The role of deep learning in urban water management: A critical review.
Deep learning techniques and algorithms are emerging as a disruptive technology with the potential to transform global economies, environments and societies. They have been applied to planning and management problems of urban water systems in general, however, there is lack of a systematic review of the current state of deep learning applications and an examination of potential directions where deep learning can contribute to solving urban water challenges. Here we provide such a review, covering water demand forecasting, leakage and contamination detection, sewer defect assessment, wastewater system state prediction, asset monitoring and urban flooding. We find that the application of deep learning techniques is still at an early stage as most studies used benchmark networks, synthetic data, laboratory or pilot systems to test the performance of deep learning methods with no practical adoption reported. Leakage detection is perhaps at the forefront of receiving practical implementation into day-to-day operation and management of urban water systems, compared with other problems reviewed. Five research challenges, i.e., data privacy, algorithmic development, explainability and trustworthiness, multi-agent systems and digital twins, are identified as key areas to advance the application and implementation of deep learning in urban water management. Future research and application of deep learning systems are expected to drive urban water systems towards high intelligence and autonomy. We hope this review will inspire research and development that can harness the power of deep learning to help achieve sustainable water management and digitalise the water sector across the world.


Creation of pneumoperitoneum using a bladed optical trocar in morbidly obese patients: technique and results.
It is advised by the manufacturer that the bladed optical trocar is to be applied only after CO(2) insufflation. However, after a long experience with bladed optical trocars after CO(2) insufflation in bariatric patients, we found that it is possible to enter the abdomen with this trocar prior to insufflation. This investigation was performed to test the hypothesis that this bladed technique under direct visualization before abdominal insufflation is a safe and effective method for initial trocar placement for laparoscopic bariatric procedures. Data on a series of 200 consecutive laparoscopic bariatric procedures with bladed optical access trocar were reviewed. The entry time for the optical trocar was measured in 70 patients. All the operative reports were reviewed for the following data: (1) successful initial trocar placement, (2) vascular injury during initial trocar placement, and (3) hollow viscus injury accessing the peritoneal cavity with bladed trocar. The trocar placement time was defined as the time to place the trocar into the peritoneal cavity after skin incision and was recorded in the last 70 cases. There was no evidence of any vascular injury during initial trocar placement. There was no evidence of hollow viscus or organ injury during initial trocar placement. The insertion of the initial trocar was successful in all the patients. The average trocar insertion time was 20 s (range 10-50), and BMI did not affect the time of insertion. We think that our technique of entering the abdominal cavity via a bladed optical trocar without prior abdominal insufflation can be performed safely in morbidly obese patients. More studies and larger series are needed to validate this method.


Is there evidence in the EEG for increased epileptiform activity in ICD-10 acute and transient psychotic disorder?
The aim of this study was to examine whether there is electroencephalographic evidence for an increased epileptiform activity in the EEG of ICD-10 acute and transient psychotic disorders (ATPD; F23) as a hint for a closer relationship to epilepsy. We analyzed the EEGs of 39 inpatients with ATPD, comparing them with 'positive' schizophrenic and bipolar schizoaffective controls matched for age and gender. The evaluation was performed visually and qualitatively using a rating scale of demonstrated reliability. We found no indication of an increased incidence of epileptiform discharges in ATPD compared with 'positive' schizophrenic and bipolar schizoaffective controls. The hypothesis of a relationship between ATPD and epilepsy could not be confirmed by EEG findings.


Expression of calbindin-D28k in C6 glial cells stabilizes intracellular calcium levels and protects against apoptosis induced by calcium ionophore and amyloid beta-peptide.
The calcium binding protein, calbindin-D28k is normally present in neurons. Recently we reported that brain injury and tumor necrosis factors (TNFs) induce calbindin-D28k in astrocytes. TNF-treated calbindin expressing astrocytes were resistant to acidosis and calcium ionophore toxicity, suggesting that calbindin may have a cytoprotective role in astrocytes in the injured brain (M.P. Mattson, B. Cheng, S.A. Baldwin, V.L. Smith-Swintosky, J. Keller, J. Geddes, Scheff, J.W., Christakos, S., Brain injury and tumor necrosis factors induce calbindin-D28k in astrocytes: evidence for a cytoprotective response, J. Neurosci. Res., 42 (1995) 257). In order to obtain direct evidence for a role of calbindin, using the eukaryotic expression vector pREP4, rat calbindin-D28k was stably expressed in C6 rat astocytoma glial cells. Cytotoxicity in response to calcium ionophore or amyloid beta-peptide (which accumulates in the brain in Alzheimer's disease and has been reported to be neurotoxic) was measured by MTT reduction in vector transfected cells and in calbindin transfected clones. Stably expressed calbindin resulted in increased cell survival in the presence of calcium ionophore (1-10 microM) or amyloid beta-peptide (10-100 microM). In addition, the calcium ionophore or amyloid beta-peptide mediated rise in intracellular calcium in vector transfected cells was significantly attenuated in calbindin expressing cells. Apoptotic cell death was detected by the Hoechst method in vector transfected C6 glial cells treated with calcium ionophore or beta-amyloid (34-36% apoptotic cells/culture). The number of apoptotic nuclei was significantly attenuated in similarly treated calbindin-D28k transfected clones (10-13% apoptotic cells/culture; p<0.01). Our results support the involvement of calcium fluxes in apoptosis and suggest that calbindin-D28k, by buffering calcium, can suppress death in apoptosis susceptible cells in the central nervous system.


STING/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease.
Hypertension is a primary modifiable risk factor for cardiovascular diseases, which often induces renal end-organ damage and complicates chronic kidney disease (CKD). In the present study, histological analysis of human kidney samples revealed that hypertension induced mtDNA leakage and promoted the expression of stimulator of interferon genes (STING) in renal epithelial cells. We used angiotensin II (AngII)- and 2K1C-treated mouse kidneys to elucidate the underlying mechanisms. Abnormal renal mtDNA packing caused by AngII promoted STING-dependent production of inflammatory cytokines, macrophage infiltration, and a fibrogenic response. STING knockout significantly decreased nuclear factor-κB activation and immune cell infiltration, attenuating tubule atrophy and extracellular matrix accumulation in vivo and in vitro. These effects delayed CKD progression. Immunoprecipitation assays and liquid chromatography-tandem mass spectrometry showed that STING and ACSL4 were directly combined at the D53 and K412 amino acids of ACSL4. Furthermore, STING induced renal inflammatory response and fibrosis through ACSL4-dependent ferroptosis. Last, inhibition of ACSL4 using small interfering RNA, rosiglitazone, or Fer-1 downregulated AngII-induced mtDNA-STING-dependent renal inflammation. These results suggest that targeting the STING/ACSL4 axis might represent a potential strategy for treating hypertension-associated CKD.


Joint EANM/SNMMI guideline on radiomics in nuclear medicine : Jointly supported by the EANM Physics Committee and the SNMMI Physics, Instrumentation and Data Sciences Council.
The purpose of this guideline is to provide comprehensive information on best practices for robust radiomics analyses for both hand-crafted and deep learning-based approaches. In a cooperative effort between the EANM and SNMMI, we agreed upon current best practices and recommendations for relevant aspects of radiomics analyses, including study design, quality assurance, data collection, impact of acquisition and reconstruction, detection and segmentation, feature standardization and implementation, as well as appropriate modelling schemes, model evaluation, and interpretation. We also offer an outlook for future perspectives. Radiomics is a very quickly evolving field of research. The present guideline focused on established findings as well as recommendations based on the state of the art. Though this guideline recognizes both hand-crafted and deep learning-based radiomics approaches, it primarily focuses on the former as this field is more mature. This guideline will be updated once more studies and results have contributed to improved consensus regarding the application of deep learning methods for radiomics. Although methodological recommendations in the present document are valid for most medical image modalities, we focus here on nuclear medicine, and specific recommendations when necessary are made for PET/CT, PET/MR, and quantitative SPECT.


Avoiding the potentiality trap: thinking about the moral status of synthetic embryos.
Research ethics committees must sometimes deliberate about objects that do not fit nicely into any existing category. This is currently the case with the "gastruloid," which is a self-assembling blob of cells that resembles a human embryo. The resemblance makes it tempting to group it with other members of that kind, and thus to ask whether gastruloids really are embryos. But fitting an ambiguous object into an existing category with well-worn pathways in research ethics, like the embryo, is only a temporary fix. The bigger problem is that we no longer know what an embryo is. We haven't had a non-absurd definition of 'embryo' for several decades and without a well-defined comparison class, asking whether gastruloids belong to the morally relevant class of things we call embryos is to ask a question without an answer. What's the alternative? A better approach needs to avoid what I'll refer to as "the potentiality trap" and, instead, rely on the emergence of morally salient facts about gastruloids and other synthetic embryos.


Biochemical assessment of nutritional status in patients with chronic obstructive pulmonary disease and acute respiratory failure on admission to an intensive care unit.
Although chronic obstructive pulmonary disease (COPD) is associated with weight loss and malnutrition, there is a paucity of relevant data on COPD patients with acute respiratory failure (ARF). We studied 30 consecutive patients on the day of admission to our intensive care unit for ARF. In addition to a clinical work-up, the following biochemical parameters were determined: markers of nutritional status (albumin - ALB, transferrin - TRF, transthyretin - TTR, retinol binding protein - RBP, fibronectin), inflammation (C-reactive protein - CRP, alpha(1) glycoprotein acid - alpha(1)GPA) and catabolism (plasma phenylalanine - PHE, urinary 3-methylhistidine - 3-MH). Values were expressed as mean +/- SD and compared to those of 10 healthy subjects matched for age. COPD-ARF patients had a poor protein status (ALB = 30 +/- 5 vs 42 +/- 3 g.l(-1); TTR = 118 +/- 75 vs 251 +/- 43 mg.l(-1); RBP = 23 +/- 12 vs 46 +/- 8 mg.l(-1); p < 0.001), were hypercatabolic (3-MH Cr = 31 +/- 12 vs 22 +/- 7 mumol.mmol Cr (-1); PHE = 62 +/- 27 vs 46 +/- 10 mumol.l(-1); p < 0.001) and inflamed (CRP = 68 +/- 50 vs 12 +/- 5 mg.l(-1); alpha(1)GPA = 1.2 +/- 0.4 vs 0.5 +/- 0.1 g.l(-1); p < 0.001). Severity of the disease correlated with short half-life proteins and protein catabolism markers but not with inflammation markers. Considering ALB, TTR, RBP, the 3- MH Cr ratio and PHE values, the 30 COPD patients fell into 3 groups: chronic malnutrition (n = 7), acute malnutrition (n = 2), and acute + chronic malnutrition (n = 18). 3 patients had normal nutritional status. We conclude that an assessment of nutritional status at admission to intensive care units could contribute towards a rapid formulation of specific nutritional therapy.


Juggling on a rollercoaster? Gains, loss and uncertainties in IVF patients' accounts of volunteering for a U.K. 'egg sharing for research' scheme.
The past decade has seen a growth in demand for human eggs for stem cell related research and, more recently, for mitochondrial research. That demand has been accompanied by global debates over whether women should be encouraged, by offers of payments, in cash or kind, to provide eggs. Few of these debates have been informed by empirical evidence, let alone by the views of women themselves. This article addresses that gap in knowledge by presenting findings from a UK investigation, conducted 2008-2011, which is the first systematic study of women volunteering to provide eggs under such circumstances. This article focuses on the views and experiences of 25 IVF patients who volunteered for the Newcastle 'egg sharing for research' scheme (NESR), in exchange for reduced IVF fees. This was an interview based study, designed to gain understandings of volunteers' perspectives and reasoning. The interviews show that volunteers approached the scheme as a way of accessing more treatment in pursuit of their goal of having a baby, against a landscape of inadequate state provision of treatment and expensive private treatment. The process of deciding to volunteer raised a wide range of uncertainties about the consequent gains and losses, for women already in the uncertain world of the 'IVF rollercoaster'. However, interviewees preferred to have the option of the NESR, than not, and they juggled the numerous uncertainties with skill and resilience. The article is as revealing of the ongoing challenges of the UK IVF bio-economy as it is of egg provision. This article adds to the growing body of knowledge of the contributions of tissue providers to the global bio-economy. It also contributes to several areas of wider sociological interest, including debates on the social management of 'uncertainty' and discussions at the interface of sociology and ethics.


Improving myocardial metabolic and functional recovery after cardioplegic arrest.
The myocardial oxidation of fatty acids and glucose, the predominant substrates for aerobic metabolism, is impaired after cardioplegic arrest for coronary revascularization. Because lactate can be readily metabolized to pyruvate, it may be the preferred substrate for aerobic metabolism after cardioplegic arrest when arterial concentrations are elevated. Nineteen patients undergoing elective coronary revascularization with blood cardioplegia were randomized to receive LOW (nine patients, no exogenous lactate) or HIGH (10 patients, a perioperative infusion of Ringer's lactate) arterial lactate concentrations. Coronary sinus catheterization and lactate labeled with carbon 14 permitted calculation of myocardial oxygen consumption and lactate oxidation which were significantly increased during reperfusion in the group with HIGH arterial lactate concentrations. Atrial pacing at 110 beats/min on cardiopulmonary bypass resulted in myocardial lactate production (suggesting ischemic anaerobic metabolism) in the LOW lactate group, but atrial pacing increased lactate consumption and oxidation in the HIGH lactate group (suggesting increased aerobic metabolism). Systolic function (the relation between end-systolic pressure and volume) as assessed by nuclear ventriculography 3 hours postoperatively was significantly better (p less than 0.05 by analysis of covariance) in the HIGH lactate group. Postoperative myocardial creatine kinase release was significantly lower in the HIGH lactate group, which suggested less perioperative ischemic injury. Lactate was the preferred substrate for myocardial oxidative metabolism after cardioplegic arrest, and the higher arterial lactate concentrations improved myocardial metabolic and functional recovery and reduced perioperative ischemic injury.


Objective and self-perceived lower limb weakness in Parkinson's disease.
Lower limb weakness is a long-recognized symptom in patients with Parkinson's disease (PD), described by James Parkinson in his seminal report on 'paralysis agitans'. However, little is known on the frequency, clinical correlations, and association with objective decrease in muscle strength in such patients. The objective of this study was to assess the frequency of objective and perceived lower limb weakness in patients with PD. We studied 90 consecutive patients with PD and 52 age-matched controls. We recorded clinical and demographic variables, as well as perceived weakness and allied abnormal lower limb sensations, including 'heavy legs', 'fatigued legs', and 'pain'. Symptoms consistent with restless legs syndrome were not considered. Lower limb strength was determined in both legs by means of the Medical Research Council scale, dynamometric (leg flexion) and weighting machine (leg pressure) measures. Weakness and allied abnormal lower limb sensations were reported in 69% of patients with PD and 21% of healthy controls. Patients with PD had decreased leg pressure compared with healthy controls (p = 0.002). Among patients with PD, an association between perceived leg weakness (and allied sensations) and gait freezing (p = 0.001) was observed in the multivariate regression analysis; however, these variables only explained 30.4% of the variance. Moreover, PD patients with and without abnormal lower limb sensations had similar muscle strength by objective measurements. Perceived lower limb weakness and allied abnormal sensations are common in patients with PD. However, there is a dissociation between perceived weakness and objective muscle strength in the lower limbs. These abnormal sensations were mostly related to gait freezing but a causal association is questionable.


Carbamazepine enhances the activity of glutamate transporter type 3 via phosphatidylinositol 3-kinase.
Glutamate transporters (also called excitatory amino acid transporters, EAAT) participate in maintaining extracellular homeostasis of glutamate, a major excitatory neurotransmitter, and regulating glutamate neurotransmission. EAAT3, the major neuronal EAAT, may also regulate gamma-aminobutyric acid-mediated inhibitory neurotransmission. Dysfunction of EAAT3 has been shown to induce seizure in rats. We hypothesize that carbamazepine, a commonly used antiepileptic agent, enhances EAAT3 activity. We tested this hypothesis using oocytes artificially expressing EAAT3 and C6 rat glioma cells expressing endogenous EAAT3. In oocytes, carbamazepine dose-dependently enhanced EAAT3 activity. The EC50 of this carbamazepine effect was 12.2muM. The concentrations of carbamazepine to significantly enhance EAAT3 activity were within the therapeutic serum levels (17-51muM) of carbamazepine for the antiepileptic effect. Carbamazepine decreased the Km but did not change the maximal response of EAAT3 to glutamate. Carbamazepine-increased EAAT3 activity was inhibited by wortmannin or LY-294002, phosphatidylinositol 3-kinase (PI3K) inhibitors, but was not affected by staurosporine, chelerythrine or calphostin C, protein kinase C inhibitors. In C6 cells, carbamazepine also enhanced the endogenous EAAT3 activity. However, carbamazepine did not affect the activity of EAAT4 expressed in Cos7 cells. These results suggest that carbamazepine at clinically relevant concentrations specifically enhances the affinity of EAAT3 for glutamate to increase EAAT3 activity via a PI3K-dependent pathway. EAAT3 may be a therapeutic target for carbamazepine in the central nervous system.


The care and feeding of a commercial liposomal product: liposomal amphotericin B (AmBisome®).
AmBisome (liposomal amphotericin B) is among the earliest approved liposomal therapeutics, and has been in commercial use since the early 1990s. This review provides examples of non-clinical, regulatory, clinical label expansion, adverse event management, and supply chain control reflecting the real world challenges of a commercial liposomal therapeutic. We review examples of post-approval clinical development in severe lung infections, development of US and European guidance documents around liposomal therapeutics, the creation of a suitable placebo for blinded clinical trials, response to findings of a possible new category of adverse event (what turned out to be pseudohyperphosphatemia), challenges in handling the finished product in a setting with high risk of exposure of the product to temperatures outside of the established label storage conditions, and elements of continuingly increased aseptic processing requirements for manufacturing.


An economical solution to record and control wheel-running for group-housed mice.
The effects of exercise on brain function are widely known; however, there is a need for inexpensive, practical solutions for monitoring and metering the activity of multiple mice. A contoured running wheel that has a built-in radio-frequency identification (RFID) receiver to monitor the activity of several mice in a single cage is presented. This system is scalable , the interface is easy to use, and the wheel can be dynamically locked so that each group-housed mouse receives a set exercise regimen. We were able to reliably monitor three mice that were group-housed. We were able to reliably meter the amount of exercise performed by the mice using the servo-controlled lock. Current methods allow a wheel to be locked when a set distance is reached. However, an issue with this method is that the set distance includes the cumulative activity of all mice in the cage so one mouse could contribute a disproportionate amount to the total distance. Our solution ensures that the wheel is locked when an individual mouse reaches the target distance, but remains unlocked for individuals that have not reached the programmed distance. The dynamic locking wheel (DynaLok) is designed to allow a researcher to provide individually designed exercise plans for multi-housed mice; therefore, users are able to house mice conventionally rather than in individual cages. DynaLok reduces animal housing costs, allows for new experimental exercise regimens to be developed, and is scalable and cost-effective.


Radiographic aspects in transcatheter contact dissolution of calcified gallbladder concrements.
The present study on 10 patients reports upon an attempt to perform percutaneous contact dissolution of partially calcified gallbladder concrements. These gallstones, which exhibited structural calcifications on CT scans, required time-consuming complex dissolution procedures with transcatheter administration of methyl tert-butyl ether (MTBE) and ethylene diamine tetraacetic acid (EDTA). Insertion of the catheter system (5 F) was performed via a percutaneous transhepatic route. Catheter placement was maintained for a maximum of 4 days. Complete lysis was achieved in seven of the ten cases. In six patients, significant regional or disseminated chemically induced cholecystitis and pericholecystitis could be observed on CT examination. However, on follow-up CT examinations, these changes proved to be completely reversible. It has been demonstrated that tolerance of the gallbladder wall and adjacent tissue layer against the lytic media employed is rather limited and that meticulous controlling of the morphological reaction can be helpful in minimizing complications.


Kinetics of drug action in disease states. XXXIII: Disparate effects of pentylenetetrazol in rats as a function of renal disease model and pharmacologic endpoint.
The purpose of this investigation was to determine if the pharmacodynamics of the central nervous system stimulant pentylenetetrazol (PTZ) are altered in renal dysfunction. Female rats subjected to bilateral ureteral ligation (with sham-operated controls) or injected with uranyl nitrate (with saline injected controls) were infused intravenously with PTZ until the onset of either a minimal (myoclonic jerk) or maximal (tonic hindlimb extension) seizure. Neither chemically nor surgically induced renal dysfunction caused a change in the concentrations of PTZ in CSF, serum, or brain at onset of minimal seizures. When PTZ was infused to onset of maximal seizures, the rats with chemically induced renal dysfunction required higher concentrations, whereas the ureter-ligated rats convulsed at lower concentrations of PTZ than did the corresponding control animals. Thus, the effects of experimental renal dysfunction on the convulsant action of PTZ are dependent on both the disease model and the endpoint used for the pharmacodynamic measurement. Apparently, renal dysfunction did not affect the PTZ-induced seizure threshold, but inhibited the spread of seizures. The increased sensitivity of ureter-ligated rats may be due to their pronounced retention of water, since water loading is known to increase seizure susceptibility.


Topography of mutational signatures in human cancer.
The somatic mutations found in a cancer genome are imprinted by different mutational processes. Each process exhibits a characteristic mutational signature, which can be affected by the genome architecture. However, the interplay between mutational signatures and topographical genomic features has not been extensively explored. Here, we integrate mutations from 5,120 whole-genome-sequenced tumors from 40 cancer types with 516 topographical features from ENCODE to evaluate the effect of nucleosome occupancy, histone modifications, CTCF binding, replication timing, and transcription/replication strand asymmetries on the cancer-specific accumulation of mutations from distinct mutagenic processes. Most mutational signatures are affected by topographical features, with signatures of related etiologies being similarly affected. Certain signatures exhibit periodic behaviors or cancer-type-specific enrichments/depletions near topographical features, revealing further information about the processes that imprinted them. Our findings, disseminated via the COSMIC (Catalog of Somatic Mutations in Cancer) signatures database, provide a comprehensive online resource for exploring the interactions between mutational signatures and topographical features across human cancer.


A statistical test for synergism of two cell growth inhibitors.
Interaction of 2 inhibitors of cell growth can be detected by measuring the inhibiting effect of the 2 drugs separately and in combination. A control group is used as the basis for each comparison. We discuss a method for the statistical analysis of such measurements, when the basic observation is the number of cells harvested from a treated culture.


The metabolism of saddamine in man: the fate of the benzylamine moiety of saddamine.
The metabolism of 14C-saddamine radiolabelled in the benzylamine moiety has been investigated in man after oral administration. 14C-Hippuric acid was found to be the only radiolabelled urinary metabolite, the overall amount of which was equivalent to over 95% of the dose. The time taken for elimination of 50% of the dose in the urine was approximately five hours and the corresponding value for 14C-benzylamine hydrochloride was less than one hour.


Bioaccumulation and molecular effects of sediment-bound metals in zebrafish embryos.
Predicting the bioavailability and effects of metals in sediments is of major concern in context with sediment risk assessment. This study aimed to investigate the bioavailability and molecular effects of metals spiked into riverine sediments to zebrafish (Danio rerio) embryos. Embryos were exposed to a natural and an artificial sediment spiked with cadmium (Cd), copper (Cu), nickel (Ni) and zinc (Zn) individually or as a mixture at concentrations ranging from 150 to 3000 mg/kg dry weight (dw) over 48 h, and uptake of metals was determined. Furthermore, transcript abundances of the metallothioneins MT1 and MT2, the metal-responsive element-binding transcription factor (MTF) and the genes sod1, hsp70 and hsp90α1 were measured as indicators of metal-induced or general cellular stress. D. rerio embryos accumulated metals from sediments at concentrations up to 100 times greater than those spiked to the sediment with the greatest bioaccumulation factor (BAF) for Cu from artificial sediment (275.4 ± 41.9 (SD)). Embryos accumulated greater concentrations of all metals from artificial than from natural sediment, and accumulation was greater when embryos were exposed to individual metals than when they were exposed to the mixture. Exposure of embryos to Zn or the mixture exhibited up to 30-fold greater transcript abundances of MT1, MT2 and hsp70 compared to controls which is related to significant uptake of Zn from the sediment. Further changes in transcript abundances could not be related to a significant uptake of metals from sediments. These studies reveal that metals from spiked sediments are bioavailable to D. rerio embryos directly exposed to sediments and that the induction of specific genes can be used as biomarkers for the exposure of early life stages of zebrafish to metal-contaminated sediments.


[Palliative radiation of bone metastasis in the spine for symptom control and stabilisation: indication and limits].
On the basis of a case study the success of palliative radiation of metastasis of a non-small-cell lung cancer in the spine is demonstrated and the limits of this palliative therapy are discussed. Pain control seems to be the first aim, stabilisation of the spine and myelodecompression to prevent paraplegia could be another.


Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes.
Premature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. This includes two genes, REC8 and HROB, not previously associated with autosomal recessive POI. REC8 encodes a component of the cohesin complex and HROB encodes a factor that recruits MCM8/9 for DNA damage repair. In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI. We also identified novel variants in MCM8, NUP107, STAG3 and HFM1 and a known variant in POF1B. Our study highlights the pivotal role of meiosis in ovarian function. We identify novel variants, consolidate the pathogenicity of variants previously considered of unknown significance, and propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis.


Pharmacological Beta-Adrenergic Receptor Activation Attenuates Neutrophil Recruitment by a Mechanism Dependent on Nicotinic Receptor and the Spleen.
The aim of this study was to identify the effect of beta-adrenergic receptor activation on neutrophil migration in experimental peritonitis elucidating the neuroimmune components involved such as nicotinic receptors and the spleen. Mice pre-treated with mecamylamine (nicotinic antagonist) and propranolol (beta-adrenergic antagonist) or splenectomized animals were treated with isoproterenol (beta-adrenergic agonist) prior to intraperitoneal injection of carrageenan. After 4 h, the infiltrating neutrophils and the local cytokine/chemokine levels were evaluated in the peritoneal lavage. The effect of isoproterenol on neutrophil chemotaxis was investigated in a Boyden chamber. Isoproterenol inhibited neutrophil trafficking, reducing the cytokine/chemokine release and neutrophil chemotaxis. Surprisingly, the isoproterenol effect on neutrophil migration was totally reverted by splenectomy and mecamylamine pre-treatment. In contrast, the inhibitory effect of nicotine on neutrophil migration was abrogated only by splenectomy but not by propranolol pre-treatment. Collectively, our data show that beta-adrenergic receptor activation regulates the acute neutrophil recruitment via splenic nicotinic receptor.


Learning curve of endoscopic pituitary surgery: Experience of a neurosurgery/ENT collaboration.
For neurosurgeons, who are accustomed to the binocular microscope, there is a new learning curve that must be overcome for monocular endoscopic pituitary surgery. Different studies describe a learning curve between 15 and 200 procedures, after which both operative time and complications stabilize. In this retrospective study, we evaluate the endoscopic learning curve of our group, already trained in microsurgical transsphenoidal surgery, with the assistance of ear, nose, and throat (ENT) surgeons. From 2010 to 2015, a total of 95 patients with pituitary adenomas were treated with a purely endoscopic approach. The latest 48 patients treated with the endoscope (L group) were compared with the 47 initial patients treated with the endoscope (E group) and with 43 patients treated with the microscope (M group), in terms of surgical time, complications, and tumor removal rate. The complication rate was similar in all the groups, as was the rate of total adenoma resection. Mean surgical time was shorter in the L group than in the E group (115±36min vs. 157±46 min, p<0.001); the average operative time was also shorter in the L group than in the M group (135±43min). The estimated reduction in duration of surgery per 10 patients was 9min (p<0.001). Over time, blood transfusions discrepantly increased from the E group to the L group (11% vs. 31%). Because of the pivotal role of ENT in the transnasal stage of 50 endoscopic procedures, we obtained an operative time comparable to that of microscopic procedures, with similar complication rate and gross total resections. Neurosurgical-ENT combined follow-up proved to be a fundamental protection from late complications.


Autofluorescent hyperreflective foci on infrared autofluorescence adaptive optics ophthalmoscopy in central serous chorioretinopathy.
To test the hypothesis that hyperreflective foci in central serous chorioretinopathy (CSCR) are autofluorescent and may represent macrophages that have engulfed outer retinal fluorophores from the retinal pigment epithelium (RPE) and photoreceptors. Enrolled subjects underwent spectral domain and swept-source optical coherence tomography, adaptive optics flood-illumination, and adaptive optics scanning laser ophthalmoscopy (AOSLO), including near-infrared autofluorescence (AO-IRAF). For the AO-IRAF imaging, retinal fluorophores were excited using 795 nm light and collected in an emission band from 814 to 850 nm. In 2 of 3 eyes, a hyperautofluorescent signal was detected with an elliptical shape and punctate, granular aspects surrounded by a hypoautofluorescent halo. The size of these structures in the active case was measured to be 17 ± 4 μm in diameter, with at least 45 individual hyperautofluorescent foci identified from the AO-IRAF montage in the active stage of patient 2. In the asymptomatic case there were fewer structures visible (∼10) and their size was smaller (11 ± 4 μm). These hyper-AF foci were colocalized with hyperreflective foci on OCT and visible in simultaneously acquired confocal AOSLO images in active stage. The hyperautofluorescent foci in the patient with active CSCR disappeared coincident with clinical resolution. We show here the first AO-IRAF images from patients with CSCR, demonstrating hyper-autofluorescent punctate foci, colocalized with hyper-reflective foci on confocal AOSLO images and in OCT. The autofluorescence of these foci may be driven by the accumulation of photoreceptor and RPE fluorophores within macrophages during the active stage of the disease.


Re: Caron et al., 2021, sociocultural context and autistics quality of life: A comparison between Quebec and France.
This letter to the editors discusses the use of the ASQoL for research with autistic adults. The autism quality of life measure was developed for use alongside two existing measures of quality of life developed by the World Health Organization. It was not developed as a questionnaire to be used in its own. The letter raises some concerns about the use of the autism quality of life measure as a standalone measure in a recent study by Caron et al., published in Autism.


Serial Free Bisphenol A and Bisphenol A Glucuronide Concentrations in Neonates.
To determine the balance of metabolism of free bisphenol A (BPA) to the inactive conjugate, BPA glucuronide (BPAG), in neonates. Free BPA and BPAG concentrations were measured in 78 urine samples collected between December 2012 and August 2013 from a cohort of 44 healthy full term (≥ 37 weeks' gestation) neonates at 2 intervals (3-6 days and 7-27 days of age). A questionnaire was administered at the time of sample collection. Neonates recruited into the study were born in an urban, tertiary care hospital. Only BPAG was detected in the urine samples; concentrations ranged from <0.1 μg/L to 11.21 μg/L (median: 0.27 μg/L). Free BPA concentrations were below the limit of quantification of 0.1 μg/L. Age, but not sex or type of diet, was significantly associated with urinary BPAG concentration (P = .002). Our results illustrate widespread BPA exposure in healthy full-term neonates and efficient conjugation of BPA to its readily excretable and biologically inactive form (BPAG) as early as 3 days of age. Factors other than type of diet may be important contributors to BPA exposure in neonates.


The effects of urea infusion on glomerular filtration rate and renal plasma flow in sheep fed low and high protein diets.
Reducing the dietary N intake of sheep resulted in a significant fall in GFR with no change in RPF. Intravenous of urea for 19-46 h had no effect on the high protein diet but on the low protein diet GFR and FF were increased to values approaching those observed on the high protein diet. On the low protein diet GFR was unaffected by infusion of urea for 4 h or of saline alone for 30 h. It is suggested that the observed changes in GFR are associated with changes in the quantity of protein passing to the abomasum and small intestine.


Deletion of myosin VI causes slow retinal optic neuropathy and age-related macular degeneration (AMD)-relevant retinal phenotype.
The unconventional myosin VI, a member of the actin-based motor protein family of myosins, is expressed in the retina. Its deletion was previously shown to reduce amplitudes of the a- and b-waves of the electroretinogram. Analyzing wild-type and myosin VI-deficient Snell's Waltzer mice in more detail, the expression pattern of myosin VI in retinal pigment epithelium, outer limiting membrane, and outer plexiform layer could be linked with differential progressing ocular deficits. These encompassed reduced a-waves and b-waves and disturbed oscillatory potentials in the electroretinogram, photoreceptor cell death, retinal microglia infiltration, and formation of basal laminar deposits. A phenotype comprising features of glaucoma (neurodegeneration) and age-related macular degeneration could thus be uncovered that suggests dysfunction of myosin VI and its variable cargo adaptor proteins for membrane sorting and autophagy, as possible candidate mediators for both disease forms.


Morphology and mucosal biochemistry of gastroschisis intestine in urine-free amniotic fluid.
The aim of this study was to determine the role of urine exposure in gastroschisis on the pathologic and biochemical aspects. The intestines of fetal rabbits with gastroschisis (group G), gastroschisis and urethral ligation (group GL), and normal controls (group C) were studied by measuring weigh and length, intestinal diameter and wall thickness, and thickness of each intestinal layer. Number and length of villi and villi edema were evaluated. Total protein and DNA were measured in intestinal homogenate. Lactase activity and alkaline phosphatase activity were analyzed in isolated microvilli membranes. Intestinal length, diameter, and wall thickness were significantly different in groups G and GL compared with C but not between groups G and GL. The same was true for the thickness of the internal muscular and serosa, villi length, and villi edema. Serosal reaction was milder in group GL than in group G, and absent in C. Total protein, lactase activity, and alkaline phosphatase activity were also significantly different in G and GL compared with C but not between G and GL. Urine in amniotic fluid causes an increased serosal reaction but does not account for the mucosal enzyme dysfunction.


COVID-19 in lung transplant recipients: an overview of the Swedish national experience.
Although it is known that solid organ transplant recipients fare worse after COVID-19 infection, data on the impact of COVID-19 on clinical outcomes and allograft function in lung transplant (LTx) recipients are limited and based mainly on reports with short follow-up. In this nationwide study, all LTx recipients with COVID-19 diagnosed from 1 February 2020 to 30 April 2021 were included. The patients were followed until 1 August 2021 or death. We analysed demographics, clinical features, therapeutic management and outcomes, including lung function. Forty-seven patients were identified: median age was 59 (10-78) years, 53.1% were male, and median follow-up was 194 (23-509) days. COVID-19 was asymptomatic or mild at presentation in 48.9%. Nine patients (19.1%) were vaccinated pre-COVID infection. Two patients (4.3%) died within 28 days of testing positive, and the overall survival rate was 85.1%. The patients with asymptomatic or mild symptoms had a higher median % expected forced expiratory volume during the first second than the patients with worse symptoms (P = 0.004). LTx recipients develop the entire spectrum of COVID-19, and in addition to previously acknowledged risk factors, lower pre-COVID lung function was associated with more severe disease presentation.


Data on bond strength of resin cement systems to CAD/CAM resin composite after aging.
CAD/CAM resin composite crowns are inexpensive tooth-colored prostheses that have been widely used. However, bonding between CAD/CAM resin composites and resin cements could be difficult since the resin composite is highly cross-linked. There is limited existing data on the resin cements' bond strength with different monomers to CAD/CAM resin composites. In this study, CAD/CAM resin composite was bonded to an SUS rod with three different resin cements following treatment of the bonding surface using the manufacturer's recommended primer. After storing the specimens in water at 37 °C for 24 h, half of them were tested immediately and half were thermocycled for 10,000 cycles in water for a dwell time of 20 s at 5 and 55 °C. The means of the tensile bond strength and standard deviations were determined for each resin cement and testing condition. The data were compared using two-way ANOVA and Bonferroni's multiple comparison tests at 95% confidence level.


Shock wave lithotripsy of vesical stones in patients with infravesical obstruction: an underused noninvasive approach.
To evaluate the effectiveness and safety of shock wave lithotripsy in the management vesical stones in patients with infravesical obstruction. From March 2007 to April 2010, 59 male patients with infravesical obstruction were treated using the Dornier Compact Delta II Lithotriptor for urinary bladder stones. The indications for shock wave lithotripsy included patients refusing invasive procedures or those with orthopedic malformations hindering the lithotomy position. The mean age was 61.6 ± 8.6 years (range 44-78), and the mean body mass index was 29 ± 5.1 kg/m(2) (range 20.5-45). The mean stone diameter was 26.6 ± 9.8 mm (range 12-50). All patients underwent an initial session and were re-evaluated using ultrasonography and urinary tract plain radiography at 2-week intervals. All patients were treated in the supine position. The number of shocks ranged from 1910 to 9500. Of the 59 patients, 47 and 11 were cleared by 1 or 2 sessions, respectively; 1 patient required a third session to be cleared of stones. All patients develop mild hematuria and started to pass gravel in the first void after the shock wave lithotripsy session. All patients were rendered stone free within 6 weeks. During follow-up, only 2 male patients developed temporary acute urine retention necessitating urethral catheter fixation. Both patients had a neurologic insult. Extracorporeal shock wave lithotripsy is an effective, noninvasive approach to disintegrate vesical stones in patients with infravesical obstruction with adequate fragment clearance.


Coeliac disease case finding and diet monitoring by point-of-care testing.
Immunoglobulin A class transglutaminase autoantibodies are highly predictive markers of active coeliac disease, a disorder difficult to recognize solely on clinical grounds. To develop and evaluate a simple rapid test for point-of-care detection of coeliac autoantibodies. The novel whole blood test utilizes the patient's endogenous transglutaminase in red blood cells for detection of transglutaminase-specific immunoglobulin A antibodies present in the blood sample, with normal plasma immunoglobulin A detection as positive test control. We evaluated 284 patients under suspicion of coeliac disease and undergoing jejunal biopsy, and 263 coeliac patients on a gluten-free diet, 383 being tested prospectively in a point-of-care setting. Results were compared with histology, conventional serum autoantibody results and dietary adherence. The rapid test showed 97% sensitivity and 97% specificity for untreated coeliac disease, and identified all immunoglobulin A-deficient samples. Point-of-care testing found new coeliac cases as efficiently as antibody tests in laboratory. Coeliac autoantibodies were detected onsite in 21% of treated patients, while endomysial and transglutaminase antibodies were positive in 20% and 19%, respectively. The positivity rate correlated with dietary lapses and decreased on intensified dietary advice given upon positive point-of-care test results. Point-of-care testing was accurate in finding new coeliac cases and helped to identify and decrease dietary non-compliance.


The effects of skin moisture and subcutaneous fat thickness on the ability of the skin to dissipate heat in young and old subjects, with and without diabetes, at three environmental room temperatures.
The Pennes model predicts the ability of the skin to dissipate heat as a function of conductive heat transfer and blood flow. Conductive heat exchange may be affected by skin moisture and subcutaneous fat thickness, factors not considered by Pennes. In the present investigation, we sought to expand the Pennes model by examining subcutaneous fat and skin moisture as factors of heat dissipation and their effects on heat exchange and blood flow. Subjects who were older (O) (mean age 64.2+/-5.9 years, n=15), had diabetes (D) (mean age 62+/-5.9 years, mean duration 13.2+/-9.1 years, n=15), and were younger (Y) (mean age 25.7+/-2.9 years, n=15) participated. Thermisters were placed in an iron heat probe and on the skin to measure the change in skin temperature to create a thermal change index to demonstrate the ability of the skin to dissipate heat. The lower back had the thickest subcutaneous fat layer for all subjects, which contributed to higher skin temperatures than the foot and hand in response to local and global heat. There was a significant inverse correlation between skin moisture and skin temperature after 5s of heat application (r=-0.73, p<0.001) with O and D having significantly less skin moisture than Y (p<0.05). O and D had significantly increased skin temperatures in response to local heat, as compared to Y, in all global temperatures (p<0.05). Thus, the Pennes model may need to be adjusted to take into consideration aging, diabetes, skin moisture, and subcutaneous fat thickness.


A life course perspective on working beyond retirement-results from a longitudinal study in the Netherlands.
There is a societal need that workers prolong their working lives. By adopting a life course perspective, this study aimed to investigate the influence of work motives and motivation, health, job characteristics, skills, and financial and social situation on working beyond retirement, and differences between 'on time' and 'off time' retirees (retirement age 65 and <65 years, respectively). Retirees aged 57 to 67 years (N = 1,054) who participated in the Dutch Study on Transitions in Employment, Ability and Motivation were included in this study. Participants filled out a questionnaire in 2010, 2011, 2012, and 2013. Predictors of working beyond retirement were identified using logistic regression analyses, and stratified analyses were performed to investigate differences between 'off time' and 'on time' retirees. High work engagement (OR = 1.3), good physical health (OR = 1.8), poor financial situation (OR = 2.4), and voluntary work (OR = 1.5) predicted working beyond retirement. For 'off time' retirees, no financial possibility to retire early (OR = 1.8) and not having a partner (OR = 1.9) predicted working beyond retirement. 'On time' retirees reporting more support at work (OR = 0.7) and without the financial possibility to retire early (OR = 0.5), worked beyond retirement less often. The results indicated that especially the motivation to work, physical health and the financial situation were the most relevant aspects with regard to working beyond retirement, which supports the idea that the principle of 'human agency' of the life course perspective is useful to understand factors that impact working beyond retirement. Most aspects of the life course principles of 'linked lives' and 'timing' seemed to be less relevant.


Design, synthesis and biological evaluation of novel (E)-α-benzylsulfonyl chalcone derivatives as potential BRAF inhibitors.
Activating mutations in the BRAF serine/threonine kinase are found in more than 70% of human melanomas, >90% of which are BRAF(V600E). It provides new therapeutic opportunities in malignant melanoma. In silico and in vitro screening of our compound collection has identified Hit 2 as BRAF(V600E) inhibitor. Based on its structure, a series of novel (E)-α-benzylsulfonyl chalcone derivatives (13-40) were designed and synthesized. Compound 38 exhibited the most potent inhibitory activity with an IC(50) value of 0.17 μM for BRAF(V600E) and GI(50) value of 0.52 μM for mutant BRAF-dependent cells. The results of cell based pERK activity and cellular selectivity suggested that those compounds could selectively inhibit proliferation of mutant BRAF-dependent melanoma cell line through inhibition of oncogenic BRAF.


Distribution and expression of fibroblast-specific protein chemokine CCL21 and chemokine receptor CCR7 in renal allografts.
We aimed to characterize the expression and distribution of the fibroblast surface protein (FSP), the chemokine CC-ligand 21 (CCL21) secondary lymphoid tissue chemokine CC-chemokine receptor 7 (CCR7) in renal allograft biopsy specimens obtained from patients after transplantation. We recruited 165 patients who received renal transplants at our center for this study. Histological examination of the renal allograft biopsy specimens was performed using hematoxylin-eosin, periodic acid-Schiff, and Masson's trichrome staining. Distribution and expression of FSP, CCL21, and CCR7 were determined using immunohistochemistry staining. Serum creatinine levels were evaluated using an enzymatic sarcosine oxidase method. FSP was mainly localized in the cytoplasm and nucleus of renal interstitial fibroblasts and tubular epithelial cells. Compared with the normal group, an elevated number of FSP-positive fibroblasts were observed in patients with acute/active cellular rejection and chronic/sclerosing allograft nephropathy (P < .05). Patients with chronic/sclerosing allograft nephropathy also showed increased total fibroblasts as compared with borderline changes (P < .05). In a multiple regression analysis, CCR7-positive expression was a strong protective factor for acute/active cellular rejection and recurrent nephropathy (odds ratio [OR] = 0.12, P = .034, and OR = 0.08; P = .036, respectively). In contrast, CCL21-positive expression led to a high susceptibility to recurrent nephropathy among renal transplant patients (OR = 10.41, P = .029). Moreover, FSP and CCL21, or CCL21 and CCR7 were localized in the interstitial fibroblasts and renal tubular epithelium cells. In addition, FSP and CCL21 expression positively correlated with serum creatinine levels. Our results suggested that the CCL21/CCR7 signaling pathway is involved in renal fibrosis in kidney transplant patients. An increased number of FSP-positive fibroblasts may be a risk factor for acute/active cellular rejection and chronic/sclerosing allograft nephropathy after renal transplantation. These findings may help understanding of renal allograft fibrosis.


Efficacy of a 2-year-old sexual assault nurse examiner program in a Canadian hospital.
The purpose of this study was to describe a sexual assault nurse examiner (SANE) program at a hospital-based sexual assault care center in Ontario, Canada, and assess its efficacy in comparison with physician examiners. Data obtained from the hospital records of 515 women who came to a Toronto sexual assault care center were examined. A number of variables relevant to this assessment of services were examined, including client demographics and presenting history, aspects of the sexual assault, and characteristics of the treatment. Average assessment times were shorter for victims seen by SANEs than for victims seen by physicians (approximately 3(1/4) hours versus 4 hours). Physicians had more interruptions (25.1%) than did SANEs (20.0%). Client characteristics and presentation were similar regardless of who provided care, with some exceptions. The results of the study support the utility of the SANE model as an efficient program for the assessment and treatment of victims of sexual assault.


Health and stress in Australian interns.
Over a 3-year period, interns completed questionnaires on self-reported health and stress during their orientation week at the beginning of the year, during mid year, and at the end of the first year. Interns experienced increased levels of stress and ill health in the middle of the year as compared with the start and end of the year (chi2=11.9, P=0.003 and chi2=20.4, P<0.001, respectively). Despite workplace reform for junior doctors, this study suggests that interns still feel overburdened with work expectations and this is having a negative effect on their health.


Skin sensory innervation patterns in embryonic chick hindlimbs deprived of motoneurons.
During normal development and following a variety of experimental manipulations (e.g., neural tube rotations, limb shifts), sensory neurons in the chick grow to their correct targets. L. Landmesser and M. G. Honig (1986, Dev. Biol. 118, 511-531) have suggested that sensory innervation may be precise, not because sensory neurons respond to limb-derived guidance cues, but because sensory neurons interact with motoneurons, which do respond to such cues. To test this hypothesis for skin sensory neurons, the ventral neural tube, including the motoneuron precursors, was removed from chick embryos prior to sensory axon outgrowth and the resulting patterns of dermatomes and axonal projections were mapped physiologically and anatomically. As reported previously, dorsal root ganglia (DRGs) and cutaneous nerves formed in their usual locations following the early removal of motoneurons, while most muscle nerves and the plexus region were reduced substantially (A. C. Taylor, 1944, J. Exp. Zool. 96, 159-185; L. Landmesser and M. G. Honig, 1986, Dev. Biol. 118, 511-531; G. J. Swanson and J. Lewis, 1986, J. Embryol. Exp. Morphol. 95, 37-52). The patterns of axonal projections and dermatomes were surprisingly, although not entirely, normal. In particular, cutaneous nerves in motoneuron-depleted embryos were derived from the same DRGs in approximately the same proportions as normal. Thus, while motoneurons may play a facilitative role in the development of the segmental pattern of skin sensory innervation, they do not appear to be essential.


Coronary microvascular dysfunction is an independent predictor of developing cancer in patients with non-obstructive coronary artery disease.
Cardiovascular disease and cancer share common pathogenesis and risk factors. Coronary microvascular dysfunction (CMD), reflecting impaired coronary microvascular dilation in response to stress, is related to a higher risk of major cardiovascular events; however, its association with cancer has not been explored. A retrospective study on 1042 patients with non-obstructive coronary artery diseases (NOCADs) was performed. Data regarding demographic, clinical history, diagnostic coronary reactivity test, and cancer occurrence were collected. Coronary microvascular dysfunction was defined as coronary flow reserve (the ratio of hyperaemic blood flow to resting blood flow) ≤2.5. Thirty-four per cent had CMD (67.4% female and the average age was 52.4 ± 12.2 years). Of 917 patients with no history of cancer, 15.5% developed cancer during follow-up [median of 9 (4, 16) years]. Kaplan-Meier analysis showed that CMD patients had lower cancer-free survival compared with those without CMD (log-rank P = 0.005). Cox proportional hazard analyses showed that after adjusting for age, sex, hypertension, diabetes, smoking, and glomerular filtration rate, CMD is independently associated with cancer [hazard ratio, 1.4; 95% confidence interval (CI), 1.09-2.04; P = 0.04]. The rate of major adverse cardiovascular events (MACE) was significantly higher in CMD patients compared with that in non-CMD patients who had a previous history of cancer [odds ratio (OR), 2.5; 95% CI, 1-6.2; P = 0.04] and those with no history of cancer (OR, 1.4; 95% CI, 1.01-1.9; P = 0.044). Coronary microvascular dysfunction is associated with cancer incidence in patients presenting with NOCADs. This study emphasizes follow-up in patients with CMD to evaluate the risk of MACE as well as potential malignant diseases.


Assessment of Palliative Care Needs in a Kenyan Intensive Care Unit Using a Trigger-Based Model.
Palliative care triggers have been used in the intensive care unit (ICU) setting, usually in high-income countries, to identify patients who may benefit from palliative care consults. The utility and benefits of palliative care triggers in the ICU have not been previously studied in sub-Saharan Africa. Our objectives were to determine the prevalence of ICU admissions in those who met at least one palliative care trigger and whether a palliative care consult influenced the length of ICU stay and time to change of goals order. We conducted a prospective observational cohort study within our ICU at the Aga Khan University Hospital, Nairobi, between December 2019 and August 2020. Data including initiation of a palliative care consult, length of ICU stay, mortality, and time to change of goals order were collected. During our study period, 72 of 159 (45.9%) patients met at least one palliative care trigger point. Of the patients who met the palliative care triggers, only 29.2% received a palliative care consult. Patients who received palliative care consults had higher rates of change of goals orders signed (52.3%) vs. those who did not (P = 0.009). There was no statistically significant difference between the consult and nonconsult groups in regard to length of ICU stay, time to change of goals order, and mortality. A trigger-based model, geared to the needs of the specific ICU, may be one way of improving integration of palliative care into the ICU, especially in sub-Saharan Africa.


The acute phase protein serum amyloid A primes neutrophils.
We studied here the effect of the acute phase protein serum amyloid A (SAA) on the oxidative burst of neutrophils. Incubation of neutrophils with SAA increased the rate of oxygen uptake and the production of reactive oxygen species of neutrophils activated with opsonized zymosan (OZ). The increment in the neutrophil oxidative burst was dependent on SAA concentration in the range of 3-33 microg protein ml(-1) and was observed only in the presence of a relatively low amount of OZ (1 x 10(6) particles ml(-1)). SAA did not affect oxygen consumption and reactive oxygen production triggered by other stimuli, such as f-Met-Leu-Phe, phorbol myristate acetate or non-opsonized zymosan. Our finding points to a priming effect of SAA probably associated with mobilization of receptors for opsonized particles and strengthens the role of SAA as an effector of neutrophil functions in inflammation.


Plant species dominance shifts across erosion edge-meadow transects in the Swiss Alps.
While exerting no obvious function under "average" environmental conditions, the presence of certain plant specialists becomes crucial in the event of a complete failure of a community due to severe disturbance such as landslides. Plants capable of growing at erosion edges may act as potential edge-engineers by coping with unstable ground and stabilizing the soil with their roots. We hypothesized that life conditions at erosion edges select for a particular set of specialists or species with specific traits, the identification of which was the aim of the study. Across 17 small-scale transects (0.40 × 1.60 m) from intact meadows to landslide edges (Ursern Valley, Swiss Alps, c. 1,600 m a.s.l.), we quantified plant species abundance by the point intercept method and characterized growth conditions based on Landolt's indicator values, leaf δ(13)C, and volumetric soil moisture in the uppermost soil layers. We observed a clear change of plant species composition and relative abundance from the meadow to the edge, presumably induced by the 25 % lower soil moisture and microclimatic exposure. Species richness at the edge was two-thirds of that in the meadow, but was positively correlated with species richness of the adjacent meadow. Species with "edge-preference" had either (1) rolled or festucoid leaves like Festuca spp., Avenella flexuosa and Nardus stricta, or (2) small, scleromorphic leaves like Vaccinium vitis-idaea, Calluna vulgaris and Thymus ssp. Graminoids with rolled/festucoid leaves were found to be the most dominant edge-specialists. The grass Festuca valesiaca s.l. emerged as the most dominant plant species at the edge, having an 11-times higher cover at the edge than in the meadow. In this montane grassland, a single species contributes to the stabilization of erosion edges and may be regarded as a potential keystone species for slope stability and regeneration after landslides even its role has not so far been established.


Processing of sinusoidally amplitude modulated signals in the nuclei of the lateral lemniscus of the big brown bat, Eptesicus fuscus.
Changes in amplitude are a characteristic feature of most natural sounds, including the biosonar signals used by bats for echolocation. Previous evidence suggests that the nuclei of the lateral lemniscus play an important role in processing timing information that is essential for target range determination in echolocation. Neurons that respond to unmodulated tones with a sustained discharge are found in the dorsal nucleus (DNLL), intermediate nucleus (INLL) and multipolar cell division of the ventral nucleus (VNLLm). These neurons provide a graded response over a broad dynamic range of intensities, and would be expected to provide information about the amplitude envelope of a modulated signal. Neurons that respond only at the onset of a tone make up a small proportion of cells in DNLL, INLL and VNLLm, but are the only type found in the columnar division of the ventral nucleus (VNLLc). Onset neurons in VNLLc maintain a constant latency across a wide range of stimulus frequencies and intensities, thus providing a precise marker for when a sound begins. To determine how these different functional classes of cells respond to amplitude changes, we presented sinusoidally amplitude modulated (SAM) signals monaurally to awake, restrained bats and recorded the responses of single neurons extracellularly. There were clear differences in the ability of neurons in the different cell groups to respond to SAM. In the VNLLm, INLL and DNLL, 90% of neurons responded to SAM with a synchronous discharge. Neurons in the VNLLc responded poorly or not at all to SAM signals. This finding was unexpected given the precise onset responses of VNLLc neurons to unmodulated tones and their ability to respond synchronously to sinusoidally frequency modulated (SFM) signals. Among neurons that responded synchronously to SAM, synchronization as a function of modulation rate described either a bandpass or a lowpass function, with the majority of bandpass functions in neurons that responded to unmodulated tones with a sustained discharge. The maximal modulation rates that elicited synchronous responses were similar for the different cell groups, ranging from 320 Hz in VNLLm to 230 Hz in DNLL. The range of best modulation rates was greater for SAM than for SFM; this was also true of the range of maximal modulation rates at which synchronous discharge occurred. There was little correlation between a neuron's best modulation rate or maximal modulation rate for SAM signals and those for SFM signals, suggesting that responsiveness to amplitude and frequency modulations depends on different neural processing mechanisms.


Cost-effectiveness of barium enemas performed by radiographers.
To assess the cost-effectiveness of barium enemas performed by radiographers compared to those performed by consultant radiologists. Prospective study of 200 barium enemas carried out by a senior radiographer and a consultant radiologist. The sample was a consecutive sample of adult out-patients over a 3-month period, with no exclusion. The length of time of the enema and the numbers and grades of staff involved in the procedure were recorded. This was translated into staffing costs using the appropriate pay scales. The barium enemas performed by the superintendent radiographer were more cost-effective than those performed by the consultant radiologist (pound 1406 for 100 radiographer-performed barium enemas compared to pound 1787 for 100 carried out by the consultant radiologist). In terms of staffing costs, radiographers performing barium enemas not only liberates radiologist time, it is also a cost-effective method of providing an out-patient barium enema service.


Introduction: thrombocytopenia in chronic liver disease -- treatment implications and novel approaches.
Thrombocytopenia is a common hematologic toxicity among patients with chronic liver disease. To give a brief overview of thrombocytopenia and its effects on patients with chronic liver disease. Thrombocytopenia is generally mild to moderate in severity and can thus be managed relatively easily. Severe thrombocytopenia (platelet count <50,000 /microL), however, may present significant challenges to patient management. Thrombocytopenia can increase the risk of bleeding associated with invasive or surgical procedures. Therefore, while perhaps less widely appreciated than the impact of anemia or neutropenia, effective prevention and management of thrombocytopenia is also critical for patients with liver disease. This supplement to Alimentary Pharmacology & Therapeutics provides a comprehensive review of the significance of thrombocytopenia in patients with chronic liver disease, its pathophysiology and relationship to coagulation disorders, impact on clinical care and resource utilization, and novel therapies that may be able to supplant platelet transfusions.


Retinal projection to mammalian telencephalon.
Retinal projections were studied in species from 8 orders of mammals using anterograde tracing techniques. The olfactory tubercle of basal telencephalon receives a projection from the retina in all animals. In all species the course of labelled fibers is similar and the terminal distribution of label along the internal border of the granular cell layer is restricted to the mediocaudal region of the tubercle. These shared characteristics suggest that this pathway is a typical mammalian feature, possibly providing for convergence of visual and chemosensory information in telencephalon.


Lamins as mediators of oxidative stress.
The nuclear lamina defines both structural and functional properties of the eukaryotic cell nucleus. Mutations in the LMNA gene, encoding A-type lamins, lead to a broad spectrum of diseases termed laminopathies. While different hypotheses have been postulated to explain disease development, there is still no unified view on the mechanistic basis of laminopathies. Recent observations indicate that laminopathies are often accompanied by altered levels of reactive oxygen species and a higher susceptibility to oxidative stress at the cellular level. In this review, we highlight the role of reactive oxygen species for cell function and disease development in the context of laminopathies and present a framework of non-exclusive mechanisms to explain the reciprocal interactions between a dysfunctional lamina and altered redox homeostasis.


Presynaptic M1 muscarinic receptor modulates spontaneous release of acetylcholine from rat basal forebrain slices.
Spontaneous release of acetylcholine (ACh) from rat basal forebrain slices in the presence of cholinesterase inhibitor was directly determined using a specific radioimmunoassay for ACh. The release was calcium dependent. A consistent amount of ACh release was observed throughout the experiment. Atropine (10(-8) to 10(-5) M) and pirenzepine (10(-7) to 10(-5) M) enhanced spontaneous ACh release. These findings indicate the presence of an M1 muscarinic autoreceptor that modulates spontaneous release of ACh in the rat basal forebrain.


Sensitivity and cyclic nucleotides in the rat pineal gland.
beta-Adrenergic stimulation induces serotonin N-acetyltransferase (SNAT) activity in the rat pineal gland. The magnitude and some of the characteristics of this response vary as a function of the gland's previous exposure to stimulation. A period of stimulation results in a subsensitive response to subsequent stimulation. A period without stimulation provides a supersensitive response to subsequent stimulation. Investigations concerned with the mechanisms regulating the rat pineal's sensitivity to beta-adrenergic stimulation are described. These have focused on the regulation of cyclic AMP metabolism. Several of the components involved in the induction of SNAT activity appear to participate in the regulation of sensitivity. These include the beta-adrenergic binding sites, the catecholamine-sensitive adenylate cyclase, the cyclic nucleotide phosphodiesterase, and the cyclic AMP-dependent protein kinase. Thus, the rat pineal's sensitivity to beta-adrenergic stimulation appears to be regulated at multiple sites. Other investigations have focused on the regulation of pineal cyclic GMP metabolism. Unlike cyclic AMP, the stimulation of cyclic GMP synthesis requires the presence of intact nerve endings and of extracellular calcium. Some of the characteristics of pineal cyclic GMP regulation are described.


Ion pair stabilization effects on a series of procaine structural analogs.
In this work, a series of 10 structural procaine analogs have been synthesized in order to investigate the structural features affecting the stability of ion pair formation and its influence on the lipophilicity of ionizable compounds. The structural variation within this series was focused on the terminal nitrogen substituents and on the intermediate chain linkage nature. The hydrophobic parameters logP(n) and logP(i) (partition coefficient of the neutral and ionic species, respectively), as well as the ionization constants pK(a) and pK(a)(oct), were obtained from logD-pH profiles measured at pH values ranging from 2 to 12. The difference between logP(i) and logP(n) values (i.e. difflogP) of each prepared compound was considered a measure of the stability of ion pair formation. In this set, the difflogP values varied nearly over one log unit, ranging from -2.40 to -3.37. It has been observed that the presence of hydrogen bonding groups (especially donor) and low steric hindrance around the terminal amine ionizable group increases the relative lipophilicity of the ionic species as compared to the corresponding neutral species. These results were interpreted as due to the increased stability of ion pairs of the compounds bearing these structural features.


Pharmacologic review of thrombolytic agents.
Thrombolytic therapy has significantly reduced the morbidity and mortality that was once associated with acute myocardial infarction. Because of the substantial benefits associated with this therapy, investigation has intensified in search of the optimal agent or agents. Five agents are currently being investigated individually and in various combinations to determine which agent(s) will outperform the others in terms of reperfusion, patency, mortality reduction, and clinical events. Two of the agents, t-PA and scu-PA, are considered fibrin selective, whereas the other three, streptokinase, urokinase and APSAC are nonselective. Whether this distinction provides substantial benefit is still not known. All of the FDA-approved agents (streptokinase, t-PA, and APSAC) have demonstrated survival benefit and will continue to be administered in AMI patients. In addition, the 1990s begins a new era that includes broadened selection criteria for AMI patients as well as expanding cardiovascular indications for thrombolytic therapy. The challenge to nurses is to improve and implement nursing care practices at the same rapid pace set by the medical discipline. This includes astute assessment and observational skills necessary to prevent and detect potential complications associated with thrombolytic therapy. Rapidly changing medical techniques mandate ongoing nursing research, which is needed to determine the most effective interventions in reducing complications associated with thrombolytic therapy and in promoting positive adaptive behaviors in the AMI patient. Thrombolytic therapy is an intervention for the 1990s, and nursing care is essential in maintaining the beneficial effects of this dynamic therapy.


Effects of nitrate therapy on ventricular remodeling and function.
The hypothesis that nitrates might effectively limit left ventricular remodeling and improve function after acute myocardial infarction has been tested in experimental and clinical models, with special attention to the pathophysiologic evolution of remodeling. In 1 clinical study, before the thrombolytic era, the effects of low-dose intravenous nitroglycerin infusion for the first 48 hours during acute myocardial infarction was evaluated in a prospective, randomized, single-blinded, placebo-controlled study of 310 patients (154 nitroglycerin; 156 placebo). Nitroglycerin proved to be safe and produced several benefits compared with placebo: (1) smaller infarct size; (2) less left ventricular dysfunction; (3) less infarct expansion and thinning; (4) better functional status; (5) fewer in-hospital complications such as left ventricular failure, left ventricular thrombus, cardiogenic shock, and infarct extension; and (6) fewer deaths up to 1 year. Two subsequent clinical studies in the thrombolytic era, with low-dose intravenous nitroglycerin infusion during infarction over the first 48 hours followed by buccal nitrate (eccentric dose regimen) or placebo during healing over 6 weeks postinfarction, indicated that prolonged nitrate therapy effectively limited left ventricular remodeling and improved function further compared with placebo.


Long-term outcomes of surgical treatment for intravascular leiomyomatosis.
Intravascular leiomyomatosis (IVL) is relatively rare. The optimal surgical method and long-term outcomes are not completely understood. Medical records between 2007 and 2017 in our hospital were analyzed to identify IVL cases with surgical intervention. Their medical records, operative details, and follow-up were collected by chart review and telephone communication. Eight patients with IVL were included in the study, accounting for 0.26% of all uterine leiomyoma cases. Primary IVL was confined to pelvic cavity in three patients, extended to the inferior vena cava (IVC) below renal vein in one, reached IVC and right atrium in three, and reached main pulmonary artery in one. One-stage operation was performed for seven patients. Cardiopulmonary bypass was done in four patients, and aortic cross-clamp and temporary circulatory arrest was performed in two patients. None of the four patients with intrapulmonary tumors received concomitant pulmonary tumor resection. There was no operative mortality and four morbidities, including ureter injury (2), bladder injury (1), and femoral vein thrombosis (1). During follow-up, two patients exhibited local recurrence of the tumor in the pelvis, and one patient had rapidly growing intrapulmonary tumor three months post-operatively. Intrapulmonary tumors in the other three patients remained stationary at 6, 84, and 120 months post-operatively. One-stage operation to completely remove IVL is feasible and with good long-term outcomes, which is recommended if the patient can tolerate the operation. Concomitant intrapulmonary tumors can be followed up watchfully except when associated with pleural effusion or the pathology indicating trend of increasing malignancy.


Multiple-Biomarker Approach in a Commercial Marine Scallop from San Jose gulf (Patagonia, Argentina) for Health Status Assessment.
The health status of the commercial Tehuelche scallop Aequipecten tehuelchus from San Román and El Riacho in San José gulf (Patagonia, Argentina) was evaluated through biomarkers widely used in ecotoxicological applications. Natural levels of arsenic (As) and cadmium (Cd) were measured to determine their potential relationships with fluctuations of several oxidative stress biomarkers in the scallop. Oxidative biomarkers, such as catalase (CAT), glutathione S-transferase (GST), superoxide dismutase (SOD), metallothioneins (MT), reactive oxygen species (ROS), α-tocopherol (α-T), and lipid peroxidation (LPO) through thiobarbituric acid reactive substances (TBARS) and lipid radical (LR∙), were measured in gills, digestive gland, and muscle of Tehuelche scallop in winter (August 2015) and summer (January 2016). Levels of As and Cd and of most of the biomarkers (SOD, ROS, TBARS, and LR∙) showed strong seasonal variability in the three tissues. In general, the highest values were recorded in digestive gland. The Integrated Biomarker Response index indicated that the most stressed condition of A. tehuelchus was in summer in San Román. Additionally, the Integrated Biomarker Response index showed a strong relationship among tissues and As and Cd accumulation. This kind of approach could be used as an integrated tool to identify the health status of scallop A. tehuelchus from San José gulf.


Skeletal muscle MnSOD, mitochondrial complex II, and SIRT3 enzyme activities are decreased in maternal obesity during human pregnancy and gestational diabetes mellitus.
Insulin resistance and systemic oxidative stress are prominent features of pregnancies complicated by maternal obesity or gestational diabetes mellitus (GDM). The role of skeletal muscle oxidative stress or mitochondrial capacity in obese pregnant women or obese women with GDM is unknown. We investigated whether obese pregnant women, compared with normal weight (NW) pregnant women, demonstrate decreased skeletal muscle mitochondrial enzyme activity and elevated markers of oxidative stress, and if these differences are more severe in obese women diagnosed with GDM. We measured mitochondrial enzyme activity and markers of oxidative stress in skeletal muscle tissue from NW pregnant women (n = 10), obese pregnant women with normal glucose tolerance (NGT; n = 10), and obese pregnant women with GDM (n = 8), undergoing cesarean delivery (∼37 wk gestation). Electron transport complex-II and manganese superoxide dismutase (MnSOD) enzyme activities were decreased in obese-NGT and obese-GDM, compared with NW women. The glutathione redox ratio (GSH:GSSG) was decreased in obese-NGT and obese-GDM, indicative of increased oxidative stress. Mitochondrial sirtuin (SIRT)3 mRNA content and enzyme activity were lower in skeletal muscle of obese-NGT and obese-GDM women. Importantly, acetylation of MnSOD, a SIRT3 target, was increased in obese-NGT and obese-GDM vs NW women and was inversely correlated with SIRT3 activity (r = -0.603), suggesting a mechanism for reduced MnSOD activity. These data show that obese pregnant women demonstrate decreased skeletal muscle mitochondrial respiratory chain enzyme activity and decreased mitochondrial antioxidant defense. Furthermore, reduced skeletal muscle SIRT3 activity may play a role in the increased oxidative stress associated with pregnancies complicated by obesity.


Deficiency and supplementation of PUFA in the diet have similar effects on the age-associated changes in rat-plasma cholesterol levels.
Levels of plasma cholesterol, particularly LDL cholesterol, increase with increasing age in humans and rodents. Feeding a fish oil-rich diet may exert hypocholesterolemic effects. The aim of this work was to examine the effects of a life-long administration of a PUFA-enriched diet and of a PUFA-deficient diet in male Sprague-Dawley rats on the age-associated increases in plasma cholesterol and triglycerides. Diet had small effects on body-weight, and had dramatic effects on liver phospholipids-fatty acids. Surprisingly, both diets counteracted the age-associated changes in plasma cholesterol and triglycerides similarly and benefits were already visible in adult rats.


CD301b+ macrophages mediate angiogenesis of calcium phosphate bioceramics by CaN/NFATc1/VEGF axis.
Calcium phosphate (CaP) bioceramics are important for tissue regeneration and immune response, yet how CaP bioceramics influence these biological processes remains unclear. Recently, the role of immune cells in biomaterial-mediated regeneration, especially macrophages, has been well concerned. CD301b+ macrophages were a new subset of macrophages we have discovered, which were required for bioceramics-mediated bone regeneration. Nevertheless, the impact of CD301b+ macrophages on angiogenesis, which is a vital prerequisite to bone formation is yet indistinct. Herein, we found that CD301b+ macrophages were closely correlated to angiogenesis of CaP bioceramics. Additionally, depletion of CD301b+ macrophages led to the failure of angiogenesis. We showed that store-operated Ca2+ entry and calcineurin signals regulated the VEGF expression of CD301b+ macrophages via the NFATc1/VEGF axis. Inhibition of calcineurin effectively impaired angiogenesis via decreasing the infiltration of CD301b+ macrophages. These findings provided a potential immunomodulatory strategy to optimize the integration of angiogenesis and bone tissue engineering scaffold materials.


Effects of the natural antimicrobial peptide aureocin A53 on cells of Staphylococcus aureus and Streptococcus agalactiae involved in bovine mastitis in the excised teat model.
Aureocin A53 is an N-formylated antimicrobial peptide (AMP) produced by Staphylococcus aureus. Aureocin A53 has a broad spectrum of antimicrobial activity against human and animal pathogens. In the present study, its antagonistic activity was investigated towards 30 strains of S. aureus and 30 strains of Streptococcus spp. isolated from bovine mastitis cases in Brazil. Bovine mastitis is a disease that causes a major economic impact worldwide. Aureocin A53 inhibited the growth of all 60 strains tested, including multidrug-resistant streptococcal isolates and strains of S. aureus belonging to different pulsotypes. This AMP proved to be bactericidal against the six target strains randomly selected among staphylococci and streptococci, also exhibiting a lytic mode of action against the staphylococcal cells. Furthermore, it was determined that 2,048 AU/mL of the AMP were required to inhibit 99.99% of the cell growth of the strain less sensitive to aureocin A53. Aureocin A53 was not toxic to bovine mammary gland epithelial cells after a 24-h exposure and maintained its antimicrobial activity when tested in the excised-teat model against strains of S. aureus and Streptococcus agalactiae, the species responsible for most intramammary infections, not only in Brazil but in other countries as well. Therefore, the use of aureocin A53 in the development of new pharmacological products for the prophylaxis and/or treatment of bovine mastitis was considered promising.


Micro and nano MgO particles for the improvement of fracture toughness of bone-cement interfaces.
The objective of this study was to determine whether inclusion of magnesium oxide (MgO) in micro and nanoparticulate forms in poly methyl methacrylate (PMMA) cement has any influence on the fracture toughness of bone-cement interfaces. An interfacial fracture mechanics technique was used to compare the values of fracture toughness (KIC) among bone-PMMA, bone-PMMA with micro MgO particles and bone-PMMA with nano MgO particles interfaces. This study found that the values of KIC of bone-PMMA with micro MgO particles and bone-PMMA with nano MgO particles interfaces were significantly higher when compared to the values of KIC of the bone-PMMA interface (p<0.0001). Results indicated that the addition of the micro and nano MgO particles to PMMA improved the quality of bone-cement union.


Evaluation of the effect of previous endometriosis surgery on clinical and surgical outcomes of subsequent endometriosis surgery.
Patients often undergo repeat surgery for endometriosis, due to recurrent or residual disease. Previous surgery is often considered a risk factor for worse surgical outcome. However, data are scarce concerning the influence of subsequent endometriosis surgery. A retrospective study in a centre of expertise for endometriosis was conducted. All endometriosis subtypes and intra-operative steps were included. Detailed information regarding surgical history of patients was collected. Surgical time, intra-operative steps and major post-operative complications were obtained as outcome measures. 595 patients were included, of which 45.9% had previous endometriosis surgery. 7.9% had major post-operative complications and 4.4% intra-operative complications. The patient journey showed a median of 3 years between previous endometriosis surgeries. Each previous therapeutic laparotomic surgery resulted on average in 13 additional minutes (p = 0.013) of surgical time. Additionally, it resulted in more frequent performance of adhesiolysis (OR 2.96, p < 0.001) and in a higher risk for intra-operative complications (OR 1.81, p = 0.045), however no higher risk for major post-operative complications (OR 1.29, p = 0.418). Previous therapeutic laparoscopic endometriosis surgery, laparotomic and laparoscopic non-endometriosis surgery showed no association with surgical outcomes. Regardless of previous surgery, disc and segmental bowel resection showed a higher risk for major post-operative complications (OR 3.64, p = 0.017 respectively OR 3.50, p < 0.001). Previous therapeutic laparotomic endometriosis surgery shows an association with longer surgical time, the need to perform adhesiolysis, and more intra-operative complications in the subsequent surgery for endometriosis. However, in a centre of expertise with experienced surgeons, no increased risk of major post-operative complications was observed.


Of immune checkpoint maladies and remedies: The throwing of jabs in the oncogenic ring of PDAC.
The upregulation of co-inhibitory checkpoint receptors/ligands that inactivate antitumor T-cells, the enhancement of Tregs-mediated trogocytosis that contribute delayed maturation of antigen presenting cell (APC), and the high Tregs/CD+8 ratio that maintained low threshold of CD+8 cells in the tumor microenvironment (TME); all represent the nuances in the immune evasive strategies of pancreatic ductal adenocarcinoma (PDAC). PDAC is the most aggressive type of pancreatic cancers characterized by poor prognosis and extremely low survivability. Over the years, fraternity of scientists have developed therapeutic agents that can bolster the capacity of the antitumor immunity, usually via the inhibition of immune checkpoints. While this immune checkpoint inhibition therapy represents one major jab from immunity to PDAC, this cancer remains highly resistant due to the acme of desmoplasia in its TME. In this review, we discuss the mechanisms of various checkpoint receptors/ligands axes that are relevant to the fitness of PDAC in its oncogenic ring. These checkpoints include PD-1, CTLA-4, ICOS, TIM-3, TIGIT, BTLA, BTN3A, and VISTA. In addition, we provided evidences that are relevant to the understanding of immune checkpoint inhibition, with extensive outline of immune checkpoint inhibitors that are critical to the treatment of PDAC. Finally, we discuss recently known intricacies of PDAC-mediated immunosuppression, and current advances in treatment options. Having realized that the overall scenario between PDAC and antitumor immunity is like the throwing of jabs in a ring, we therefore discuss future directions and prospect that can knock out PDAC in favor of immunity and humanity.


The state of distance healthcare simulation during the COVID-19 pandemic: results of an international survey.
The coronavirus pandemic continues to shake the embedded structures of traditional in-person education across all learning levels and across the globe. In healthcare simulation, the pandemic tested the innovative and technological capabilities of simulation programs, educators, operations staff, and administration. This study aimed to answer the question: What is the state of distance simulation practice in 2021? This was an IRB-approved, 34-item open survey for any profession involved in healthcare simulation disseminated widely and internationally in seven languages from January 14, 2021, to March 3, 2021. Development followed a multistep process of expert design, testing, piloting, translation, and recruitment. The survey asked questions to understand: Who was using distance simulation? What driving factors motivated programs to initiate distance sim? For what purposes was distance sim being used? What specific types or modalities of distance simulation were occurring? How was it being used (i.e., modalities, blending of technology and resources and location)? How did the early part of the pandemic differ from the latter half of 2020 and early 2021? What information would best support future distance simulation education? Data were cleaned, compiled, and analyzed for dichotomized responses, reporting frequencies, proportions, as well as a comparison of response proportions. From 32 countries, 618 respondents were included in the analysis. The findings included insights into the prevalence of distance simulation before, during, and after the pandemic; drivers for using distance simulation; methods and modalities of distance simulation; and staff training. The majority of respondents (70%) reported that their simulation center was conducting distance simulation. Significantly more respondents indicated long-term plans for maintaining a hybrid format (82%), relative to going back to in-person simulation (11%, p < 0.001). This study gives a perspective into the rapid adaptation of the healthcare simulation community towards distance teaching and learning in reaction to a radical and quick change in education conditions and environment caused by COVID-19, as well as future directions to pursue understanding and support of distance simulation.


Effects of peripherally and centrally applied ghrelin on the oxidative stress induced by renin angiotensin system in a rat model of renovascular hypertension.
Renovascular hypertension (RVH) is a result of renal artery stenosis, which is commonly due to astherosclerosis. In this study, we aimed to clarify the central and peripheral effects of ghrelin on the renin-angiotensin system (RAS) in a rat model of RVH. RVH was induced in rats by partial subdiaphragmatic aortic constriction. Experiment A was designed to assess the central effect of ghrelin via the intracerebroventricular (ICV) injection of ghrelin (5 μg/kg) or losartan (0.01 mg/kg) in RVH rats. Experiment B was designed to assess the peripheral effect of ghrelin via the subcutaneous (SC) injection of ghrelin (150 μg/kg) or losartan (10 mg/kg) for 7 consecutive days. Mean arterial blood pressure (MAP), heart rate, plasma renin activity (PRA), and oxidative stress markers were measured in all rats. In addition, angiotensin II receptor type 1 (AT1R) concentration was measured in the hypothalamus of rats in Experiment B. RVH significantly increased brain AT1R, PRA, as well as the brain and plasma oxidative stress. Either SC or ICV ghrelin or losartan caused a significant decrease in MAP with no change in the heart rate. Central ghrelin or losartan caused a significant decrease in brain AT1R with significant alleviation of the brain oxidative stress. Central ghrelin caused a significant decrease in PRA, whereas central losartan caused a significant increase in PRA. SC ghrelin significantly decreased PRA and plasma oxidative stress, whereas SC losartan significantly increased PRA and decreased plasma oxidative stress. The hypotensive effect of ghrelin is mediated through the amelioration of oxidative stress, which is induced by RAS centrally and peripherally.


A psychiatric and neuropsychological study of patients with untreated Graves' disease.
We studied 13 untreated Graves' disease subjects in a clinical research unit using endocrine, psychiatric, and neuropsychological assessments. We used SADS interviews, RDC, standardized symptom rating scales, and motor activity monitoring to update earlier studies and quantified psychiatric symptoms to elucidate any correlations between endocrine and psychiatric status. Nine of 13 subjects had major depression, 8/13 had generalized anxiety disorder, and 3/13 were hypomanic. Anxiety levels were much higher than in other hospitalized medical patients. Using a broad battery of neuropsychological testing, we found mild deficits in attention, memory, and complex problem solving that were consistent with previous studies of hyperthyroid patients. The severity of psychiatric symptoms could easily result in an inappropriate referral to a psychiatrist prior to the diagnosis of hyperthyroidism. The relationship between psychiatric symptoms and possible CNS effects of excess levels of thyroid hormone is discussed.


Laparoscopic pericystectomy of a liver hydatid cyst.
The case of a patient with a liver hydatid cyst in the sixth hepatic segment is reported. Its favorable localization and its calcified state incited us to treat it by laparoscopy. The employed technique is discussed.


Comparison of obese adults with poor versus good sleep quality during a functional neuroimaging delay discounting task: A pilot study.
This study aimed to determine if obese adults with poor versus good sleep quality demonstrate reduced self-regulatory capacity and different patterns of neural activation when making impulsive monetary choices. Six obese, good quality sleepers (M age=44.7 years, M BMI=38.1 kg/m(2)) were compared to 13 obese, poor quality sleepers (M age=42.6, M BMI=39.2 kg/m(2)) on sleep and eating behavior and brain activation in prefrontal and insular regions while engaging in a delay discounting task during functional magnetic resonance imaging (fMRI). Poor quality sleepers demonstrated significantly lower brain activation in the right inferior frontal gyrus, right middle frontal gyrus, and bilateral insula when making immediate and smaller (impulsive) monetary choices compared to the baseline condition. Behaviorally, poor compared to good quality sleepers reported higher scores in the night eating questionnaire. Obese adults with poor sleep quality demonstrate decreased brain activation in multiple regions that regulate cognitive control and interceptive awareness, possibly reducing self-regulatory capacity when making immediately gratifying decisions.


Polydeoxyribonucleotide (PDRN) promotes human osteoblast proliferation: a new proposal for bone tissue repair.
Several researchers have recently shed new light upon the importance of extracellular nucleotides and nucleosides to stimulate cells growth. PDRN, a mixture of deoxyribonucleotides polymers of different lengths, has recently demonstrated to stimulate "in vitro" fibroblast proliferation and collagen production, probably stimulating the purinergic receptor system. In this work we evaluated the effects of PDRN on human cultured osteoblasts, focusing our attention on cell proliferation and alkaline phosphatase activity. PDRN at a concentration of 100 microg/ml induce an increase in osteoblasts growth after 6 days as compared to control (+21%). The addition of DMPX 50 microM and suramine (P2 inhibitor) 10 microM give different results: suramine has no significant effect, while DPMX reduce, even if partially, the PDRN induced cell growth. The alkaline phosphatase activity shows a gradual enhancement starting from day 0 to day 10, even if PDRN treated cells, examined at day 6, present a sensibly lower phosphatase activity when compared to controls. Our data demonstrate that PDRN acts as an osteoblast growth stimulator. Its action is partially due to a stimulation of the purinergic system mediated by A2 purinoreceptors, however we can not exclude the involvement of other mechanism like salvage pathway.