaboration exists between specialties in the USA, a model that incorporates both a public health and psychosocial approach is needed to assess the risk for exposure to violence and the effects of violence as well as developing prevention strategies. Prevention and intervention includes primary, secondary and tertiary levels that focus on either the community or individual. However, primary and secondary prevention, such as anticipatory guidance and screening, can be implemented by both community and primary care nurses. A review of the literature and on-line resources focusing on children's exposure to violence provided the basis for discussion of the commonalities and differences between the public health and psychosocial approach to assessing, preventing and intervening with children exposed to violence. This discussion led to the development of the proposed model. This model can identify more children at risk for social, physical and psychological harm because of exposure to violence. Implementing prevention or treatment interventions can decrease the impact of violence on children. This model can be implemented by public health, psychiatric and primary care nurses by incorporating the model into the well-child exam, school screenings and after-school programs. Collaboration between specialties will increase referrals for participation in anti-violence programs or treatment interventions.


THE NATURE OF THE LATENT PERIOD IN THE PHOTIC RESPONSE OF MYA ARENARIA.
The latent period in the response of Mya to illumination varies inversely as the duration of the exposure to which it is subjected. The reciprocal of the latent period, measuring the velocity of the process which underlies it, is a linear function of the exposure period. Since the duration of the exposure represents the amount of photochemical activity, it is concluded that the substances formed at that time act to catalyze a chemical reaction which determines the duration of the latent period. This explanation is in accord with the previous work on the photochemical reaction and with the effect of temperature on the latent period. As a result of the combined investigations there is presented a concrete hypothesis for the mechanism of photic reception in Mya.


Prevalence of rheumatic regional pain syndromes in adults from Mexico: a community survey using COPCORD for screening and syndrome-specific diagnostic criteria.
To assess the prevalence of rheumatic regional pain syndromes (RRPS) in 3 geographical areas of México using the Community Oriented Program in the Rheumatic Diseases (COPCORD) screening methodology and validate by expert consensus on case-based definitions. By means of an address-based sample generated through a multistage, stratified, randomized method, a cross-sectional survey was performed on adult residents (n = 12,686; age 43.6 ± 17.3 yrs; women 61.9%) of the states of Nuevo León, Yucatán, and México City. Diagnostic criteria for specific upper (Southampton group criteria) and lower limb (ad hoc expert consensus) RRPS were applied to all subjects with limb pain as detected by COPCORD questionnaire. The overall prevalence of RRPS was 5.0% (95% CI 4.7-5.4). The most frequent syndrome was rotator cuff tendinopathy (2.36%); followed by inferior heel pain (0.64%); lateral epicondylalgia (0.63%); medial epicondylalgia (0.52%); trigger finger (0.42%); carpal tunnel syndrome (0.36%); anserine bursitis (0.34%); de Quervain's tendinopathy (0.30%); shoulder bicipital tendinopathy (0.27%); trochanteric syndrome (0.11%); and Achilles tendinopathy (0.10%). There were anatomic regional variations in the prevalence of limb pain: Yucatán 3.1% (95% CI 2.5-3.6); Nuevo León 7.0% (95% CI 6.3-7.7); and México City 10.8% (95% CI 9.8-11.8). Similarly, the prevalence of RRPS showed marked geographical variation: Yucatán 2.3% (95% CI 1.8-2.8); Nuevo León 5.6% (95% CI 5.0-6.3); and México City 6.9% (95% CI 6.2-7.7). The overall prevalence of RRPS in México was 5.0%. Geographical variations raise the possibility that the prevalence of RRPS is influenced by socioeconomic, ethnic, or demographic factors.


Differentially Expressed Genes and Signaling Pathways Potentially Involved in Primary Resistance to Chemo-Immunotherapy in Advanced-Stage Gastric Cancer Patients.
Recently, the combination of chemotherapy plus nivolumab (chemo-immunotherapy) has become the standard of care for advanced-stage gastric cancer (GC) patients. However, despite its efficacy, up to 40% of patients do not respond to these treatments. Our study sought to identify variations in gene expression associated with primary resistance to chemo-immunotherapy. Diagnostic endoscopic biopsies were retrospectively obtained from advanced GC patients previously categorized as responders (R) or non-responders (NR). Thirty-four tumor biopsies (R: n = 16, NR: n = 18) were analyzed by 3′ massive analysis of cDNA ends (3′MACE). We found >30 differentially expressed genes between R and NRs. Subsequent pathway enrichment analyses demonstrated that angiogenesis and the Wnt-β-catenin signaling pathway were enriched in NRs. Concomitantly, we performed next generation sequencing (NGS) analyses in a subset of four NR patients that confirmed alterations in genes that belonged to the Wnt/β-catenin and the phosphoinositide 3-kinase (PI3K) pathways. We speculate that angiogenesis, the Wnt, and the PI3K pathways might offer actionable targets. We also discuss therapeutic alternatives for chemo-immunotherapy-resistant advanced-stage GC patients.


Clinical Risk Score for Invasive Pulmonary Aspergillosis in Patients With Liver Failure: A Retrospective Study in Zhejiang.
Purpose: The mortality of invasive pulmonary aspergillosis (IPA) in patients with liver failure was high. However, the prophylactic treatment in those patients with a high-risk factor in IPA has not been researched. Patients and methods: A multicenter, retrospective study was conducted in patients with liver failure. The study cohort of liver failure was randomly split into a training set for model development and the other served as the testing set for model verification. Multivariate analysis was performed to identify the risk factors of IPA. A weighted risk score for IPA was established. Anti-fungal treatment was prophylactically used in patients with medium and high IPA risk to evaluate the effect. Results: In total, 1,722 patients with liver failure were enrolled. Fifty-seven patients who received prophylactic treatment were excluded from the risk factor system study. About 1,665 patients were randomly split at a ratio of 2:1 into two datasets. Diabetes, glucocorticoids, plasma exchange, and hepatorenal syndrome (HRS) were risk factors in IPA in patients with liver failure, with weighted risk scores of 4, 7, 2, and 3, respectively. In the validation set and test set, the patients with risk scores of ≤ 3 presented low incidences of IPA at 4 and 2.7%. Patients with risk scores of 4-5 had an IPA incidence of 7.6% and 10.1%, and could be considered as a medium-risk group (p < 0.01 vs. the group with scores of ≤ 3), whereas those with risk scores of >5 manifested a significantly higher IPA incidence of 21.2 and 12.7%, who were considered a high-risk group (p < 0.01 vs. the groups with scores of 4-5 and >5, respectively). The IPA risk scores in the training set and the testing set were also analyzed by the ROC with an area under the ROC of 0.7152 and 0.6912. In this study, 57 patients received antifungal prophylaxis; the incidence of IPA was 1.8%, which was significantly lower after prophylactic antifungal therapy (p < 0.001). Conclusions: A weighted risk score for patients with liver failure, complicated with IPA, was established and confirmed in the testing cohort. Voriconazole prophylactic treatment to patients with liver failure with medium and high IPA risk can effectively prevent Aspergillus infection.


Winter bloom of a rare betaproteobacterium in the Arctic Ocean.
Extremely low abundance microorganisms (members of the "rare biosphere") are believed to include dormant taxa, which can sporadically become abundant following environmental triggers. Yet, microbial transitions from rare to abundant have seldom been captured in situ, and it is uncertain how widespread these transitions are. A bloom of a single ribotype (≥99% similarity in the 16S ribosomal RNA gene) of a widespread betaproteobacterium (Janthinobacterium sp.) occurred over 2 weeks in Arctic marine waters. The Janthinobacterium population was not detected microscopically in situ in January and early February, but suddenly appeared in the water column thereafter, eventually accounting for up to 20% of bacterial cells in mid February. During the bloom, this bacterium was detected at open water sites up to 50 km apart, being abundant down to more than 300 m. This event is one of the largest monospecific bacterial blooms reported in polar oceans. It is also remarkable because Betaproteobacteria are typically found only in low abundance in marine environments. In particular, Janthinobacterium were known from non-marine habitats and had previously been detected only in the rare biosphere of seawater samples, including the polar oceans. The Arctic Janthinobacterium formed mucilagenous monolayer aggregates after short (ca. 8 h) incubations, suggesting that biofilm formation may play a role in maintaining rare bacteria in pelagic marine environments. The spontaneous mass occurrence of this opportunistic rare taxon in polar waters during the energy-limited season extends current knowledge of how and when microbial transitions between rare and abundant occur in the ocean.


Circuit feedback increases activity level of a circuit input through interactions with intrinsic properties.
Central pattern generator (CPG) motor circuits underlying rhythmic behaviors provide feedback to the projection neuron inputs that drive these circuits. This feedback elicits projection neuron bursting linked to CPG rhythms. The brief periodic interruptions in projection neuron activity in turn influence CPG output, gate sensory input, and enable coordination of multiple target CPGs. However, despite the importance of the projection neuron activity level for circuit output, it remains unknown whether feedback also regulates projection neuron intraburst firing rates. I addressed this issue using identified neurons in the stomatogastric nervous system of the crab, Cancer borealis, a small motor system controlling chewing and filtering of food. Mechanosensory input triggers long-lasting activation of two projection neurons to elicit a chewing rhythm, during which their activity is patterned by circuit feedback. Here I show that feedback increases the intraburst firing rate of only one of the two projection neurons (commissural projection neuron 2: CPN2). Furthermore, this is not a fixed property because the CPN2 intraburst firing rate is decreased instead of increased by feedback when a chewing rhythm is activated by a different modulatory input. I establish that a feedback pathway that does not impact the CPN2 activity level in the control state inhibits CPN2 sufficiently to trigger postinhibitory rebound following mechanosensory stimulation. The rebound increases the CPN2 intraburst firing rate above the rate due only to mechanosensory activation of CPN2. Thus in addition to patterning projection neuron activity, circuit feedback can adjust the intraburst firing rate, demonstrating a novel functional role for circuit feedback to central projection neurons.NEW & NOTEWORTHY Feedback from central pattern generator (CPG) circuits patterns activity of their projection neuron inputs. However, whether the intraburst firing rate between rhythmic feedback inhibition is also impacted by CPG feedback was not known. I establish that CPG feedback can alter the projection neuron intraburst firing rate through interactions with projection neuron intrinsic properties. The contribution of feedback to projection neuron activity level is specific to the modulatory condition, demonstrating a state dependence for this novel role of circuit feedback.


Prognostic Value of Excision Repair Cross-Complementing Gene 1, Dihydropyrimidine Dehydrogenase, and Human Equilibrative Nucleotide Transporter 1 Expression and Their Implications for Adjuvant Treatment in Patients With Ampullary Carcinoma.
The purpose of this study was to characterize the intratumoral expression profiles of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), and human equilibrative nucleotide transporter 1 (hENT1) in ampullary carcinomas (ACs) to evaluate their prognostic values and better tailor adjuvant chemotherapy for individual patients with AC after surgery. This study included 49 patients with AC who underwent a curative pancreaticoduodenectomy. Various clinicopathological factors, including ERCC1, DPD, and hENT1, were analyzed in relation to postoperative disease recurrence and the patients' survival. The median recurrence-free survival and overall survival were 24.5 months and 32.4 months, respectively. Multivariate Cox regression analysis of recurrence-free survival identified a DPD expression (hazard ratio [HR], 8.18; 95% confidence interval [CI], 2.00-34.8; P = 0.003) and combined ERCC1/DPD expression (HR, 134.8; 95% CI, 11.8-1920; P < 0.001) as independent predictors of disease recurrence. Multivariate Cox regression analysis of overall survival also identified a DPD expression (HR, 8.48; 95% CI, 1.71-46.3; P = 0.008) and combined ERCC1/ DPD expression (HR, 135.6; 95% CI, 11.8-1940; P < 0.001) as independent predictors of survival. The DPD and ERCC1 expression profile could potentially serve as a useful prognostic biomarker and therapeutic target for surgically resected patients with AC.