Association of Medicare Mandatory Bundled Payment Reform With Joint Replacement Surgery Use for Beneficiaries With Alzheimer Disease and Related Dementias.
Medicare beneficiaries with Alzheimer disease and related dementias (ADRD) are a particularly vulnerable group in whom arthritis is a frequently occurring comorbidity. Medicare's mandatory bundled payment reform-the Comprehensive Care for Joint Replacement (CJR) model-was intended to improve quality and reduce spending in beneficiaries undergoing joint replacement surgical procedures for arthritis. In the absence of adjustment for clinical risk, hospitals may avoid performing elective joint replacements for beneficiaries with ADRD. To evaluate the association of the CJR model with utilization of joint replacements for Medicare beneficiaries with ADRD. This cohort study used national Medicare data from 2013 to 2017 and multivariable linear probability models and a triple differences estimation approach. Medicare beneficiaries with a diagnosis of arthritis were identified from 67 metropolitan statistical areas (MSAs) mandated to participate in CJR and 104 control MSAs. Data were analyzed from July 2020 to July 2021. Implementation of the CJR model in 2016. Outcomes were separate binary indicators for whether or not a beneficiary underwent hip or knee replacement. Key independent variables were the MSA group, before-CJR and after-CJR phase, ADRD diagnosis, and their interactions. The linear probability models controlled for beneficiary characteristics, MSA fixed effects, and time trends. The study included 24 598 729 beneficiary-year observations for 9 624 461 unique beneficiaries, of which 250 168 beneficiaries underwent hip and 474 751 underwent knee replacements. The mean (SD) age of the 2013 cohort was 77.1 (7.9) years, 3 110 922 (66.4%) were women, 3 928 432 (83.8%) were non-Hispanic White, 792 707 (16.9%) were dually eligible for Medicaid, and 885 432 (18.9%) had an ADRD diagnosis. Before CJR implementation, joint replacement rates were lower among beneficiaries with ADRD (hip replacements: 0.38% vs 1.17% for beneficiaries with and without ADRD, respectively; P < .001; knee replacements: 0.70% vs 2.25%; P < .001). After controlling for relevant covariates, CJR was associated with a 0.07-percentage-point decline in hip replacements for beneficiaries with ADRD (95% CI, -0.13 to -0.001; P = .046) and a 0.07-percentage-point decline for beneficiaries without ADRD (95% CI, -0.12 to -0.02; P = .01) residing in CJR MSAs compared with beneficiaries in control MSAs. However, this change in hip replacement rates for beneficiaries with ADRD was not statistically significantly different from the change for beneficiaries without ADRD (percentage point difference: 0.01; 95% CI, -0.08 to 0.09; P = .88). No statistically significant changes in knee replacement rates were noted for beneficiaries with ADRD compared with those without ADRD with CJR implementation (percentage point difference: -0.03, 95% CI, -0.09 to 0.02; P = .27). In this cohort study of Medicare beneficiaries with arthritis, the CJR model was not associated with a decline in joint replacement utilization among beneficiaries with ADRD compared with beneficiaries without ADRD in the first 2 years of the program, thereby alleviating patient selection concerns.


Adenosine, 'pertussis-sensitive' G-proteins, and K+ conductance in central mammalian neurones under energy deprivation.
There is a striking similarity between the effects of adenosine and of hypoxia or glucose depletion on membrane potential and conductance of hippocampal neurones in tissue slices of rat brain. Both induce a membrane hyperpolarization by an increase in potassium conductance. It seemed likely, therefore, that a rise in extracellular adenosine concentration during energy deprivation may link neuronal metabolism with membrane K+ conductance. To test this hypothesis, we have now investigated the effects of hypoxia/glucose deprivation on hippocampal neurones from pertussis toxin-treated rats. In such slices adenosine had no effect on postsynaptic membrane potential and input resistance. Nevertheless, hypoxia or glucose depletion were as effective as in controls. These data provide evidence against adenosine as the main mediator between cell metabolism and potassium conductance.


High-affinity uptake system for cysteine in crude synaptosomal fractions of rat cerebral cortex.
The in vitro uptake of [35S] cysteine was studied in crude synaptosomal preparation of the cerebral cortex of rat. The accumulation of cysteine was found to be temperature- and time-dependent. It was linear at least for four minutes at 37 C with characteristics of saturable kinetics. Uptake of cysteine was Na+- and K+-dependent. Increasing the Na+ ion concentration increased the accumulation of cysteine in synaptosomal preparations; unlike the Na+ ion, an increase was accumulated against concentration gradients by a saturable mechanism. Double reciprocal plot of the cysteine uptake suggests two types of affinity systems, with Km values for the high-affinity uptake of about 12.2 microM and for the low-affinity uptake of about 4 mM. The high-affinity uptake was also significantly inhibited by ouabain, a potent inhibitor of the Na+-K+-dependent ATPase, and other metabolic inhibitors. The results of the effects of cysteine analogues and uptake also suggested that it is a substrate-specific high-affinity uptake system for cysteine.


Toll-like receptor 4-mediated cAMP production up-regulates B-cell activating factor expression in Raw264.7 macrophages.
B-cell activating factor (BAFF) plays a role in the generation and the maintenance of mature B cells. Lipopolysaccharide (LPS) increased BAFF expression through the activation of toll-like receptor 4 (TLR4)-dependent signal transduction. Here, we investigated the mechanism of action on mouse BAFF (mBAFF) expression by cAMP production in Raw264.7 mouse macrophages. mBAFF expression was increased by the treatment with a cAMP analogue, dibutyryl-cAMP which is the activator of protein kinase A (PKA), cAMP effector protein. PKA activation was measured by the phosphorylation of cAMP-response element binding protein (CREB) on serine 133 (S133). cAMP production and CREB (S133) phosphorylation were augmented by LPS-stimulation. While mBAFF promoter activity was enhanced by the co-transfection with pS6-RSV-CREB, it was reduced by siRNA-CREB. PKA inhibitor, H-89, reduced CREB (S133) phosphorylation and mBAFF expression in control and LPS-stimulated macrophages. Another principal cAMP effector protein is cAMP-responsive guanine nucleotide exchange factor (Epac), a Rap GDP exchange factor. Epac was activated by the treatment with 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (CPT), Epac activator, as judged by the measurement of Rap1 activation. Basal level of mBAFF expression was increased by CPT treatment. LPS-stimulated mBAFF expression was also slightly enhanced by co-treatment with CPT. In addition, dibutyryl-cAMP and CPT enhanced mBAFF expression in bone marrow-derived macrophages (BMDM). With these data, it suggests that the activation of PKA and cAMP/Epac1/Rap1 pathways could be required for basal mBAFF expression, as well as being up-regulated in the TLR4-induced mBAFF expression.


Allyl-ammonium hydrogen oxalate hemihydrate.
In the title hydrated mol-ecular salt, C3H8N(+)·C2HO4 (-)·0.5H2O, the water O atom lies on a crystallographic twofold axis. The C=C-C-N torsion angle in the cation is 2.8 (3)° and the dihedral angle between the CO2 and CO2H planes in the anion is 1.0 (4)°. In the crystal, the hydrogen oxalate ions are linked by O-H⋯O hydrogen bonds, generating [010] chains. The allyl-ammonium cations bond to the chains through N-H⋯O and N-H⋯(O,O) hydrogen bonds. The water mol-ecule accepts two N-H⋯O hydrogen bonds and makes two O-H⋯O hydrogen bonds. Together, the hydrogen bonds generate (100) sheets.


miR-488 Inhibits Cell Growth and Metastasis in Renal Cell Carcinoma by Targeting HMGN5 [Retraction].
[This retracts the article DOI: 10.2147/OTT.S156361.].


The effect of exercise on hip muscle strength, gait speed and cadence in patients with total hip arthroplasty: a randomized controlled study.
To evaluate the effect of home versus in-hospital exercise (under supervision) programmes on hip strength, gait speed and cadence in patients with total hip arthroplasty at least one year after operation. Physical therapy and rehabilitation department. Twenty-six patients who had had a total hip arthroplasty operation 12-24 months prior to the study were enrolled. The patients were randomized into three groups: group 1 patients were assigned a home exercise programme, group 2 patients exercised under physiotherapist supervision in hospital, and group 3 served as the control group, with no specific intervention. The study duration was six weeks. Maximum isometric abduction torque of operated hip muscle, gait speed and cadence were measured before and after the study. Maximum isometric abduction torques of the hip abductor muscles improved in groups 1 and 2, but not in group 3 (30 +/- 12 to 38 +/- 11 ft.lb in group 1, 18 +/- 10 to 30 +/- 9.8 ft.lb in group 2). Gait speed improved from 67.8 +/- 23 to 74.35 +/- 24 m/min in group 1, from 48.53 +/- 4 to 56.7 +/- 5 m/min in group 2 and from 58.01 +/- 12 to 59.8 +/- 14 m/min in group 3. Cadence also improved, from 97.7 +/- 18 to 111 +/- 17 steps/min in group 1, from 90.75 +/- 6 to 104.75 +/- 7 steps/min in group 2, and from 87 +/- 16 to 88.22 +/- 16 steps/min in group 3. When the three groups were compared, group 2 showed the best improvement (P = 0.006) only in maximum isometric abduction torque. Our findings suggest that both home and supervised exercise programmes are effective one year after total hip arthroplasty. Home exercise programmes with close follow-up could be recommended.


Cushing's disease-from Minnie G to key issues in the early 21st century.
Oct 7, 2019, marks the 80th anniversary of the death of Harvey Cushing, the father of modern neurosurgery. Here we give a historical perspective from Cushing's original description of the clinical syndrome that now bears his name through to the modern day. We highlight some of the key milestones that allowed improved understanding and management of this extraordinarily challenging condition, and identify some of the key issues that still exist in the 21st century.


Talk to Patients About: Cleanliness vs. Vaccines.
Historical data proves vaccines work. Year-over-year rates for vaccine-preventable diseases like measles and whooping cough show that the number of cases drops sharply and remains low after a vaccine is introduced. Anti-vaccine activists have a theory to explain away this data. They say the rise of cleanliness and hygiene in the late 1800s - not vaccines - was the real force in stopping these diseases.


Managing an outpatient parenteral antibiotic therapy team: challenges and solutions.
Outpatient parenteral antimicrobial therapy (OPAT) programs should strive to deliver safe, cost effective, and high quality care. One of the keys to developing and sustaining a high quality OPAT program is to understand the common challenges or barriers to OPAT delivery. We review the most common challenges to starting and managing an OPAT program and give practical advice on addressing these issues.


Effect of Chinese prescription Kangen-karyu on lipid metabolism in type 2 diabetic db/db mice.
Chinese prescription Kangen-karyu is clinically used as a treatment for cardiovascular diseases, and we have reported the beneficial effects on chemically induced hyperlipidemic animal models. The present study was investigated to evaluate the hypolipidemic effect of Kangen-karyu in type 2 diabetic db/db mice which has not been explored yet. Male db/db mice were divided into three groups, vehicle (control), Kangen-karyu 100, or 200 mg/kg body weight/day, and orally administered for 5 weeks every day. Age-matched non-diabetic m/m mice were used as a normal group. Serum triglyceride (TG) and total cholesterol levels in db/db mice were increased compared with those of m/m mice. However, the administration of Kangen-karyu reduced hyperlipidemia in db/db mice through a decline in the serum levels of TG and total cholesterol. The hepatic TG and total cholesterol levels of db/db mice were markedly higher than those of m/m mice, but these elevated lipid levels were significantly reduced by 200 mg/kg Kangen-karyu administration. Also, oil red O staining showed that the increased lipid deposition level in the liver of db/db control mice was improved by Kangen-karyu administration. The expression of sterol regulatory element-binding protein-1 in the liver of db/db mice was significantly down-regulated by the administration of Kangen-karyu at a dose of 200 mg/kg body weight. Kangen-karyu caused a slight elevation in the expression of peroxisome proliferator-activated receptor alpha in the liver of db/db mice. This study provides scientific evidence that Kangen-karyu improves hyperlipidemia and lipid deposition via the regulation of hepatic SREBP-1 expression in type 2 diabetic db/db mice.


Integration of Stereotactic Body Radiation Therapy into the Multidisciplinary Management of Pancreatic Cancer.
Although most patients with pancreatic cancer die of metastatic disease, an autopsy study showed that up to one-third of patients die of predominantly local disease. This patient population stands to benefit the most from radiation, surgery, or both. Unfortunately, however, single-agent chemotherapy has had minimal benefit in pancreatic cancer, and most patients progress distantly before receiving radiation therapy (RT). With the addition of multiagent chemotherapy, patients are living longer, and RT has emerged as an important modality in preventing local progression. Standard chemoradiation delivered over 5-6 weeks has been shown to improve local control, but this approach delays full-dose systemic therapy and increases toxicity when compared to chemotherapy alone. Stereotactic body RT (SBRT) delivered in 3-5 fractions can be used to accurately target the pancreatic tumor with small margins and limited acute treatment-related toxicity. Given the favorable toxicity profile, SBRT can easily be integrated with other therapies in all stages of pancreatic cancer. However, future studies are necessary to determine optimal dose or fractionation regimens and sequencing with targeted therapies and immunotherapy. The purpose of this review is to discuss our current understanding of SBRT in the multidisciplinary management of patients with pancreatic cancer and future implications.


Imaging of low-grade bone infection with a technetium-99m labelled monoclonal anti-NCA-90 Fab' fragment in patients with previous joint surgery.
Low-grade bone infection represents a serious clinical problem. Diagnostic options are often insufficient, yet the therapeutic implications of proven disease are important, especially in patients with prosthetic joint replacement. Technetium-99m labelled monoclonal anti-NCA-90 granulocyte antibody Fab' fragment (MN3 Fab') has been shown to be useful in bone and joint infection, but there are no data specifically referring to low-grade bone infection. We therefore analysed 38 scans in 30 consecutive patients (age range, 30-85 years; median age, 62 years) referred for suspected low-grade bone infection. There were 17 patients (21 scans) with total hip arthroplasty (THA), six with total knee arthroplasty (TKA), three who had undergone hip or knee surgery for trauma and five (seven scans) with resected hips and no endoprostheses (Girdlestone situations); one of these five patients had been investigated before with THA in situ and another prior to surgery for low-grade coxitis. There were no patients with rheumatoid arthritis as the underlying disease. Results were verified by means of bacteriological cultures, histopathological findings and/or follow-up and compared with the respective Zimmerli scores, which were used for clinical assessment of inflammatory activity. In one patient, the final diagnosis could not be established. One, 5 and 24 h after intravenous injection of up to 1.1 GBq of MN3 Fab', whole-body and planar scans were performed using a dual-head gamma camera. Scans were analysed visually and semiquantitatively adopting an arbitrary score ranging from 0 to 3. There were 13 true positive, 14 true negative and 10 false positive outcomes, yielding an overall sensitivity of 100%, an overall specificity of 58%, an accuracy of 73% and positive and negative predictive values of 57% and 100%, respectively. In patients with THA or TKA, accuracy was 81% and 80%, respectively, while it dropped to 43% in patients with Girdlestone situations owing to a high proportion of false positive findings (4/7) in this subgroup. Scintigraphic score was 1 in all of the false positive and in 11/13 true positive findings. The two remaining true positive findings displayed scintigraphic scores of 2 and 3, respectively. Scintigraphic and Zimmerli scores were loosely correlated (Spearman rho=0.38, P<0.05). Infection was excluded in 22/24 investigations with Zimmerli scores of <6. In this group, there were 13 scintigraphically true negative, nine false positive outcomes, and just two true positive outcomes. In 11/12 investigations with Zimmerli scores of 6 or 7, infection was verified and scintigraphic outcome was accordingly true positive, while the remaining patient was true negative. In conclusion, MN3 Fab' scintigraphy proved to be highly sensitive but not specific in diagnosing low-grade infections of the hip and knee regions in patients with previous joint surgery. The method seems reliable in excluding but not in proving the presence of infection. MN3 Fab' scintigraphy should not be applied in patients with Girdlestone situations. Assessment of infection using the Zimmerli score was more reliable than MN3 Fab' scintigraphy in this group of patients without rheumatoid arthritis as the underlying disease. Considering results from the literature concerning leucocyte scintigraphy, MN3 Fab' scintigraphy may be clinically useful in evaluating low-grade bone infection in THA and TKA patients with Zimmerli scores above 5 and concomitant rheumatoid arthritis or other inflammatory diseases.


Synthesis, Biological Evaluation and Molecular Docking Study of 2-Substituted-4,6-Diarylpyrimidines as α-Glucosidase Inhibitors.
A novel series of 2-substituted-4,6-diarylpyrimidines 6a-6t has been synthesized, characterized by ¹H-NMR, 13C-NMR and HRMS, and screened for in vitro α-glucosidase inhibitory activity. The majority of the screened compounds possessed significant α-glucosidase inhibitory activity with IC50 values ranging from 19.6 ± 0.21 to 38.9 ± 0.35 μM, which is more potent than the positive control α-glucosidase inhibitor acarbose (IC50 = 817.38 ± 6.27 μM). Among them, 6j was found to be the most active compound against α-glucosidase with an IC50 of 19.6 ± 0.21 μM. In addition, molecular docking studies were carried out to explore the binding interactions of 2-substituted-4,6-diarylpyrimidine derivatives with α-glucosidase.


Temporal patterns of heart rate and selected arrhythmias for 48 hours after cardiac surgery.
To describe the temporal patterns of heart rate and arrhythmias in the immediate postoperative period following cardiac surgery. Six postoperative cardiac surgical patients with a mean age of 48.3 years were studied. Descriptive longitudinal design. Cardiac surgical ICU. Heart rate and arrhythmias were recorded continuously for 48 hours from a cardiac monitor using a Holter tape recorder. Environmental and treatment data were noted throughout data collection by trained nonparticipant observers. Mean heart rate and incidence of arrhythmias were different between the 2 study days; therefore, data were divided into two segments (A and B). These differences coincided with extubation in most cases. Individual subject cosinor analysis revealed 24-hour rhythms of heart rate in both segments in all subjects except segment B for one subject. Rhythms of shorter periods were also found. In segment A individual subjects' acrophases (peak times of fitted curves) occurred later than expected for subjects' prehospitalization sleep-wake schedule, whereas in segment B they occurred earlier. Cosinor analysis of arrhythmias revealed significant 24-hour rhythms in both segments in one of the three subjects with premature atrial complexes, two of the four subjects with premature ventricular complexes and both subjects with ventricular couplets. Four-hour rhythms were found in premature atrial complexes (n = 1), atrial tachycardia (n = 1) and premature ventricular complexes (n = 3). Acrophases for arrhythmias varied among patients. During segment B the 4-hour-rhythm acrophases in heart rate and arrhythmias were related to the timing of respiratory therapy. Temporal variations in heart rate could be identified in these six critically ill adults. Rhythm parameters changed during the first 48 hours after cardiac surgery. In those who had arrhythmias, some patients demonstrated temporal patterns in the incidence of selected arrhythmias. Further study is needed to describe the temporal patterns of heart rate and arrhythmias in varied groups of critically ill persons in a variety of settings.


A de novo TUBB4A mutation in a patient with hypomyelination mimicking Pelizaeus-Merzbacher disease.
Hypomyelinating leukoencephalopathy is a heterogeneous disorder caused by mutations in several-different genes. Clinical entity of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is one of them. A male patient showed pendular nystagmus, infantile hypotonia, an abnormal pattern of brain auditory evoked potential, and hypomyelination on brain magnetic resonance imaging, which suggested Pelizaeus-Merzbacher disease (PMD) as the candidate diagnosis; however, no abnormality was found in the proteolipid protein 1 gene (PLP1) that is responsible for PMD. Whole exome sequencing was performed to identify pathogenic mutations in this patient. A de novo mutation was identified in the tubulin 4a gene (TUBB4A), which has been recently reported to be associated with H-ABC. Although the patient did not show any neurological features suggesting H-ABC, such as extrapyramidal or cerebellar signs, radiological findings demonstrated the finding of cerebellar atrophy at the age of 36months. This study suggested us the difficulty of clinical diagnosis for H-ABC early in the life of the patient, which makes predication of prognosis and genetic counseling difficult.


Modulatory effects of Punica granatum L juice against 2115 MHz (3G) radiation-induced reproductive toxicity in male Wistar rat.
Advancements in telecommunication sector result in increasing exposure to electromagnetic (EM) radiation, which has been correlated with incidence of male infertility. Therefore, the present study focused on analyzing the consequence of EM radiation (2115 MHz) exposure on the reproductive system of male Wistar rats. Besides, the antioxidant protective effect of Punica granatum juice was also evaluated. For experimental analysis, rats were divided into five groups (control, sham exposed, exposed, herbal plus exposed, and herbal only). Individual group consisted of 6 rats which were exposed to radiation for 45 days (2 h/day). The herbal-treated groups were given 1 ml of Punica granatum extract orally. Various parameters such as organ to body ratio, sperm count, motility, viability, and testis histopathology were studied. Furthermore, oxidative stress parameters and free radical generation were analyzed. The exposed group showed changes in sperm parameters along with decrease in seminiferous tubule diameter. On the contrary, herbal-exposed group showed enhanced sperm count, increased motility, and viability in comparison to exposed group. Histopathology studies also revealed the protective role of herbal juice. Significant alteration in oxidative parameters along with an enhanced free radical generation in exposed group and reduction in herbal groups was observed. The results thus indicate that continuous exposure to EM radiation can lead to oxidative stress which induces biochemical changes in rat sperms. However, Punica granatum extract has a protective role against oxidative damage induced by EM radiation.


Synthesis and tissue distribution of substituted [125I]iodophenylamine derivatives: possible brain imaging agents.
The synthesis and brain uptake in mice of the radioiodinated derivatives of N,N-dimethyl-N'-(iododimethoxyphenyl)-1,3-propanediamine, as well as the N-substituted derivatives of (iodoalkylphenyl)isopropyl, iodoalkylphenylethylamine and 3,4-(methylenedioxy)phenyl-amphetamine (MDA) are described. These compounds contain structural features of both IMP and HIPDM, the cerebral perfusion agents currently in clinical use. The radiolabeled analogs were obtained via the [125I]I exchange method, or by [125I]NaI treatment of the iodo-free precursor in the presence of an oxidant. Following intravenous injection in mice, all compounds showed important radioactivity concentrations in the lungs and kidneys. The N-substituted (iodoalkylphenyl)isopropyl and iodoalkylphenyl-ethylamine derivatives displayed a high initial brain uptake (> 10% IDg-1) followed by a rapid clearance phase, resulting in lower brain-to-blood ratios as those reported for IMP and HIPDM. In contrast, N,N-dimethyl-N'-(iododimethyphenyl)-1,3-propanediamine derivatives featuring the iodo substituent on the benzene carbon adjacent to the methyl amine group and the methoxy substituents on the 2,5- or 2,4-positions, showed low but more persistant brain uptake. Combined with fast blood clearance, this resulted in high brain-to-blood ratios at later time points. Among all compounds tested, the highest brain-to-blood ratio was observed with compound N,N-dimethyl-N'-(6-iodo-3,4-dimethyoxyphenyl)-1,3-propanediamine (27e), reaching a maximum of > 20 at 12 h post-injection.


Accuracy of image registration between MRI and light microscopy in the ex vivo brain.
A multistep procedure was developed to register magnetic resonance imaging (MRI) and histological data from the same sample in the light microscopy image space, with the ultimate goal of allowing quantitative comparisons of the two datasets. The fixed brain of an owl monkey was used to develop and test the procedure. In addition to the MRI and histological data, photographic images of the brain tissue block acquired during sectioning were assembled into a blockface volume to provide an intermediate step for the overall registration process. The MR volume was first registered to the blockface volume using a combination of linear and nonlinear registration, and two dimensional (2D) blockface sections were registered to corresponding myelin-stained sections using a combination of linear and nonlinear registration. Before this 2D registration, two major types of tissue distortions were corrected: tissue tearing and independent movement of different parts of the brain, both introduced during histological processing of the sections. The correction procedure utilized a 2D method to close tissue tears and a multiple iterative closest point (ICP) algorithm to reposition separate pieces of tissue in the image. The accuracy of the overall MR to micrograph registration procedure was assessed by measuring the distance between registered landmarks chosen in the MR image space and the corresponding landmarks chosen in the micrograph space. The average error distance of the MR data registered to micrograph data was 0.324±0.277 mm, only 8% larger than the width of the MRI voxel (0.3 mm).


Tracking of fetal breathing movements by pulsed Doppler ultrasound.
Fetal breathing movements form a useful means of monitoring fetal conditions and functional development. Precise quantitative evaluation of fetal breathing movements requires the development of a continuous automated technique. A preliminary study of Doppler signals due to fetal breathing movements was carried out using a cardiotocograph in which the normal high-pass 'thump' filter had been removed. A pulsed Doppler system was then modified to produce five simultaneous outputs representing movement at depths separated by 1.5-cm intervals. These outputs represent the displacement inside tissue at the various depths. Signal processing was executed on a 32-bit computer with an analog-to-digital converter. On-line processing using a zero-crossing method and an off-line high-accuracy displacement estimation technique using an arc-tangent method were applied. Using computerized signal processing, it was possible to detect movements of a few hundred microns representing fetal breathing movements while rejecting gross movements due to maternal breathing, etc. Although further studies are required before clinical application, it appears that quantitative assessments of fetal breathing movements should be possible with this technique.


Canonical and 1-Deoxy(methyl) Sphingoid Bases: Tackling the Effect of the Lipid Structure on Membrane Biophysical Properties.
Compared to the canonical sphingoid backbone of sphingolipids (SLs), atypical long-chain bases (LCBs) lack C1-OH (1-deoxy-LCBs) or C1-CH2OH (1-deoxymethyl-LCBs). In addition, when unsaturated, they present a cis-double bond instead of the canonical Δ4-5 trans-double bond. These atypical LCBs are directly correlated with the development and progression of hereditary sensory and autonomic neuropathy type 1 and diabetes type II through yet unknown mechanisms. Changes in membrane properties have been linked to the biological actions of SLs. However, little is known about the influence of the LCB structure, particularly 1-deoxy(methyl)-LCB, on lipid-lipid interactions and their effect on membrane properties. To address this question, we used complementary fluorescence-based methodologies to study membrane model systems containing POPC and the different LCBs of interest. Our results show that 1-deoxymethyl-LCBs have the highest ability to reduce the fluidity of the membrane, while the intermolecular interactions of 1-deoxy-LCBs were found to be weaker, leading to the formation of less-ordered domains compared to their canonical counterparts-sphinganine and sphingosine. Furthermore, while the presence of a trans-double bond at the Δ4-5 position of the LCB increased the fluidity of the membrane compared to a saturated LCB, a cis-double bond completely disrupted the ability of the LCB to segregate into ordered domains. In conclusion, even small changes on the structure of the LCB, as seen in 1-deoxy(methyl)-LCBs, strongly affects lipid-lipid interactions and membrane fluidity. These results provide evidence that altered balance between species with different LCBs affect membrane properties and may contribute to the pathobiological role of these lipids.


[Absence of effect of ethanol and apple brandy on the upper digestive tract and esophagus of the Wistar rat. Part of a research project to assess etiological factors of cancer of the esophagus in the west of France (author's transl)].
Epidemiological studies have shown the role of alcohol in esophageal cancer in the West of France. Experiments were undertaken on Wistar rats to study the effect of locally consumed alcoholic beverages on the esophagus. Neither histological modifications, precancerous lesions nor cancer were observed in the animals. There was no significant excess of benign or malignant tumours in treated animals when compared with controls.


Gonadotropin releasing hormone (GnRH) is not degraded by intact pituitary tissue in vitro.
The possible degradation of GnRH by intact pituitary tissue was investigated. Trypsin-, collagenase- and mechanically dispersed pituitary cells in culture and fresh pituitaries cut into eight segments were incubated with specifically tritiated GnRH or unlabeled GnRH which were detected by HPLC and RIA in incubation media. Degradation of GnRH could not be detected by either method during incubations with any of the pituitary cell cultures or fresh tissue. The results suggest that pituitary degradation is not involved in the regulation of circulating levels of GnRH.


Problems and pitfalls in a clinical research data management system.
The problems and pitfalls encountered in the computerized data bank for the Netherlands Coronary Surgery (NCS) study are reviewed. This study involved 848 patients seen before coronary artery surgery and at 1 and 3 yr after surgery. Nineteen data forms were used resulting in maximally 1142 variables per patient. The importance of quality control is emphasized as well as the efficient transfer of information from data bank to statistical processing.


An Up-conversion signal probe-MnO2 nanosheet sensor for rapid and sensitive detection of tetracycline in food.
The irrational use of tetracycline (TC) poses a serious threat to human health, which calls for the development of efficient and reliable detection methods. Herein, an ideal sensor based on luminescence resonance energy transfer (LRET) between aptamer modified up-conversion nanoparticles as signal probes (donors) and manganese dioxide (MnO2) nanosheets (acceptors) was developed for TC detection in food samples. As a result of van der Waals forces between the nucleobases of the aptamer and the basal plane of MnO2 nanosheets, the distance of the donors and acceptors was shortened. The emission spectrum of the signal probes and the absorption spectrum of MnO2 nanosheets overlapped, resulting in LRET, and quenching of up-conversion luminescence. The TC-specific aptamer could fold into a complex conformational structure to provide recognition sites for TC. In the presence of TC, the aptamer was found to preferentially combine with TC due to the stacking of planar moieties, hydrogen bonding interactions and molecular shape complementarity, causing the separation of signal probes and nanosheets, and luminescence recovery. Consequently, a low detection limit of 0.0085 ng/mL was achieved with a wide detection range of 0.01-100 ng/mL. Moreover, the ability of the sensor to detect TC was confirmed in actual food samples and compared with the traditional ELISA with satisfactory results (p > 0.05).


Deflation reflex: description and clinical significance.
During our study of the defecation mechanism, we found that the external anal sphincter contracted not only upon rectal inflation but also upon deflation. As this reflex relationship was reproducible, it was studied to elucidate its clinical significance in the light of its function. A catheter with a condom at its end was introduced into the rectum of 16 healthy volunteers (mean age 45.2 years). The EMG response of the external anal sphincter to rapid rectal inflation and deflation was studied by means of a concentric needle electrode inserted into the muscle. The procedure was repeated in eight subjects after sphincter infiltration with xylocaine or saline. The external sphincter contracted twice on rectal distension: once on inflation and another time on deflation. The amplitude increased and latency decreased with increasing rectal inflation, while neither was affected on deflation. The anesthetized sphincter did not respond, while the saline-infiltrated sphincter responded to rectal distension. The deflation reflex functions to interrupt or terminate the act of defecation. It may prove of diagnostic significance in defecation disorders.


Pulmonary flow resistance.
In the past it has been generally assumed that pulmonary flow resistance (RL) increases with increasing flow and decreases with increasing lung volume. Recent work indicates that RL decreases with increasing flow, at least up to flow rates 3-4 times greater than those at rest, and increases progressively with increasing lung volume. This behaviour results mainly from dynamic pressure dissipations within the pulmonary tissues due to viscoelastic phenomena. In fact, during resting breathing the contribution of the latter to RL is more important than that of airway resistance.


A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma.
Noise-induced hearing loss (NIHL) results from a complex interplay of damage to the sensory cells of the inner ear, dysfunction of its lateral wall, axonal retraction of type 1C spiral ganglion neurons, and activation of the immune response. We use RiboTag and single-cell RNA sequencing to survey the cell-type-specific molecular landscape of the mouse inner ear before and after noise trauma. We identify induction of the transcription factors STAT3 and IRF7 and immune-related genes across all cell-types. Yet, cell-type-specific transcriptomic changes dominate the response. The ATF3/ATF4 stress-response pathway is robustly induced in the type 1A noise-resilient neurons, potassium transport genes are downregulated in the lateral wall, mRNA metabolism genes are downregulated in outer hair cells, and deafness-associated genes are downregulated in most cell types. This transcriptomic resource is available via the Gene Expression Analysis Resource (gEAR; https://umgear.org/NIHL) and provides a blueprint for the rational development of drugs to prevent and treat NIHL.


Improvement of cerebral ischemia/reperfusion injury by daucosterol palmitate-induced neuronal apoptosis inhibition via PI3K/Akt/mTOR signaling pathway.
Traditional Chinese medicine has growing importance in the treatment of ischemia stroke due to its abundance and low drug resistance. In this study, we aim to investigate the therapeutic potential of daucosterol palmitate against ischemia stroke, as well as its neuro-protective mechanism. The dose-response effects of daucosterol palmitate in the protection from brain damage were evaluated in a cerebral ischemia/reperfusion (I/R) rat model. The correlation of neuro-protective effects of daucosterol palmitate with apoptosis inhibition was examined and the possible signaling targets were identified. Our findings revealed that daucosterol palmitate treatment after 2 h' ischemia significantly lowered brain damage, and neuronal cell apoptosis caused by I/R injury in a dose-response mode (20, 40 and 80 mg/kg). Western blot analysis indicated that daucosterol palmitate could reverse the effects of I/R injury on protein expression of PI3K and mTOR, and phosphorylation of Akt. Contrarily, inactivation of PI3K using wortmannin dramatically antagonized the effect of daucosterol palmitate for I/R injury. With these findings, it supports the application potential of daucosterol palmitate in the treatment of ischemia stroke. Besides, the PI3K/Akt/mTOR pathway might be potential cellular targets for daucosterol palmitate.


The regulation of aortic endothelial cells by purines and pyrimidines involves co-existing P2y-purinoceptors and nucleotide receptors linked to phospholipase C.
1. We have examined the phospholipase C responses in bovine aortic endothelial cells to purines (ATP, ADP and analogues) and the pyrimidine, uridine triphosphate (UTP). 2. The cells responded to purines in a manner consistent with the presence of P2y purinoceptors; both 2-methylthioadenosine 5'-triphosphate (2MeSATP) and adenosine 5'-0-(2-thiodiphosphate) (ADP beta S) were potent agonists (EC50 0.41 microM and 0.85 microM respectively) while beta, gamma-methylene ATP at 300 microM was not. 3. The cells also responded to UTP. The maximal response to UTP was less than that for either 2MeSATP and ADP beta S while adenosine 5'-0-(3-thiotriphosphate) (ATP gamma S) gave the largest maximal response. 4. The concentration-effect curve to UTP was additive in the presence of either 2MeSATP or ADP beta S. However, the concentration-effect curves to ATP gamma S reached the same maximum in the presence or absence of UTP. 5. Suramin, at concentrations between 10 microM and 100 microM was a competitive antagonist for the response to ADP beta S and 2MeSATP but not the response to UTP. 6. The results show that there are two separate, co-existing, receptor populations: P2y-purinoceptors (responding to purines) and nucleotide receptors (responding to both purines and pyrimidines). We conclude that purines such as ATP/ADP may regulate aortic endothelial cells by interacting with two phospholipase C-linked receptors.


Long head biceps tendon instability: diagnostic performance of known and new MRI diagnostic signs.
The aim of this work was to evaluate the inter-observer agreement and diagnostic performance values of 7 MRI signs (3 known and 4 new) of long head biceps tendon instability. MRI of 86 patients were retrospectively evaluated. Inter-observer agreement and diagnostic performance of each diagnostic sign and of all combined signs (with the exception of detour sign) were tested for identification of biceps tendon instability, with arthroscopy as the reference standard. Agreement between expert operators was moderate to good. Sensitivity, specificity, and sign accuracy showed a variation respectively of the following: humeral chondral print 72-80%, 62-68%, and 70-76%; subchondral bone edema 24-31%, 84-97%, and 50%; biceps tendon angle 60-71%, 97-100%, and 74-81%, biceps tendon-groove distance 31-47%, 90-100%, and 56-64%; long head biceps subluxation/dislocation on axial plane 49-53%, 97-100%, and 66-70%; displacement sign 74-80%, 74-100%, and 74-87%; detour sign 51-64%, 58-81%, and 62-64%; and all signs 98-100%, 32-61%, and 75-86%. These diagnostic signs, both known and new, individually and/or in combination, provide a valid tool in the MRI diagnosis of long head biceps tendon instability.


Bone Substitute Materials and Minimally Invasive Surgery: A Convergence of Fracture Treatment for Compromised Bone.
This article focuses on the understanding of the biochemistry and surgical application of bone substitute materials (BSMs) and particularly the newer calcium phosphate materials that can form a structural orthobiologic matrix within the metaphyseal components of the periarticular bone. Six characteristics of BSMs are detailed that can be used as a guide for the proper selection and application of the optimal BSM type for periarticular fracture repair. These 6 characteristics of BSMs are divided into 2 pillars. One pillar details the 3 biochemical features of BSMs and the other pillar details the 3 surgical application properties.


L-Phenylalanine ammonia-lyase and pisatin induction by 5-bromodeoxyuridine in Pisum sativum.
The substitution of the base analogue 5-bromodeoxyuridine (BrdU) for thymidine in the DNA of pea pods (Pisum sativum) induces or enhances the level of phenylalanine ammonia-lyase (PAL) and also induces the phytoalexin, pisatin, a product of the same metabolic pathway. Cordycepin, a polyadenylate inhibitor at the RNA level, is a potent inhibitor of pisatin synthesis. Kinetic studies on the inhibition of the PAL-pisatin production by hydroxyurea indicate that BrdU must be incorporated into DNA before any induction takes place. 5-Iododeoxyuridine is also an inducer while 5-fluorodeoxyuridine is ineffective when applied alone. BrdU is incorporated into the DNA of pea cells and the nuclei undergoes condensation just prior to the detection of the induced responses.


Strategies to load therapeutics into polysaccharide-based nanogels with a focus on microfluidics: A review.
Nowadays nanoparticles are increasingly investigated for the targeted and controlled delivery of therapeutics, as suggested by the high number of research articles (2400 in 2000 vs 8500 in 2020). Among them, almost 2% investigated nanogels in 2020. Nanogels or nanohydrogels (NGs) are nanoparticles formed by a swollen three-dimensional network of synthetic polymers or natural macromolecules such as polysaccharides. NGs represent a highly versatile nanocarrier, able to deliver a number of therapeutics. Currently, NGs are undergoing clinical trials for the delivery of anti-cancer vaccines. Herein, the strategies to load low molecular weight drugs, (poly)peptides and genetic material into polysaccharide NGs as well as to formulate NGs-based vaccines are summarized, with a focus on the microfluidics approach.


Role of the melanocortin system in zebrafish skin physiology.
The agouti-signaling protein (ASIP) acts as both a competitive antagonist and inverse agonist of melanocortin receptors which regulate dorsal-ventral pigmentation patterns in fish. However, the potential role of ASIP in the regulation of additional physiological pathways in the skin is unknown. The skin plays a crucial role in the immune function, acting as a physical limitation against infestation and also as a chemical barrier due to its ability to synthesize and secrete mucus and many immune effector proteins. In this study, the putative role of ASIP in regulating the immune system of skin has been explored using a transgenic zebrafish model overexpressing the asip1 gene (ASIPzf). Initially, the structural changes in skin induced by asip1 overexpression were studied, revealing that the ventral skin of ASIPzf was thinner than that of wild type (WT) animals. A moderate hypertrophy of mucous cells was also found in ASIPzf. Histochemical studies showed that transgenic animals appear to compensate for the lower number of cell layers by modifying the mucus composition and increasing lectin affinity and mucin content in order to maintain or improve protection against microorganism adhesion. ASIPzf also exhibit higher protein concentration under crowding conditions suggesting an increased mucus production under stressful conditions. Exposure to bacterial lipopolysaccharide (LPS) showed that ASIPzf exhibit a faster pro-inflammatory response and increased mucin expression yet severe skin injures and a slight increase in mortality was observed. Electrophysiological measurements show that the ASIP1 genotype exhibits reduced epithelial resistance, an indicator of reduced tissue integrity and barrier function. Overall, not only are ASIP1 animals more prone to infiltration and subsequent infections due to reduced skin epithelial integrity, but also display an increased inflammatory response that can lead to increased skin sensitivity to external infections.


Outcomes of teachers away from work forvoicedisorders, State Secretariat of Education, Federal District, 2009-2010.
Voice is an important working tool for teachers. These professionals are often forced to stay away from work due to voice disorders, resulting in high frequency of sick leaves, function restriction and professional readjustment. Toevaluate the epidemiological profile of teacher absenteeism due to voice disorders and the impact of dysphonia on reduction of work activities, function restriction and professional readjustment. A retrospective study of teachers away from work for more than 30 days was performed from January 2009 to December 2010 based on data collected from medical records at State Secretariat of Education, Federal District, Brazil. A total of 153 teachers away from work due to dysphonia were analyzed. The highest prevalence of voice disorders corresponded to women (96.7%). Vocal nodules were the most prevalent diagnosis, corresponding to 40% of the vocal lesions. The average time away from work was 120 days. About 55% of the teachers on sick leave were indicated function restriction and remained in that condition for 166 days, on average. In total, 25.5% of the teachers needed professional readjustment, and 73.8% were able to return to the classroom. Voice disorders are a frequent cause of sick leaves, resulting in high annual costs. Preventive measures and vocal orientation might significantly reduce the number of teachers with function restriction or requiring readjustment.


Enhanced Contaminated Human Remains Pouch: initial development and preliminary performance assessments.
To produce a proof of concept prototype Enhanced Contaminated Human Remains Pouch (ECHRP) with self-decontamination capability to provide increased protection to emergency response personnel. The key objective was to decrease the concentration of toxic chemicals through the use of an absorbent and reactive nanocellulose liner. Additionally, nanomaterials with biocidal properties were developed and tested as a "stand-alone" treatment. Private company research laboratory. Not applicable. Not applicable. Production of a functional prototype. A functional prototype capable of mitigating the threats due to sulfur mustard, Soman, and a large variety of liquid and vapor toxic industrial chemicals was produced. Stand-alone biocidal treatment efficacy was validated. The ECHRP provides superior protection from both chemical and biological hazards to various emergency response personnel and human remains handlers.


Regulatory issues for computerized electrocardiographic devices.
Computerized electrocardiogram (ECG) devices are regulated in the U.S. by the FDA Center for Devices and Radiological Health (CDRH). This article aims to highlight the salient points of the FDA regulatory review process, including the important distinction between a "tool" claim and a "clinical" claim in the intended use of a computerized ECG device. Specifically, a tool claim relates to the ability of the device to accurately measure a certain ECG parameter, such as T-wave alternans (TWA), while a clinical claim imputes a particular health hazard associated with the identified parameter, such as increased risk of ventricular tachyarrhythmia or sudden death. Given that both types of claims are equally important and receive the same regulatory scrutiny, the manufacturer of a new ECG diagnostic device should consider the distinction and regulatory pathways for approval between the two types of claims discussed in this paper.


Stroke: awareness of the signs, symptoms and risk factors--a population-based survey.
This article reports the findings from a population-based survey conducted to determine baseline knowledge regarding the signs, symptoms and risk factors of stroke. Data were collected in Northern Ireland from 892 adults using a self-completed questionnaire. In general, the results indicate that respondents appeared knowledgeable about the risk factors of stroke but their recognition of the warning signs was poor. In addition, approximately half of those surveyed would not contact the ambulance service in the case of a suspected stroke but instead would make initial contact with their general practitioner (41.5%) or family/relatives (2.3%). Given the importance of early hospital presentation for effective stroke rehabilitation, these findings are of particular concern in a community where the death rate from stroke is one of the highest in Europe. Future health education campaigns should provide accurate and appropriate information regarding the warning signs of stroke and highlight the importance of early hospital presentation.


Cancer dose--response assessment for acrylonitrile based upon rodent brain tumor incidence: use of epidemiologic, mechanistic, and pharmacokinetic support for nonlinearity.
A cancer dose-response assessment was conducted for acrylonitrile (AN) using updated information on mechanism of action, epidemiology, toxicity, and pharmacokinetics. Although more than 10 chronic bioassays indicate that AN produces multiple tumors in rats and mice, a number of large, well-conducted epidemiology studies provide no evidence of a causal association between AN exposure and cancer mortality of any type. The epidemiological data include early industry exposures that are far higher than occur today and that approach or exceed levels found to be tumorigenic in animals. Despite the absence of positive findings in the epidemiology data, a dose-response assessment was conducted for AN based on brain tumors in rats. Mechanistic studies implicate the involvement of oxidative stress in rat brain due to a metabolite (2-cyanoethylene oxide or CEO, cyanide), but do not conclusively rule out a potential role for the direct genotoxicity of CEO. A PBPK model was used to predict internal doses (peak CEO in brain) for 12 data sets, which were pooled together to provide a consistent characterization of the dose-response relationship for brain tumor incidence in the rat. The internal dose corresponding to a 5% increase in extra risk (ED 05=0.017 mg/L brain) and its lower confidence limit (LED 05=0.014 mg/L brain) was used as the point of departure. The weight-of-evidence supports the use of a nonlinear extrapolation for the cancer dose-response assessment. A quantitative comparison of the epidemiology exposure-response data (lung and brain cancer mortality) to the rat brain tumor data in terms of internal dose adds to the confidence in the nonlinear extrapolation. Uncertainty factors of 200 and 220 (for the oral and inhalation routes, respectively) were applied to the LED 05 to account for interspecies variation, intraspecies variation, and the severity of the response measure. Accordingly, oral doses below 0.009 mg/kg-day and air concentrations below 0.1mg/m(3) are not expected to pose an appreciable risk to human populations exposed to AN.


Is Therapy Needed After Distal Radius Fracture Treatment, What Is the Evidence?
The role of hand therapy in management of distal radius fractures remains unclear. Some evidence demonstrates that initiating early range of motion and urging patients to return to routine activities of daily living as soon as possible may produce favorable outcomes that are as effective as formal supervised therapy. Extended supervised therapy does not appear to impact outcomes and a single instruction session with a home-based program produces similar results. Although we feel that formal structured therapy may have a role in select high-risk patients, the literature remains unclear on which patients would benefit most from formal supervised therapy.


The relationship of mineral and geochemical composition to artificial radionuclide partitioning in Yenisei river sediments downstream from Krasnoyarsk.
Discharges from the Mining-and-Chemical Combine (MCC) of Rosatom, downstream from Krasnoyarsk, resulted in radioactive contamination of sediments of the River Yenisei. The concentration of artificial gamma-emitting radionuclides ((137)Cs, (60)Co, (152)Eu, and (241)Am) was determined with the objective to analyze the migration processes leading to the transport of these radionuclides. The content of artificial radionuclides in the surface layers of the study area varied in wide ranges: (137)Cs-318-1,800 Bq/kg, (60)Co-87-720 Bq/kg, (152)Eu-12-287 Bq/kg and (241)Am-6-76 Bq/kg. There was a sequence of migration of radionuclides investigated in the surface layer of sediments that were collected in the near zone of influence of the MCC: (241)Am ≈ (152)Eu > (60)Co > (137)Cs. Radionuclide species have been found to be directly related to sediment structure and composition.


Gonadotrophin response to releasing hormone in post-menopausal patients with ovarian tumours.
Gonadotrophin response to intravenous administration of 100 micrograms synthetic gonadotrophin-releasing hormone (GnRH) was evaluated in 14 post-menopausal women (aged 53-77) with non-endocrine ovarian tumours and 11 post-menopausal control subjects. Neither in the case of follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels, was any significant difference seen between the mean basal levels in the tumour and the control subjects. No significant release was seen in either group as regards FSH response. The mean increases in serum FSH in the tumour patients were not significantly different from those in the control subjects. In the case of LH response, the mean percentage increases in the tumour group as well as the mean area under the curves were significantly greater (P less than 0.01) than those in the control subjects. Androstenedione and oestrone levels were also evaluated in the two groups. Significantly increased levels of these hormones were seen in the tumour group in relation to those in the control group (P less than 0.001). These data are consistent with an increased LH response to GnRH in post-menopausal patients with ovarian tumours. The augmented LH release may be related to increased steroid plasma levels.


Histochemistry of glandular metaplasia at the trigone of the urinary bladder in cows.
The epithelium at the trigone of the urinary bladder showed intestinal metaplasia of a colonic type in three Holstein-Friesian cows affected with chronic polypoid cystitis. Except for Ricinus communis (RCA-I), almost all goblet cells in the whole crypt were positive to periodic acid-Schiff (PAS), alcian blue (AB) pH 2.5, AB pH 1.0, periodate borohydride-potassium hydroxide-PAS (PB-KOH-PAS), Ulex europaeus (UEA-I), Triticum vulgare (WGA) and Arachis hypogaea (PNA) after neuraminidase digestion. This result indicated that most goblet cells contained acidic and neutral glycoconjugates as O-acetylated sialomucin, L-fucose, N-acetyl-glucosamine, neuraminic acid residues and sialic acid-galactose dimers and were devoid of beta-D-galactose. The goblet cells at the surface in the upper half of the crypt contained both sulpho- and sialo-mucins with N-acetyl-galactosamine residues by AB (pH 2.5)-PAS, high iron diamine (HID)-AB (pH 2.5), Dolichos biflorus (DBA) and Glycine maximus (SBA) reactions. On the other hand, the lower goblet cells were found to contain predominantly sulphated mucins with D-mannose and D-glucose residues by AB-PAS, HID-AB and Concanavalia ensiformis (Con A) reactivities. This suggested that mucin secreted from these cells was similar to that secreted from the goblet cells of the large intestine in cattle.


Overexpression of Notch ligand Dll1 in B16 melanoma cells leads to reduced tumor growth due to attenuated vascularization.
Notch signaling plays an important role in vascular development and tumor angiogenesis. It has been shown that disruption of Dll4-triggered Notch signal activation effectively inhibits tumor growth, but this treatment also results in the formation of vascular neoplasms. In this study, we investigate the effects of over-expressing Notch ligand Dll1 in B16 melanoma cells on tumor cell proliferation and tumor growth in vitro and in vivo. Our results showed that over-expression of Dll1 could activate Notch signaling in tumor cells, and promote tumor cell proliferation in vitro. In contrast, growth of Dll1-over-expressing tumors in vivo was reduced, due to abnormal tumor vessel formation. Impaired tumor vasculature enhanced hypoxia and necrosis in tumor tissues, leading to retarded tumor growth. These results suggest that activation of Notch signaling may serve as an anti-angiogenesis strategy in the treatment of malignant tumors.


Mechanisms, kinetics, and dynamics of oxidation and reactions on oxide surfaces investigated by scanning probe microscopy.
Advances in scanning probe microscopies (SPM) have allowed the mechanisms and rates of adsorption, diffusion and reactions on surfaces to be characterized by directly observing the motions of the individual atoms and molecules involved. The importance of oxides as thermal and photocatalysts, chemical sensors, and substrates for epitaxial growth has motivated dynamical SPM studies of oxide surfaces and their formation. Work on the TiO(2) (110) surface is reviewed as an example of how dynamic SPM studies have revealed unexpected interactions between adsorbates and defects that influence macroscopic reaction rates. Studies following diffusion, adsorption and phase transitions on bulk and surface oxides are also discussed. A perspective is provided on advanced SPM techniques that hold great promise for yielding new insights into the mechanisms and rates of elemental processes that take place either during oxidation or on oxide surfaces, with particular emphasis on methods that extend the time and chemical resolution of dynamical SPM measurements.


Low applicability of the ''Six-and-twelve score" in hepatocellular carcinoma treated with Drug-Eluting Beads Transarterial Chemoembolization.
The effectiveness of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) depends on the selection of suitable patients. The ''Six-and-twelve score" distinguishes three groups of ideal patients with different overall survival, based on the sum of the number and size of tumors. This may impact on clinical practice and trial design. The aim of this study was to assess the reproducibility and prognostic value of the model in western patients treated with Drug-Eluting Beads (DEB)-TACE. Observational, retrospective, unicentric study with consecutive compensated patients treated with DEB-TACE from October 2008 to October 2017. Exclusion criteria were Child-Pugh ≥ 8 and DEB-TACE used as a bridge to liver transplantation. 225 HCC consecutive patients were included; BCLC-0/A n=131 (single nodules > 5, n=29) and BCLC-B n=94. The median overall survival (OS) was 27 months (95% CI 23.8-30.2). OS was different between BCLC-0/A vs BCLC-B: 30 vs 24 months (p= 0.03), Child-Pugh A5 vs A6-B7: 30 vs 27 months (p= 0.003). ''Six-and-twelve score" groups discriminated OS: group 1, n=123, 32 months (95% CI 27.5-63.5), group 2, n=101, 24 months (95% CI 19.6-28.4) and group 3, n=1, 27 months (p=0.024). When comparing the three scores, the ''Six-and-twelve score" showed the best discrimination power: C-index 0.603, Akaike's information criterion (AIC) 1.642, likelihood ratio test (LRT) 16.21. The ''Six-and-twelve score" is a prognostic tool for patients with HCC treated with DEB-TACE. However, few patients were included in the third group (score >12) and no differences were observed with BCLC, therefore its applicability is limited. .


Detection of CHD7 deletions by MLPA in CHARGE syndrome patients with a less typical phenotype.
Bergman et al. performed a search for exon copy number alterations in the CHD7 gene using MLPA in CHARGE syndrome patients who did not have a CHD7 mutation. Based on their results they recommended to extend testing using MLPA solely in individuals with a typical CHARGE syndrome phenotype. However, since we have found deletions comprising the CHD7 gene in three patients with a less typical phenotype we recommend performing MLPA testing in all CHARGE syndrome patients without causal CHD7 mutations.


[An additional nerv-lesion in cases of total hip replacement (author's transl)].
Report of early secundary paresis of the sciatic nerve after the implantation of a total artificial hip-joint by the dorso-lateral exposure. The paresis is caused by a cicatrical stenosis of the nerve following a peri- and intranerval bleeding.


Choledochal cysts presenting in late childhood and adulthood.
Primary excision is well accepted in children. Although the length of follow-up is inadequate, our review of the literature and experience with five patients suggests primary excision as the procedure of choice in older children and adults. Although the number of cases is too small and the follow-up too sporadic to draw statistically valid conclusions, excision has a lower morbidity, mortality and reoperation rate than internal cyst drainage, and definitive removal of tissue at risk for malignant degeneration seems intuitively more appealing.


Distribution of hepatitis C virus genotypes in German patients with chronic hepatitis C: correlation with clinical and virological parameters.
The hepatitis C virus genotypes have been shown to be differently distributed between distinct geographical areas and to be associated with different clinical presentations. In the present study we investigated the distribution of HCV genotypes in 379 German patients with chronic hepatitis C in relation to age, sex, route of infection, liver histology and viremia. Typing of HCV was done using restriction fragment length polymorphism analysis as well as a DNA enzyme immunoassay. HCV RNA concentrations were determined by quantitative polymerase chain reaction. Liver biopsies were performed in 187 patients and the histological activity was graded by the Knodell score. Seventy percent were infected with genotype 1 (20% subtype 1a, 80% subtype 1b), 4% with genotype 2 and 26% with genotype 3 (all subtype 3a). Genotype 3a and 1a infection was significantly associated with intravenous drug abuse. In contrast, genotype 1 predominated in patients with post-transfusion hepatitis and infection of unknown origin. A changing relative prevalence of HCV genotypes in relation to age was also observed. Patients with genotype 3 infection showed significantly lower HCV RNA levels and a lower mean histological activity score as compared to patients with genotype 1 and genotype 2. However, using multivariate analysis, only age and mode of transmission but not histological activitiy score were shown to be independent variables. Our study confirms previous reports from other countries that HCV variants can be classified into a relatively small number of discrete genotypes, and that the subtype 1b clearly predominates. However, we found evidence that there is a changing relative prevalence of HCV genotypes in relation to age, and that the mode of transmission is reflected in the predominance of certain genotypes.


Hippocampal Microglia Activation Induced by Acute Pancreatic Injury in Rats.
Acute pancreatitis is an inflammation of the pancreatic glandular parenchyma that causes injury with or without the destruction of pancreatic acini. Clinical and experimental evidence suggest that certain systemic proinflammatory mediators may be responsible for initiating the fundamental mechanisms involved in microglial reactivity. Here, we investigated the possible repercussions of acute pancreatitis (AP) on the production of inflammatory mediators in the brain parenchyma focusing on microglial activation in the hippocampus. The acute pancreatic injury in rats was induced by a pancreas ligation surgical procedure (PLSP) on the splenic lobe, which corresponds to approximately 10% of total mass of the pancreas. Blood samples were collected via intracardiac puncture for the measurement of serum amylase. After euthanasia, frozen or paraffin-embedded brains and pancreas were analyzed using qRT-PCR or immunohistochemistry, respectively. Immunohistochemistry assays showed a large number of Iba1 and PU.1-positive cells in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus of the PLSP group. TNF-α mRNA expression was significantly higher in the brain from PLSP group. NLRP3 inflammasome expression was found to be significantly increased in the pancreas and brain of rats of the PLSP group. High levels of BNDF mRNA were found in the rat brain of PLSP group. In contrast, NGF mRNA levels were significantly higher in the control group versus PLSP group. Our findings suggest that AP has the potential to induce morphological changes in microglia consistent with an activated phenotype.


Clinical implementation of pre-biopsy magnetic resonance imaging pathways for the diagnosis of prostate cancer.
To assess the outcomes of pre-biopsy magnetic resonance imaging (MRI) pathways, as a tool in biopsy-naïve men with suspicion of prostate cancer, in routine clinical practice. Secondary outcomes included a comparison of transrectal MRI-directed biopsy (TR-MRDB) and transperineal (TP)-MRDB in men with suspicious MRI. We retrospectively assessed a two-centre cohort of consecutive biopsy-naïve men with suspicion of prostate cancer who underwent a Prostate Imaging-Reporting and Data System version 2 (PI-RADS v2) compliant pre-biopsy MRI in a single, high-volume centre between 2015 and 2019 (Centre 1). Men with suspicious MRI scans underwent TR-MRDB in Centre 1 and TP-MRDB with additional random biopsies (RB) in Centre 2. The MRI and histopathology were assessed in the same institution (Centre 1). Outcomes included: (i) overall detection rates of Grade Group (GG) 1, GG ≥2, and GG ≥3 cancer in men with suspicious MRI; (ii) Biopsy-avoidance due to non-suspicious MRI; and (iii) Cancer detection rates and biopsy-related complications between TR- and TP-MRDB. To reduce confounding bias for MRDB comparisons, inverse probability weighting (IPW) was performed for age, digital rectal examination, prostate-specific antigen (PSA), prostate volume, PSA density, and PI-RADS category. Of the 2597 men included, the overall GG 1, GG ≥2, and GG ≥3 prevalence was 8% (210/2597), 27% (697/2597), and 15% (396/2597), respectively. Biopsy was avoided in 57% (1488/2597) of men. After IPW, the GG 1, GG ≥2 and GG ≥3 detection rates after TR- and TP-MRDB were comparable at 24%, 57%, and 32%; and 18%, 64%, and 38%, respectively; with mean differences of -5.7% (95% confidence interval [CI] -13% to 1.4%), 6.1% (95% CI -2.1% to 14%), and 5.7% (95% CI -1.7% to 13%). Complications were similar in TR-MRDB (0.50%) and TP-MRDB with RB (0.62%; mean difference 0.11%, 95% CI -0.87% to 1.1%). This high-volume, two-centre study shows pre-biopsy MRI as a decision tool is implementable in daily clinical practice. Compared to recent trials, a substantially higher biopsy avoidance rate was achieved without compromising GG ≥2/GG ≥3 detection and coinciding with lower over detection rates of GG 1 cancer. Prostate cancer detection and complication rates were comparable for TR- and TP-MRDB.


Immunoassay of enzymes--an overview.
Immunochemical techniques with enzymes as the antigen have grown in frequency during the last few years. These techniques have allowed evaluation of enzymes in the presence of endogenous inhibitors. Among those enzymes measured by immunochemical techniques and which have found diagnostic application, mention will be made of alkaline phosphatase (with particular reference to the intestinal, placental, and Regan isoenzymes), lactate dehydrogenase (in which renewed interest has developed due to techniques for specifically measuring the LD-1 isoenzyme), aspartate aminotransferase (of which the cytosolic and mitochondrial forms can now be independently measured by immunochemical techniques), acid phosphatase (for which a specific immunochemical assay for the prostatic enzyme has been widely introduced in diagnostic laboratories), and creatine kinase (for which a variety of immunochemical techniques to measure the M- and B-subunits are now part of standard laboratory assays). Other enzymes which will be discussed in this review include phosphohexose isomerase, amylase, ribonuclease, and lysozyme (muramidase). Finally, the use of enzymes, particularly asparaginase, in the chemotherapy of cancer will be outlined.


Glycated hemoglobin predicts mortality in nondiabetic patients receiving chronic peritoneal dialysis.
patients with chronic peritoneal dialysis (CPD) use glucose-based dialysate to maintain their life; however, whether the glycemic status influences outcome of these patients without diabetes remains unknown. we conducted a cross-sectional and 18-month prospective study, and 269 nondiabetic patients with CPD were enrolled in a medical center. Glycated hemoglobin (HbA1c) levels were measured at baseline and categorized in tertiles of HbA1c: high (>5.4%), middle (5.1-5.4%) and low normal (<5.1%). Mortality and cause of death were recorded for longitudinal analyses. the study results showed high HbA1c group patients had a trend of being older and having higher body mass index (BMI) than other group patients. Stepwise multiple linear regression analysis showed HbA1c was positively related to age, BMI and the peritoneal solute transport rate. After 18 months of follow-up, Cox multivariate analysis showed that HbA1c (HR: 4.114; 95% CI: 1.426-11.872; p = 0.009) was the significant risk factor for all-cause mortality after relating variables were adjusted. Moreover, high HbA1c (HR: 3.892; 95% CI: 1.273-11.959; p = 0.026) and low HbA1c (HR: 1.179; 95% CI: 1.160-1.198; p = 0.039), with middle HbA1c group as the reference, also significantly predicted for mortality in these patients. HbA1c levels, or presence of low or high HbA1c, are associated with 18-month all-cause mortality in nondiabetic patients with CPD.


Associations between Facets and Aspects of Big Five Personality and Affective Disorders:A Systematic Review and Best Evidence Synthesis.
Big Five personality traits correlate with affective disorders, with neuroticism considered a risk factor, and conscientiousness and extroversion considered protective factors. However, the relationships between affective disorders and lower-order personality facets and aspects are less clear. A systematic review was carried out to identify studies measuring associations between lower-order personality constructs and affective disorders. Big Five facets were measured using the NEO-PI-R, and aspects using the BFAS. PsycINFO, EMBASE, MedLine and OpenGrey were searched from January 1st, 1985 to June 30th, 2020. Fifteen studies met criteria and reported a total of 408 associations. Data were analysed using best evidence synthesis. Most facets of neuroticism were positively associated with affective disorders. Positive emotion in extroversion, and competence and self-discipline in conscientiousness, were negatively associated with affective disorders. Trust in agreeableness, and actions in openness, were negatively associated with anxiety disorders, whereas fantasy in openness was positively associated with anxiety disorders. At the aspect level, withdrawal in neuroticism was positively associated with MDD, whereas industriousness in conscientiousness was negatively associated with MDD. Due to the use the heterogenous measures between studies, a meta-analysis could not be performed. Only Big Five personality constructs were investigated, limited to BFAS personality aspects, and NEO-PI-R personality facets. Neuroticism, positive emotion, competence and self-discipline correlate with various anxiety and depressive disorders. These facets may be endophenotypes for affective disorders in general. Future research is needed to investigate mediating pathways between personality facets and affective disorders.


A novel alternatively spliced interleukin-1 receptor accessory protein mIL-1RAcP687.
The 570-amino acid membrane form of IL-1RAcP (mIL-1RAcP) plays a pivotal role in the IL-1 signal transduction and response. We have identified another membrane form of IL-1RAcP with 687 amino acids (named as mIL-1RAcP687 hereon). Its except the last amino acid N-terminal 448 amino acid portion, containing three extracellular immunoglobulin domains, one transmembrane domain, and Box 1 and Box 2 of Toll/IL1 Receptor (TIR) domain, is identical to that of mIL-1RAcP. In contrast, the C-terminal 239 amino acid portion of mIL-1RAcP687, containing Box 3 of TIR domain, is unique. The mIL-1RAcP687 splice variant is derived from the first 11 exons except 9b, and a newly identified exon 13 of IL-1RAcP gene, while mIL-1RAcP is derived from the first 12 exons except 9b. Furthermore, mIL-1RAcP687 can associate with proteins involved in the upstream IL-1 signaling pathway such as IL-1RI, Tollip, and MyD88. It thus activates downstream signaling events to activate transcription factor NF-kappaB, and induce the expression of IL-1 responsive genes such as TNF-alpha and GM-CSF. These results demonstrate that like mIL-1RAcP, mIL-1RAcP687 functions in the IL-1 signal transduction and response. Identification of mIL-1RAcP687 adds further complexity to the regulation of IL-1 signaling and its subsequent response.


The role of provincial social policies and economic environments in shaping food insecurity among Canadian families with children.
Food insecurity, inadequate access to food due to financial constraints, affects 17.3% of Canadian children, with serious health repercussions. Capitalizing on the geo-temporal variation in social policies and economic environments across Canadian provinces between 2005 and 2018, we examined the association between provincial policies and economic environments and likelihood of experiencing food insecurity among households with children. Drawn from 13 years of the Canadian Community Health Survey, our sample comprised 123,300 households with below-median income with children under 18 in the ten provinces. We applied generalized ordered logit models on the overall sample and subsamples stratified by Low-Income Measure (LIM). Higher minimum wage, lower income tax, and lower unemployment rate were associated with lower odds of food insecurity in the overall sample. A hypothetical one-dollar increase in minimum wage was associated with 0.8 to 1.0-percentage-point decrease in probability of food insecurity. The probability of food security increased by 1.2 to 1.6 percentage points following a one-percentage-point drop in bottom-bracket income tax rate. One-percentage-point lower unemployment rate corresponded to 0.6 to 0.8-percentage-point higher probability of food security. Higher welfare income and lower housing price predicted lower likelihood of severe food insecurity in the below-LIM subsample. Higher sales tax and median wage predicted higher likelihood of food insecurity among above-LIM households. Income support policies, favorable labor market conditions, and affordable living costs were all related to reduced food insecurity among Canadian households with children. Policies that increase minimum wage, reduce taxes, and create jobs may help alleviate food insecurity.


Relative risk reduction: Misinformative measure in clinical trials and COVID-19 vaccine efficacy.
Treatment and vaccine efficacy in clinical trials are often reported in the media and medical journals as the relative risk reduction. The present article explains why the relative risk reduction is a misinformative measure that promotes disinformation when reporting efficacy in clinical research studies such as randomized controlled trials for COVID-19 vaccines. The relative risk reduction is based on the relative risk, a proportional measure or ratio used in epidemiologic studies to estimate the probability of a disease associated with an exposure. The present article demonstrates how the relative risk reduction and relative risk obscure the magnitude of disease risk reduction in clinical research. The absolute risk reduction is shown to be a more precise and reliable measure of treatment and vaccine efficacy in clinical research studies. The absolute risk reduction reciprocal also measures the number needed to treat or vaccinate, and is a more accurate measure than the relative risk reduction for comparing risk reductions of clinical studies. Additionally, the present article reviews consequences of COVID-19 vaccine efficacy misinformation disseminated through media reports. The article concludes that relative risk reduction should not be used to measure treatment and vaccine efficacy in clinical trials. •Unreliability of relative measures in clinical trials is graphically illustrated, demonstrating constant relative measures as absolute measures change.•Misuse of relative measures in clinical research is historically linked to misinterpretation of Jerome Cornfield's advice on measuring causative and associative effects.•Consequences of disinformation and misinformation related to COVID-19 vaccine efficacy and modern clinical medicine are described.•The proper use of absolute measures in meta-analyses is explained.


Promoted Sb removal with hydrogen production in microbial electrolysis cell by ZIF-67-derived modified sulfate-reducing bacteria bio-cathode.
Bio-cathode Microbial electrolysis cell (MEC) has been widely discovered for heavy metals removal and hydrogen production. However, low electron transfer efficiency and heavy metal toxicity limit MEC treatment efficiency. In this study, ZIF-67 was introduced to modify Sulfate-reducing bacteria (SRB) bio-cathode to enhance the bioreduction of sulfate and Antimony (Sb) with hydrogen production in the MEC. ZIF-67 modified bio-cathode was developed from a bio-anode microbial fuel cell (MFC) by operating with an applied voltage of 0.8 V to reverse the polarity. Cyclic voltammetry, linear sweep voltammetry and electrochemical impedance were done to confirm the performance of the ZIF-67 modified SRB bio-cathode. The synergy reduction of sulfate and Sb was accomplished by sulfide metal precipitation reaction from SRB itself. Maximum sulfate reduction rate approached 93.37 % and Sb removal efficiency could reach 92 %, which relies on the amount of sulfide concentration generated by sulfate reduction reaction, with 0.923 ± 0.04 m3 H2/m3 of hydrogen before adding Sb and 0.857 m3 H2/m3 of hydrogen after adding Sb. The hydrogen was mainly produced in this system and the result of gas chromatography (GC) indicated that 73.27 % of hydrogen was produced. Meanwhile the precipitates were analyzed by X-ray diffraction and X-ray photoelectron spectroscopy to confirm Sb2S3 was generated from Sb (V).


Alterations of adipokines, pancreatic hormones and incretins in acute and convalescent COVID-19 children.
The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), accountable for Coronavirus disease 2019 (COVID-19), may cause hyperglycemia and additional systemic complexity in metabolic parameters. It is unsure even if the virus itself causes type 1 or type 2 diabetes mellitus (T1DM or T2DM). Furthermore, it is still unclear whether even recuperating COVID-19 individuals have an increased chance to develop new-onset diabetes. We wanted to determine the impact of COVID-19 on the levels of adipokines, pancreatic hormones, incretins and cytokines in acute COVID-19, convalescent COVID-19 and control children through an observational study. We performed a multiplex immune assay analysis and compared the plasma levels of adipocytokines, pancreatic hormones, incretins and cytokines of children presenting with acute COVID-19 infection and convalescent COVID-19. Acute COVID-19 children had significantly elevated levels of adipsin, leptin, insulin, C-peptide, glucagon and ghrelin in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had elevated levels of adipsin, leptin, insulin, C-peptide, glucagon, ghrelin and Glucagon-like peptide-1 (GLP-1) in comparison to control children. On the other hand, acute COVID-19 children had significantly decreased levels of adiponectin and Gastric Inhibitory Peptide (GIP) in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had decreased levels of adiponectin and GIP in comparison to control children. Acute COVID-19 children had significantly elevated levels of cytokines, (Interferon (IFN)) IFNγ, Interleukins (IL)-2, TNFα, IL-1α, IL-1β, IFNα, IFNβ, IL-6, IL-12, IL-17A and Granulocyte-Colony Stimulating Factors (G-CSF) in comparison to convalescent COVID-19 and controls. Convalescent COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IL-1β, IFNα, IFNβ, IL-6, IL-12, IL-17A and G-CSF in comparison to control children. Additionally, Principal component Analysis (PCA) analysis distinguishes acute COVID-19 from convalescent COVID-19 and controls. The adipokines exhibited a significant correlation with the levels of pro-inflammatory cytokines. Children with acute COVID-19 show significant glycometabolic impairment and exaggerated cytokine responses, which is different from convalescent COVID-19 infection and controls.


Black Representation in the Primary Care Physician Workforce and Its Association With Population Life Expectancy and Mortality Rates in the US.
Studies have suggested that greater primary care physician (PCP) availability is associated with better population health and that a diverse health workforce can improve care experience measures. However, it is unclear whether greater Black representation within the PCP workforce is associated with improved health outcomes among Black individuals. To assess county-level Black PCP workforce representation and its association with mortality-related outcomes in the US. This cohort study evaluated the association of Black PCP workforce representation with survival outcomes at 3 time points (from January 1 to December 31 each in 2009, 2014, and 2019) for US counties. County-level representation was defined as the ratio of the proportion of PCPs who identifed as Black divided by the proportion of the population who identified as Black. Analyses focused on between- and within-county influences of Black PCP representation and treated Black PCP representation as a time-varying covariate. Analysis of between-county influences examined whether, on average, counties with increased Black representation exhibited improved survival outcomes. Analysis of within-county influences assessed whether counties with higher-than-usual Black PCP representation exhibited enhanced survival outcomes during a given year of heightened workforce diversity. Data analyses were performed on June 23, 2022. Using mixed-effects growth models, the impact of Black PCP representation on life expectancy and all-cause mortality for Black individuals and on mortality rate disparities between Black and White individuals was assessed. A combined sample of 1618 US counties was identified based on whether at least 1 Black PCP operated within a county during 1 or more time points (2009, 2014, and 2019). Black PCPs operated in 1198 counties in 2009, 1260 counties in 2014, and 1308 counties in 2019-less than half of all 3142 Census-defined US counties as of 2014. Between-county influence results indicated that greater Black workforce representation was associated with higher life expectancy and was inversely associated with all-cause Black mortality and mortality rate disparities between Black and White individuals. In adjusted mixed-effects growth models, a 10% increase in Black PCP representation was associated with a higher life expectancy of 30.61 days (95% CI, 19.13-42.44 days). The findings of this cohort study suggest that greater Black PCP workforce representation is associated with better population health measures for Black individuals, although there was a dearth of US counties with at least 1 Black PCP during each study time point. Investments to build a more representative PCP workforce nationally may be important for improving population health.


Special coverage: 9th Conference on Retroviruses. TB, pneumonia deaths down, but heart attacks up.
The profile of AIDS deaths has changed since HIV-infected patients began to receive highly active antiretroviral therapy in 1996. While fewer people are now dying overall, more are dying from non-AIDS-related diseases. Research from the Centers for Disease Control and Prevention and other sources is showing an increase in non-AIDS-defining illnesses. One CDC study presented at the recent retroviruses conference showed that while there have been declines in the proportions of deaths from some AIDS-related causes, there is an increase in deaths from non-AIDS-related causes, including liver and kidney disease and possibly ischemic heart disease.


Efficacy and safety of neoadjuvant immune checkpoint inhibitors in early-stage triple-negative breast cancer: a systematic review and meta-analysis.
There is uncertainty regarding the role of adding immune checkpoint inhibitors (ICIs) to neoadjuvant chemotherapy (NACT) in early-stage triple-negative breast cancer (TNBC). We identified randomized controlled trials (RCTs) comparing ICIs combined with NACT to NACT in early-stage TNBC. Efficacy outcomes included pathological complete response (pCR) and event-free survival (EFS). Toxicity data included any grade 3/4 adverse events (AEs), serious AEs, AEs leading to death, common and meaningful AEs associated with chemotherapy and immune-related AEs. Odds ratio (ORs), hazard ratios (HR) and their respective 95% confidence intervals (CI) for efficacy and toxicity were extracted and pooled in a meta-analysis. Differences in the odds for pCR between programmed death ligand 1 (PD-L1) status and between PD-L1 and PD-1 inhibitors were also assessed. Five RCTs comprising 2,075 patients were analyzed. Compared to NACT alone, combination of ICIs and NACT significantly improved pCR (OR 1.75, 95% CI 1.25-2.47, p = 0.001) and EFS (HR 0.66, 95% CI 0.48-0.91, p = 0.01). Magnitude of effect on pCR was similar between PD-L1-positive and PD-L1-negative tumors (p for the subgroup difference = 0.80) and between PD-L1 and PD-1 inhibitors (p = 0.27). The combination treatment resulted in higher odds of any grade 3/4 AEs (OR 1.31, p = 0.02) and serious AEs (OR 1.84, p = 0.006), with no statistically significant difference in AEs leading to death (OR 1.67, p = 0.51). Higher magnitude of toxicity was observed for immune-related AEs. Combination of ICIs and NACT were associated with improved outcome in early-stage TNBC while increasing toxicity significantly. Longer follow-up is desired to better understand the risk and benefit ratio of this combination.


Towards a green and sustainable recovery from COVID-19.
Whilst COVID-19 has left a devastating trail of economic and social losses, it has spurred incidental transitory positive externalities for the environment and climate. Key among these include; improved air and water quality, clearer skies and a projected 8% global blip in carbon emissions by the end of 2020. The global wave of restrictive lock downs implemented to contain the spread of COVID-19 in the short term account for these gains. The lockdowns were defined by limited public and private travel, closure of airports and borders, and a decline in industrial activity. However, most of these climate and environmental gains were secondary effects of the COVID-19 induced lockdowns and not based on decisive deliberate policy action, which casts doubts on their sustainability and ability to contribute to a green economy transition. Sustaining accrued environmental and climate benefits will depend on the direction of the COVID-19 stimuli and recovery packages - whether they are designed to work for the planet or against it. This article therefore elaborates on how state and non-state actors across the globe ought to be agile in building back sustainably to upend the ongoing collision course between the planet and economic development. It emphasizes the use of Sustainable Development Goals and Nationally Determined Contributions on climate change (NDCs) as a compass to shape the direction of COVID-19 recovery packages. It further enumerates six strategies that must underpin recovery packages to ensure win-win for the economy, society, and the planet.


Prolongation of neutrophil survival by the culture supernatant of Pseudomonas aeruginosa.
The pathogenesis of airway inflammation in diffuse panbronchiolitis (DPB) is unknown. Neutrophil survival-enhancing activity, partially mediated by granulocyte-macrophage colony-stimulating factor (GM-CSF), has been shown in the sputum from DPB patients. This study investigated the mechanisms of GM-CSF expression in the airways of DPB patients. This involved examining the effects of mucoid Pseudomonas aeruginosa strains derived from chronically colonized patients with DPB on neutrophil survival and GM-CSF expression. Neutrophils from healthy subjects were cultured with the culture supernatants of P. aeruginosa isolated from sputum of DPB patients in the presence or absence of anti-GM-CSF and anti-GM-CSF receptor (alpha chain) antibodies, and viable neutrophils were counted daily. GM-CSF gene expression in neutrophils was evaluated by RT-PCR. Neutrophils cultured with the culture supernatants showed significantly prolonged survival, compared with neutrophils cultured with the control broth. The neutrophil survival-enhancing activity in the culture supernatants was lost by heating. The enhanced survival of neutrophils was abolished in the presence of anti-GM-CSF and anti-GM-CSF receptor (alpha chain) antibodies. GM-CSF mRNA was detected in neutrophils cultured with the bacterial supernatants, but not in those with the control broth. P. aeruginosa-derived factors (rich in proteins) stimulated neutrophils to synthesize GM-CSF, which enhanced neutrophil survival in an autocrine/paracrine fashion.


Interferon-α activates interleukin-1 receptor-associated kinase 1 to induce regulatory T-cell apoptosis in patients with systemic lupus erythematosus.
Impaired regulatory T-cell (Treg) responses and upregulated interleukin-1 receptor-associated kinase 1 (IRAK1) expression are associated with the development of human systemic lupus erythematosus (SLE). Here, we show that the levels of upregulated IRAK1 expression in circulating Tregs are correlated with the percentages of apoptotic Tregs, Systemic Lupus Erythematosus Disease Activity Index scores, and serum complement C3 levels in SLE patients. High levels of plasma interferon (IFN)-α in SLE patients induced IRAK1 phosphorylation to trigger Treg apoptosis, which was mitigated by IRAK1 inhibitor (IRAK-Inh) treatment. Bioinformatics indicated that IRAK1 activation was related to the IFN-α/β and mitogen-activated protein kinase (MAPK) signaling in Tregs and IFN-α treatment induced the p38 and MAPK/ERK kinase 3/6 phosphorylation, which was attenuated by IRAK-Inh in Tregs. Treatment with IRAK-Inh effectively alleviated renal injury and promoted the survival of lupus-prone B6.MRL-Faslpr /Nju mice. Therefore, IFN-α induced IRAK1 activation to promote Treg apoptosis, contributing to the pathogenesis of SLE and IFN-α/IRAK1 may be therapeutic targets for SLE.


Hyaluronic acid-lipid binding.
Phospholipid (PL)-hyaluronic acid (HA) interactions are relevant to aging-associated vitreous humor liquefaction, therapies for dry eye disease, skin-care products and synovial joint lubrication. Phosphatidyl choline-HA interactions have been well characterized. However, other major lipids found in tears, vitreous humor and synovial joints have not. The purpose of this study was to bridge this gap of knowledge. HA (1600 kDa) at 5 mg/mL, was mixed with various lipids ranging in concentration from 0.1 to 10 mg/mL in D2O. HA-PL binding was measured from the decrease in HA proton resonance intensity with binding using a nuclear magnetic resonance spectrometer. Cholesterol weakly bound to HA, followed by monoglyceride and palmitoyl palmitate < phosphatidyl choline, phosphatidic acid and sphingomyelin. The maximum amount of PL bound was 14 ± 1 µmoles inferring a 1 to 1 molar ratio of bound PL to HA dimer. Monoglyceride and palmitoyl palmitate required two to three times more lipid to achieve 100% bound HA compared to PL. Physiological levels of HA, phosphatidyl choline and sphingomyelin would result in only 4% of the hydrophobic hydrogens of HA to be bound. HA-PL binding interactions could be important for therapeutic use of HA in eye drops in future studies to treat dry eye and to trap PL entering the VH to keep them from forming light scattering micelles. HA-lipid binding may also be relevant to the therapeutic effects of topical skin-care products. Both head group and hydrocarbon chain moieties influence HA-lipid interactions.


Continuous oral chloroquine as a novel route for Plasmodium prophylaxis and cure in experimental murine models.
Chloroquine (CQ) is utilized as both cure and prophylaxis to Plasmodium infection. In animal studies, CQ administration to experimental animals is via intraperitoneal (i.p.) injection of a single dose that varies from daily to several times per week. Such daily administration can be distressing to the animals and provoke aggressive behaviors that may affect the immune responses of the animal and interfere with data read-outs. We describe a novel, viable and efficacious prophylactic and curative administration route whereby chloroquine is continuously supplied in the drinking water to experimental animals. The prophylactic effect is robust and the curative effect against patent blood stage infection comparable to the traditional route of i.p. administration. Continuous drinking water administration may decrease animal stress responses and thus improve the reliability of experimental data.


Association of waist-calf circumference ratio with incident cognitive impairment in older adults.
The longitudinal relation of central fat and muscle mass with cognitive function remains unclear. We aimed to evaluate the relation of anthropometric measures, including BMI, waist circumference (WC), calf circumference (CC), and waist-calf circumference ratio (WCR), with incident cognitive impairment in older adults. A total of 3312 participants aged ≥65 y (mean: 81.8 y) who were free of cognitive impairment [the Chinese version of the Mini-Mental State Examination (MMSE) scores ≥24 points] in the Chinese Longitudinal Healthy Longevity Survey were included. The primary outcome was incident cognitive impairment, defined as MMSE scores <24 points at the exit visit. Secondary outcomes were incident cognitive decline, defined as a reduction of MMSE scores ≥3 points at the exit visit, and incident decline in different cognitive domains, defined as a reduction of MMSE scores in the domain ≥15% at the exit visit. During a median follow-up duration of 3.6 y, 565 (17.1%) participants developed incident cognitive impairment. Overall, with mutual adjustments, higher WC [≥89 cm (fourth quartile) compared with <75 cm (first quartile); adjusted HR: 1.56; 95% CI: 1.19, 2.04] and higher WCR [≥2.9 (fourth quartile) compared with <2.4 (first quartile); adjusted HR: 1.96; 95% CI: 1.52, 2.52] were significantly associated with a higher risk of cognitive impairment, and higher CC [≥34 cm (fourth quartile) compared with <28 cm (first quartile); adjusted HR: 0.44; 95% CI: 0.33, 0.59] was associated with a lower hazard of cognitive impairment. Similar results were found for the secondary outcomes. However, BMI was not significantly associated with the study outcomes. High WC and low CC were significantly associated with higher incident cognitive impairment in older adults. Moreover, WCR had a relatively stronger association with cognitive impairment compared with each circumference, suggesting maintaining both higher lean mass and lower central fat in older adults for the prevention of cognitive impairment.


The Perception of Preparedness in Undergraduate Nursing Students During COVID-19.
The purpose of this study was to explore the perception of preparedness in nursing students who transitioned to online and virtual learning platforms brought about by Coronavirus disease 2019 (COVID-19). Descriptive, correlational, nonexperimental research design. Data collection was attained through Facebook groups using the Casey-Fink Readiness for Practice Survey and questions about comfort in nursing skills and multiple patient assignments. The sample size of 103 included nursing students and those with less than two years of experience. As school support during the transition increased, comfort in performing nursing skills improved. As the number of patients within a nurse's assignment increased, comfort decreased. Participants expressed a desire for more hands-on in person education and postgraduate support. With the reduction in clinical hours during COVID-19, Learning Techniques and Trials and Tribulations revealed diminished readiness. Low scores within the Trials and Tribulations subgroup impacted feelings of comfort when performing nursing skills independently. COVID-19 dramatically changed how undergraduate nurses were educated. The transition from live didactic instruction and in person clinical experience to online learning and simulated clinical experience impacted nursing students' readiness for practice. As this topic is still evolving, additional research will be needed to fully understand the impact on healthcare.