Developing a FHIR-based EHR phenotyping framework: A case study for identification of patients with obesity and multiple comorbidities from discharge summaries.
Standards-based clinical data normalization has become a key component of effective data integration and accurate phenotyping for secondary use of electronic healthcare records (EHR) data. HL7 Fast Healthcare Interoperability Resources (FHIR) is an emerging clinical data standard for exchanging electronic healthcare data and has been used in modeling and integrating both structured and unstructured EHR data for a variety of clinical research applications. The overall objective of this study is to develop and evaluate a FHIR-based EHR phenotyping framework for identification of patients with obesity and its multiple comorbidities from semi-structured discharge summaries leveraging a FHIR-based clinical data normalization pipeline (known as NLP2FHIR). We implemented a multi-class and multi-label classification system based on the i2b2 Obesity Challenge task to evaluate the FHIR-based EHR phenotyping framework. Two core parts of the framework are: (a) the conversion of discharge summaries into corresponding FHIR resources - Composition, Condition, MedicationStatement, Procedure and FamilyMemberHistory using the NLP2FHIR pipeline, and (b) the implementation of four machine learning algorithms (logistic regression, support vector machine, decision tree, and random forest) to train classifiers to predict disease state of obesity and 15 comorbidities using features extracted from standard FHIR resources and terminology expansions. We used the macro- and micro-averaged precision (P), recall (R), and F1 score (F1) measures to evaluate the classifier performance. We validated the framework using a second obesity dataset extracted from the MIMIC-III database. Using the NLP2FHIR pipeline, 1237 clinical discharge summaries from the 2008 i2b2 obesity challenge dataset were represented as the instances of the FHIR Composition resource consisting of 5677 records with 16 unique section types. After the NLP processing and FHIR modeling, a set of 244,438 FHIR clinical resource instances were generated. As the results of the four machine learning classifiers, the random forest algorithm performed the best with F1-micro(0.9466)/F1-macro(0.7887) and F1-micro(0.9536)/F1-macro(0.6524) for intuitive classification (reflecting medical professionals' judgments) and textual classification (reflecting the judgments based on explicitly reported information of diseases), respectively. The MIMIC-III obesity dataset was successfully integrated for prediction with minimal configuration of the NLP2FHIR pipeline and machine learning models. The study demonstrated that the FHIR-based EHR phenotyping approach could effectively identify the state of obesity and multiple comorbidities using semi-structured discharge summaries. Our FHIR-based phenotyping approach is a first concrete step towards improving the data aspect of phenotyping portability across EHR systems and enhancing interpretability of the machine learning-based phenotyping algorithms.


Tension pneumothorax complicating diagnostic upper endoscopy: a case report.
Hypoxemia is common during various endoscopic procedures and may result from a variety of causes. These causes range from benign and otherwise easily reversible events like oversedation to potentially life threatening complications such as pneumothorax. Although pneumothorax has been reported secondary to gastrointestinal perforation as a complication of various therapeutic endoscopic procedures, there has been no report of pneumothorax without perforation. We report a case of a patient who developed severe hypoxemia and hemodynamic instability during diagnostic upper endoscopy as a result of pneumomediastinum and tension pneumothorax in the absence of any signs of gastrointestinal perforation and comment on various possible mechanisms. Immediate endotracheal intubation and bilateral chest tube placement resulted in prompt return of the patient's oxygenation and vital signs back to normal. This report enlarges the list of possible causes of hypoxemia during endoscopy and shows the importance of early and prompt recognition, which allowed directed therapy with a good outcome.


Regulation of mTOR complex 2 signaling in neurofibromatosis 2-deficient target cell types.
Inactivating mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene results in the development of schwannomas and meningiomas. Using NF2-deficient meningioma cells and tumors, together with the normal cellular counterparts that meningiomas derive, arachnoid cells, we identified merlin as a novel negative regulator of mTOR complex 1 (mTORC1). We now show that merlin positively regulates the kinase activity of mTORC2, a second functionally distinct mTOR complex, and that downstream phosphorylation of mTORC2 substrates, including Akt, is reduced upon acute merlin deficiency in cells. In response to general growth factor stimulation, Akt signaling is attenuated in merlin RNA interference-suppressed human arachnoid and Schwann cells by mechanisms mediated by hyperactive mTORC1 and impaired mTORC2. Moreover, Akt signaling is impaired differentially in a cell type-dependent manner in response to distinct growth factor stimuli. However, contrary to activation of mTORC1, the attenuated mTORC2 signaling profiles exhibited by normal arachnoid and Schwann cells in response to acute merlin loss were not consistently reflected in NF2-deficient meningiomas and schwannomas, suggesting additional genetic events may have been acquired in tumors after initial merlin loss. This finding contrasts with another benign tumor disorder, tuberous sclerosis complex, which exhibits attenuated mTORC2 signaling profiles in both cells and tumors. Finally, we examined rapamycin, as well as the mTOR kinase inhibitor, Torin1, targeting both mTOR complexes to identify the most efficacious class of compounds for blocking mTOR-mediated signaling and proliferation in merlin-deficient meningioma cells. These studies may ultimately aid in the development of suitable therapeutics for NF2-associated tumors.


The influence of insurance status on access to and utilization of a tertiary hand surgery referral center.
The purpose of this study was to systematically examine the impact of insurance status on access to and utilization of elective specialty hand surgical care. We hypothesized that patients with Medicaid insurance or those without insurance would have greater difficulty accessing care both in obtaining local surgical care and in reaching a tertiary center for appointments. This retrospective cohort study included all new patients with orthopaedic hand problems (n = 3988) at a tertiary center in a twelve-month period. Patient insurance status was categorized and clinical complexity was quantified on an ordinal scale. The relationships of insurance status, clinical complexity, and distance traveled to appointments were quantified by means of statistical analysis. An assessment of barriers to accessing care stratified with regard to insurance status was completed through a survey of primary care physicians and an analysis of both patient arrival rates and operative rates at our tertiary center. Increasing clinical complexity significantly correlated (p < 0.001) with increasing driving distance to the appointment. Patients with Medicaid insurance were significantly less likely (p < 0.001) to present with problems of simple clinical complexity than patients with Medicare and those with private insurance. Primary care physicians reported that 62% of local surgeons accepted patients with Medicaid insurance and 100% of local surgeons accepted patients with private insurance. Forty-four percent of these primary care physicians reported that, if patients who were underinsured (i.e., patients with Medicaid insurance or no insurance) had been refused by community surgeons, they were unable to drive to our tertiary center because of limited personal resources. Patients with Medicaid insurance (26%) were significantly more likely (p < 0.001) to fail to arrive for appointments than patients with private insurance (11%), with no-show rates increasing with the greater distance required to reach the tertiary center. Economically disadvantaged patients face barriers to accessing specialty surgical care. Among patients with Medicaid coverage or no insurance, local surgical care is less likely to be offered and yet personal resources may limit a patient's ability to reach distant centers for non-emergency care.


Overexpression of VpsS, a hybrid sensor kinase, enhances biofilm formation in Vibrio cholerae.
Vibrio cholerae causes the disease cholera and inhabits aquatic environments. One key factor in the environmental survival of V. cholerae is its ability to form matrix-enclosed, surface-associated microbial communities known as biofilms. Mature biofilms rely on Vibrio polysaccharide to connect cells to each other and to a surface. We previously described a core regulatory network, which consists of two positive transcriptional regulators, VpsR and VpsT, and a negative transcriptional regulator HapR, that controls biofilm formation by regulating the expression of vps genes. In this study, we report the identification of a sensor histidine kinase, VpsS, which can control biofilm formation and activates the expression of vps genes. VpsS required the response regulator VpsR to activate vps expression. VpsS is a hybrid sensor histidine kinase that is predicted to contain both histidine kinase and response regulator domains, but it lacks a histidine phosphotransferase (HPT) domain. We determined that VpsS acts through the HPT protein LuxU, which is involved in a quorum-sensing signal transduction network in V. cholerae. In vitro analysis of phosphotransfer relationships revealed that LuxU can specifically reverse phosphotransfer to CqsS, LuxQ, and VpsS. Furthermore, mutational and phenotypic analyses revealed that VpsS requires the response regulator LuxO to activate vps expression, and LuxO positively regulates the transcription of vpsR and vpsT. The induction of vps expression via VpsS was also shown to occur independent of HapR. Thus, VpsS utilizes components of the quorum-sensing pathway to modulate biofilm formation in V. cholerae.


Safety of colchicine therapy during pregnancy.
A 27-year-old patient in our clinic with familial Mediterranean fever (FMF) has been treated with colchicine for the last decade. She is planning her first pregnancy. What recommendations should we give her regarding use of colchicine before and during pregnancy, bearing in mind that discontinuation of colchicine could lead to complications from amyloidosis? Colchicine passes through the placenta in humans, is teratogenic in animals, and raises rates of male and female infertility. Based on several patients with chromosomal anomalies, some authorities recommend that patients who require colchicine therapy during pregnancy undergo amniocentesis with karyotyping. In contrast, an increasing body of evidence suggests that colchicine use throughout pregnancy carries no substantial teratogenic or mutagenic risk when used at recommended doses. Its use prevents febrile attacks of FMF and reduces the frequency of renal complications.


Reliability and Concurrent Validity of Seven Commercially Available Devices for the Assessment of Movement Velocity at Different Intensities During the Bench Press.
Pérez-Castilla, A, Piepoli, A, Delgado-García, G, Garrido-Blanca, G, and García-Ramos, A. Reliability and concurrent validity of seven commercially available devices for the assessment of movement velocity at different intensities during the bench press. J Strength Cond Res 33(5): 1258-1265, 2019-The aim of this study was to compare the reliability and validity of 7 commercially available devices to measure movement velocity during the bench press exercise. Fourteen men completed 2 testing sessions. One-repetition maximum (1RM) in the bench press exercise was determined in the first session. The second testing session consisted of performing 3 repetitions against 5 loads (45, 55, 65, 75, and 85% of 1RM). The mean velocity was simultaneously measured using an optical motion sensing system (Trio-OptiTrack; "gold-standard") and 7 commercially available devices: 1 linear velocity transducer (T-Force), 2 linear position transducers (Chronojump and Speed4Lift), 1 camera-based optoelectronic system (Velowin), 1 smartphone application (PowerLift), and 2 inertial measurement units (IMUs) (PUSH band and Beast sensor). The devices were ranked from the most to the least reliable as follows: (a) Speed4Lift (coefficient of variation [CV] = 2.61%); (b) Velowin (CV = 3.99%), PowerLift (3.97%), Trio-OptiTrack (CV = 4.04%), T-Force (CV = 4.35%), and Chronojump (CV = 4.53%); (c) PUSH band (CV = 9.34%); and (d) Beast sensor (CV = 35.0%). A practically perfect association between the Trio-OptiTrack system and the different devices was observed (Pearson's product-moment correlation coefficient (r) range = 0.947-0.995; p < 0.001) with the only exception of the Beast sensor (r = 0.765; p < 0.001). These results suggest that linear velocity/position transducers, camera-based optoelectronic systems, and the smartphone application could be used to obtain accurate velocity measurements for restricted linear movements, whereas the IMUs used in this study were less reliable and valid.


Pneumonic plague protection induced by a monophosphoryl lipid A decorated Yersinia outer-membrane-vesicle vaccine.
A newly constructed Yersinia pseudotuberculosis mutant (YptbS46) carrying the lpxE insertion and pmrF-J deletion exclusively synthesized an adjuvant form of lipid A, monophosphoryl lipid A (MPLA). Outer membrane vesicles (OMVs) isolated from YptbS46 harboring an lcrV expression plasmid, pSMV13, were designated OMV 46 -LcrV, which contained MPLA and high amounts of LcrV and displayed low activation of Toll-like receptor 4 (TLR4). Similar to the previous OMV 44 -LcrV, intramuscular prime-boost immunization with 30 µg of OMV 46 -LcrV exhibited substantially reduced reactogenicity and conferred complete protection to mice against a high-dose of respiratory Y. pestis challenge. OMV 46 -LcrV immunization induced robust adaptive responses in both lung mucosal and systemic compartments and orchestrated innate immunity in the lung, which were correlated with rapid bacterial clearance and unremarkable lung damage during Y. pestis challenge. Additionally, OMV 46 -LcrV immunization conferred long-term protection. Moreover, immunization with reduced doses of OMV 46 -LcrV exhibited further lower reactogenicity and still provided great protection against pneumonic plague. Our studies strongly demonstrate the feasibility of OMV 46 -LcrV as a new type of plague vaccine candidate.


A randomized pilot trial of a telephone-based collaborative care management program for caregivers of individuals with dementia.
Dementia care is largely provided in primary care settings. This article describes a pilot project aimed at evaluating the effectiveness of an accessible, telephone-based, patient- and caregiver (CG)-centered, collaborative care management program that involves CG education and psychosocial support in improving CG and patient outcomes. CGs (n = 75) of older veterans with dementia receiving care from Veterans Affairs (VA) Medical Center primary care practices were randomized to receive either dementia care management or usual care (UC). Of interest in this study were the frequency and severity of patients' dementia-related symptom, CG distress related to patients' behavioral and neuropsychiatric symptoms (primary outcomes), and CG coping and mastery (secondary outcomes). Adjusted, intention-to-treat longitudinal models suggest that CGs receiving care management reported significantly greater reductions in distress due to patients' dementia-related (p = .05) and neuropsychiatric (p = .01) symptoms compared with CGs in UC. Additionally, CGs in the intervention reported significantly larger improvements in their ability to cope (p = .03) and caregiving mastery (p = .03). No significant group differences were found in CG burden or patients' dementia-related symptom frequency or severity over time. Findings suggest that CGs of veterans with dementia may benefit from a telephone-delivered, care management program in improving CG-related outcomes. Further research of care management programs for CG of veterans with dementia in addressing barriers to care and reducing CG burden is warranted. These findings highlight the potential for such programs as adjuncts to dementia care offered in primary care practices. (PsycINFO Database Record


Synthesis by the DNA primase of Drosophila melanogaster of a primer with a unique chain length.
The primase associated with the DNA polymerase alpha from embryos of Drosophila melanogaster catalyzes the synthesis of ribo-oligonucleotide primers on single-stranded M13 DNA or polydeoxythymidylate templates, which can be elongated by DNA polymerase action [Conaway, R. C. & Lehman, I. R. (1982) Proc, Natl. Acad. Sci, USA 79, 2523--2527]. The primers synthesized in a coupled primase-DNA polymerase alpha reaction with an M13 DNA template are of a unique size (15 residues); those synthesized with poly(dT) range from 8 to 15 nucleotides. Primer synthesis is initiated at multiple but nonrandom sites. Like the DNA primase of Escherichia coli and the comparable activity in intact nuclei of polyoma-infected mouse cells, the DNA primase of D. melanogaster can substitute deoxynucleotides for ribonucleotides during primer synthesis.


Evaluating the effect of distractions in the operating room on clinical decision-making and patient safety.
Answering telephone calls and pagers is common distraction in the operating room. We sought to evaluate the impact of distractions on patient care by (1) assessing the accuracy and safety of responses to clinical questions posed to a surgeon while operating and (2) determining whether pager distractions affect simulation-based surgical performance. We conducted a randomized crossover study of obstetrics and gynecology residents. After studying a patient sign-out list, subjects performed a virtual salpingectomy. They were randomized to a distraction phase followed by quiet phase or vice versa. In the distraction phase, a pager beeped and subjects were asked questions based on the sign-out list. Accuracy of responses and the number of unsafe responses were recorded. In the quiet phase, trainees performed the task uninterrupted. Measures of surgical performance were successful task completion, time to task completion and operative blood loss. The mean score for correct responses to clinical questions during the distracted phase was 80 % (SD ±14 %). Nineteen residents (63 %) made at least 1 unsafe clinical decision while operating on the simulator (range 0-3). Subjects were more likely to successfully complete the surgical task in the allotted time under the quiet compared to distraction condition (OR 11.3, p = 0.03). There was no difference between the conditions in paired analysis for mean time (seconds) to task completion [426 (SD 133) vs. 440 (SD 186), p = 0.61] and mean operative blood loss (mL) [73.14 (SD 106) vs. 112.70 (SD 358), p = 0.47]. Distractions in the operating room may have a profound impact on patient safety on the wards. While multitasking in a simulated setting, the majority of residents made at least one unsafe clinical decision. Pager distractions also hindered surgical residents' ability to complete a simulated laparoscopic task in the allotted time without affecting other variables of surgical performance.


Qualitative and Quantitative Assessment of Abdominal and Pelvic CT Image Quality Using Iopromide With Different Concentrations of Iodine (300 and 370 mg I/mL).
The purpose of this study was to analyze the quality of MDCT images obtained using iopromide with two different concentrations of iodine (300 and 370 mg I/mL) in daily clinical settings. Patients from 38 hospitals in China undergoing abdominal or pelvic CT with iopromide were prospectively recruited. MDCT was performed using iopromide with an iodine concentration of 300 or 370 mg I/mL. CT quality image was graded as excellent, good, adequate, and poor. Objective indicators were the contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR). Outcomes were compared according to organ studied, tumor type (benign vs malignant), saline usage, and type of MDCT (16-MDCT vs 64-MDCT). A total of 4506 patients (63.7% men) with a mean (± SD) age of 56.3 ± 14.1 years and mean body mass index (weight in kilograms divided by the square of height in meters) of 23.2 ± 3.3 were included. Iopromide with 300 mg I/mL was used for 3042 patients (67.5%), and 370 mg I/mL was used for 1464 patients (32.2%). A total of 1847 scans (41.0%) had excellent image quality, 2454 (54.5%) had good quality, 176 (3.9%) had adequate quality, and 29 (0.6%) had poor quality. No differences were noted between CT scans that did or did not use saline, 16-MDCT versus 64-MDCT scans, and 300 versus 370 mg I/mL iopromide. Variations in the CNR and SNR were noted between the two iodine concentrations with respect to other parameters examined. Iopromide with both concentrations of iodine provided acceptable image quality, though according to CNR and SNR, one or the other may provide better quality in different situations.


Chronic pancreatitis beginning in childhood and adolescence.
We identified 10 patients with symptoms beginning before the age of 20 years in a group of 69 patients with proven chronic pancreatitis. Six of the 10 patients were women. There was a family history of pancreatitis in three patients and alcohol exposure in seven patients. Three patients were dependent on narcotics at the time of presentation. Six of the 10 patients had pancreatic duct dilatation to 10 mm or more in diameter during observation. These six patients underwent pancreaticojejunostomy, with clinical improvement in five patients. The median time of follow-up was 19 years from presentation. No patient developed diabetes and one developed malabsorption. Only three patients were free of pain, but four other patients had only mild episodes that rarely required hospital admission. One patient died of metastatic abdominal carcinoma of unknown origin 51 years after developing familial pancreatitis. Chronic pancreatitis beginning at a young age is sufficiently common to merit special awareness. It is compatible with prolonged survival, and pancreaticojejunostomy may help if the pancreatic duct reaches sufficient size. The disease does not seem to burn out with time.


Kinetics of virus-specific CD8+ T cells and the control of human immunodeficiency virus infection.
Several primate models indicate that cytotoxic T lymphocyte-inducing vaccines may be unable to prevent human immunodeficiency virus infection but may have a long-term benefit in controlling viral replication and delaying disease progression. Here we show that analysis of the kinetics of antigen-specific CD8+ T-cell expansion suggests a delay in activation following infection that allows unimpeded early viral replication. Viral kinetics do not differ between controls and vaccinees during this delay phase. An increase in virus-specific CD8+ T-cell numbers around day 10 postinfection coincides with a slowing in viral replication in vaccinees and reduces peak viral loads by around 1 log. However, this response is too little too late to prevent establishment of persistent infection.


Prospective evaluation of a continuous infusion vancomycin dosing nomogram in critically ill patients undergoing continuous venovenous haemofiltration.
The most optimal method of attaining therapeutic vancomycin concentrations during continuous venovenous haemofiltration (CVVH) remains unclear. Studies have shown continuous infusion vancomycin (CIV) achieves target concentrations more rapidly and consistently when compared with intermittent infusion. Positive correlations between CVVH intensity and vancomycin clearance (CLvanc) have been noted. This study is the first to evaluate a CIV regimen in patients undergoing CVVH that incorporates weight-based CVVH intensity (mL/kg/h) into the dosing nomogram. This was a prospective, observational study of patients undergoing CVVH and receiving CIV based on the nomogram. The primary outcome was achievement of a therapeutic vancomycin concentration (15-25 mg/L) at 24 h. Secondary outcomes included the achievement of therapeutic concentrations at 48 and 72 h. The nomogram was analysed in 52 critically ill adults. Vancomycin concentrations were therapeutic in 43/52 patients (82.7%) at 24 h. Of the nine patients who were not therapeutic at 24 h, seven were supratherapeutic and two were subtherapeutic. The mean (SD) concentration was 20.1 (4.2) mg/L at 24 h, 20.7 (3.7) mg/L at 48 h and 21.9 (3.5) mg/L at 72 h. Patients with CVVH intensity >20 mL/kg/h experienced higher CLvanc at 24 h compared with patients with CVVH intensity <20 mL/kg/h (3.1 versus 2.6 L/h; P = 0.013). By incorporating CVVH intensity into the CIV dosing nomogram, the majority of patients achieved therapeutic concentrations at 24 h and maintained them within range at 48 and 72 h. Additional studies are required to validate this nomogram before widespread implementation may be considered.


An unusual presentation of zollinger-ellison syndrome.
Zollinger-Ellison syndrome is an often progressive, persistent and frequently life-threatening disease, described for the first time as characterized by ulceration of the upper jejunum, hypersecretion of gastric acid and non-beta islet cell tumors of the pancreas; this syndrome is due to the hypersecretion of gastrin. We report a case of Zollinger-Ellison syndrome presenting as severe esophagitis evolving in stenosis, which demonstrates how a delayed diagnosis may induce risk of disease spreading. In this setting new diagnostic approaches, such as somatostatin receptor scanning and positron emission tomography with 68 Ga-labeled octreotide, could be particularly useful, as well as further new therapeutic options, such as molecular targeted treatments and peptide receptor radionuclide therapy, though surgery is currently the only form of curative treatment, and the role of the therapeutic options mentioned needs to be clarified by forthcoming studies.


Provirus activation plus CD59 blockage triggers antibody-dependent complement-mediated lysis of latently HIV-1-infected cells.
Latently HIV-1-infected cells are recognized as the last barrier toward viral eradication and cure. To purge these cells, we combined a provirus stimulant with a blocker of human CD59, a key member of the regulators of complement activation, to trigger Ab-dependent complement-mediated lysis. Provirus stimulants including prostratin and histone deacetylase inhibitors such as romidepsin and suberoylanilide hydroxamic acid activated proviruses in the latently HIV-1-infected T cell line ACH-2 as virion production and viral protein expression on the cell surface were induced. Romidepsin was the most attractive provirus stimulant as it effectively activated proviruses at nanomolar concentrations that can be achieved clinically. Antiretroviral drugs including two protease inhibitors (atazanavir and darunavir) and an RT inhibitor (emtricitabine) did not affect the activity of provirus stimulants in the activation of proviruses. However, saquinavir (a protease inhibitor) markedly suppressed virus production, although it did not affect the percentage of cells expressing viral Env on the cell surface. Provirus-activated ACH-2 cells expressed HIV-1 Env that colocalized with CD59 in lipid rafts on the cell surface, facilitating direct interaction between them. Blockage of CD59 rendered provirus-activated ACH-2 cells and primary human CD4(+) T cells that were latently infected with HIV-1 sensitive to Ab-dependent complement-mediated lysis by anti-HIV-1 polyclonal Abs or plasma from HIV-1-infected patients. Therefore, a combination of provirus stimulants with regulators of complement activation blockers represents a novel approach to eliminate HIV-1.


Spindle cell hemangioendothelioma of the sacrum: case report.
Spindle cell hemangioendothelioma is a rare benign vascular tumor that is not known to involve the sacrum. The authors describe the case of a 31-year-old woman presenting with low-back and radicular pain without weakness or bowel or bladder dysfunction. Admission CT and MRI studies revealed a large S1-3 lytic sacral lesion. The patient initially underwent a nondiagnostic percutaneous biopsy. She subsequently underwent an open biopsy, during which the lesion was found to be highly vascular. Histological investigation revealed a vasoformative lesion consistent with spindle cell hemangioendothelioma. Preoperative embolization followed by resection via intralesional currettage resulted in resolution of symptoms up to 9 months postintervention. Despite the authors' recommendation, the patient became pregnant at that time and requested no additional follow-up imaging. The authors present the first reported case of a spindle cell hemangioendothelioma of the sacrum and review the current literature.


Proteasome inhibition induces developmentally deregulated programs of apoptotic and autophagic cell death during Drosophila melanogaster oogenesis.
Ubiquitin/proteasome-mediated degradation of eukaryotic proteins is critically implicated in a number of signalling pathways and cellular processes. To specifically impair proteasome activities, in vitro developing Drosophila melanogaster egg chambers were exposed to the MG132 or epoxomicin proteasome inhibitors, while a GAL4/UAS binary genetic system was employed to generate double transgenic flies overexpressing β2 and β6 conditional mutant proteasome subunits in a cell type-specific manner. MG132 and epoxomicin administration resulted in severe deregulation of in vitro developing egg chambers, which was tightly associated with precocious induction of nurse cell-specific apoptotic and autophagic death programmes, featured by actin cytoskeleton disorganization, nuclear chromatin condensation, DRICE caspase activation and autophagosome accumulation. In vivo targeted overexpression of β2 and β6 conditional mutants, specifically in the nurse cell compartment, led to a notable up-regulation of sporadic apoptosis potency during early and mid-oogenesis 'checkpoints', thus reasonably justifying the observed reduction in eclosion efficiency. Furthermore, in response to the intracellular abundance of β2 and β6 conditional mutant forms, specifically in numerous tissues of third instar larval stage, the developmental course was arrested, and lethal phenotypes were obtained at this particular embryonic period, with the double transgenic heterozygote embryos being unable to further proceed to complete maturation to adult flies. Our data demonstrate that physiological proteasome function is required to ensure normal oogenesis and embryogenesis in D. melanogaster, since targeted and cell type-dependent proteasome inactivation initiates developmentally deregulated apoptotic and autophagic mechanisms.


Biosynthesis of the anti-diabetic metabolite montbretin A: glucosylation of the central intermediate mini-MbA.
Type 2 diabetes (T2D) affects over 320 million people worldwide. Healthy lifestyles, improved drugs and effective nutraceuticals are different components of a response against the growing T2D epidemic. The specialized metabolite montbretin A (MbA) is being developed for treatment of T2D and obesity due to its unique pharmacological activity as a highly effective and selective inhibitor of the human pancreatic α-amylase. MbA is an acylated flavonol glycoside found in small amounts in montbretia (Crocosmia × crocosmiiflora) corms. MbA cannot be obtained in sufficient quantities for drug development from its natural source or by chemical synthesis. To overcome these limitations through metabolic engineering, we are investigating the genes and enzymes of MbA biosynthesis. We previously reported the first three steps of MbA biosynthesis from myricetin to myricetin 3-O-(6'-O-caffeoyl)-glucosyl rhamnoside (mini-MbA). Here, we describe the sequence of reactions from mini-MbA to MbA, and the discovery and characterization of the gene and enzyme responsible for the glucosylation of mini-MbA. The UDP-dependent glucosyltransferase CcUGT3 (UGT703E1) catalyzes the 1,2-glucosylation of mini-MbA to produce myricetin 3-O-(glucosyl-6'-O-caffeoyl)-glucosyl rhamnoside. Co-expression of CcUGT3 with genes for myricetin and mini-MbA biosynthesis in Nicotiana benthamiana validated its biological function and expanded the set of genes available for metabolic engineering of MbA.


Climate variability hypothesis is partially supported in thermal limits of juvenile Northwest Atlantic coastal fishes.
As ocean warming continues to impact marine species globally, there is a need to understand the mechanisms underlying shifts in abundance and distribution. There is growing evidence that upper and lower temperature tolerances rather than mean preferences explain range shifts, but the full thermal niche is unknown for many marine species and observational data are often ill-suited to estimate the upper and lower thermal tolerances. We quantified critical thermal maximum (CTmax ) and critical thermal minimum (CTmin ) using standard methods to quantify temperature limits and thermal ranges of 14 economically and ecologically important juvenile fish species on the US Atlantic coast. We then tested the climate variability hypothesis (CVH), which states that higher-latitude species should have a wider temperature tolerance due to higher climatic variability closer to the poles. Our findings generally support the CVH in the juvenile fishes that we evaluated. However, low-latitude species were not uniformly stenothermal. Rather, species with median occurrences across a wide range of latitudes had wide temperature tolerances, but only the tropical species we tested had more narrow ranges. These findings suggest that quantifying temperature tolerances may be used to predict which low-latitude species are most likely to shift in response to warming water and those that may be more sensitive to climate change in this region.


[USE OF PHYTOTHERAPY IN COMBINATION TREATMENT OF CHRONIC PYELONEPHRITIS].
The present paper reports results of a comparative study of 48 patients with latent chronic pyelonephritis and 3-18 years of duration of the disease. Patients assigned to group 1 (n=23) received standard treatment. In patients of group 2 (n=25) standard treatment was supplemented by the administration of 30-day course of Kanferon N 2 dragees twice daily. Kanferon N supplementation was found to be effective as an anti-inflammatory-measure due to its positive impact on renal microcirculation and urinary bacterial composition. It reduces the level of proinflammatory cytokines, stimulates humoral and cellular immunity thus preventing further disease progression.


Squamous cell carcinoma cell aggregates escape suspension-induced, p53-mediated anoikis: fibronectin and integrin alphav mediate survival signals through focal adhesion kinase.
Resistance to anoikis, or apoptosis triggered by detachment from the extracellular matrix (ECM), lengthens the survival of malignant cells, facilitating reattachment and colonization of secondary sites. To examine the molecular mechanisms underlying resistance to anoikis in human oral squamous cell carcinoma (SCC) cells, we cultured human squamous carcinoma (HSC-3) cells in suspension on plates coated with poly-2-hydroxyethyl methacrylate, which blocks access to the ECM. Cells in suspension that formed multicellular aggregates had significantly lower levels of apoptosis than single cells. Aggregates, but not single cells, had high levels of fibronectin. Preincubation with a cyclic arginine-glycine-aspartic acid peptide or fibronectin-blocking antibody significantly increased anoikis. Single cells had markedly lower expression of the integrin alpha(v) receptor than aggregates. Blocking alpha(v) function with a blocking antibody or by transfection with an antisense oligonucleotide increased apoptosis and inhibited aggregation. In single cells but not aggregates, phosphorylation of the integrin-associated focal adhesion kinase (FAK) at tyrosine 397 was reduced, and p53 levels were increased. Apoptosis was increased by blocking FAK with an antisense oligonucleotide and reduced by blocking p53. These findings show that SCC cells escape suspension-induced anoikis by forming multicellular aggregates that avail themselves of fibronectin survival signals mediated by integrin alpha(v). Single cells in suspension that do not form aggregates undergo anoikis because of decreased FAK phosphorylation and increased p53 levels. Thus, SCC cells appear to use neighboring cells and the ECM molecule FN to promote the metastatic phenotype.


The uncertainty of thyroid dose estimate in chest CT.
Dose to the thyroid from helical chest CT can vary significantly due to the random tube start point, pitch factor, thyroid position relative to the isocenter, and beam width. We used optically stimulated luminescence dosimeters (OSLDs) and an adult anthropomorphic phantom to investigate the uncertainty of thyroid dose estimate. Maximum gap or overlap in the helical beam was estimated using the above factors. Using the maximum gap/overlap over the thyroid, different possible scenarios were simulated and the degree of missed thyroid tissue by the primary beam was estimated. Results showed a variation of >30% in the average thyroid dose, and >50% if a single dosimeter was used to determine dose to the thyroid. Furthermore, measured doses were compared to those calculated by Monte Carlo simulation software, which automatically matches the anatomy of the localizer radiograph with the stylized computational phantom used for dose calculation. The difference was significant: the dose given by the Monte Carlo software was ∼50% lower than the average dose measured with the phantom in all three chest protocols. In addition, the software does not take the effect of the random tube start angle into account.


Anticancer effect of aromatic isoniazid derivatives in human gastric adenocarcinoma cells.
Current treatments for stomach cancer are often effective in curing cancer. However, these treatments can also have significant side effects, and they may not be effective in all cases. Hence synthetic compounds exhibit promise as potential agents for cancer treatment. In a previous study, we identified (E)-N'- (2,3,4-trihydroxybenzylidene) isonicotinohydrazide (ITHB4) as a novel antimycobacterial derivative of isoniazid with cytotoxic effects on the MCF-7 breast cancer cell line. This led us to investigate the potential anti-cancer properties of ITHB4 against adenocarcinoma gastric (AGS) cell line. The cytotoxic effect of ITHB4 has been determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and further confirmed for anticancer properties by means of apoptosis, reactive oxygen species (ROS), nuclear fragmentation, lactate dehydrogenase (LDH), caspases, cytokines and morphological including phenotypic changes of cells assay. The ITHB4 demonstrated a lower IC50 in inhibiting growth of AGS cells at 24 h compared to 48 and 72 h. ITHB4 has also shown no toxicity human immune cells. Treatment of ITHB4 against AGS for 24 h eventually lead to formation of early apoptotic AGS cells, reduced mitochondrial membrane potential, nuclear condensation, and nuclear fragmentation lastly increased in ROS levels together with the release of LDH, and secretion of caspases. The altered cytokine profile in ITHB4 treated AGS hints at the possibility that ITHB4 may possess anti-tumor and anti-inflammatory properties. Our results in this study demonstrate that ITHB4 has almost similar chemotherapeutic properties against gastric adenocarcinoma cells compared to breast cancer cell. This is suggesting that the anticancer capabilities of this compound should be in vivo and clinically assessed.


Properties of Oils From Plantain Pseudostem Biotransformed Using Crude Local Enzyme Sources: A Comparison of Poultry Feed Oil.
Plantain Pseudostem (PPS) wastes were biotransformed by applying Simultaneous Saccharification and Fermentation (SSF) using excised snail digestive juice and yeast slurry, and their oil properties compared with oils from commercially sold poultry feeds (PF). Patents suggesting the inclusion of certain additives (US20090226558A1), spices (US5741508A), cysteamine (US4711897A), and dextrin (US6326051B1) in animal diets are regarded as expensive, thus, requiring cheaper and readily available sources of growth. The analysis of their free radical scavenging potentials was carried by spectrophotometry, while fatty acids, volatile fatty acids, essentials oils, and phytosterols were determined by chromatography. After biotransformation, the melting point, specific gravity, acid, and peroxide values of the oils from SSF-PPS were significantly lower than those of PF, and showed elevations of C6:0- C18:1(trans-9) fatty acids, palmitic, stearic, γ-Linolenic, α-linolenic, behenic, and lignoceric acids. Camphene, β-phelandrene, eugenol, β-elemene, bicyclogermacrene, guaiol, tetradecanoic acid, and hexadecanoic acid levels decreased when PPS was biotransformed. Lactic (1575.75 mg/100g), acetic (1234.26 mg/100g), propionic (845.74 mg/100g), and n-butyric (68.56 mg/100g) acids were the predominant Volatile Fatty Acids (VFAs) in the SSF-PPS oils, which were higher than those found in the PF oil while PF oil contained higher campesterol, Stigmasterol, and 5-avesmasterol. The 2,2- azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), 1,1-diphenyl-2- picrylhydrazyl (DPPH), superoxide, and nitric oxide radical scavenging potentials of PPS oil at high concentrations after biotransformation were equivalent to the standards and the PF oil. This study has shown that biotransformation involving snail digestive juice and yeasts extensively improves the oil qualities of agricultural residues sufficient enough for poultry nutrition.


Primary palliative care. Caring for patients with life-limiting illness in the community.
The 9th October 2021, was World Palliative Care Day. This year's theme for world palliative care is "Leave No One Behind - Equity in Access to Palliative Care". Evidence for the outcomes of early palliative care is growing. In 2014, the World Health Assembly passed a resolution that was co-sponsored by Malaysia. The resolution called for countries to improve access to palliative care as a core component of health systems, with an emphasis on primary health care and community/home-based care.1 One study conducted in Malaysia in 2019 estimated that by 2030, with the increase in non-communicable diseases, 246 000 patients would require palliative care. For Malaysia to achieve equity in access to palliative care, care for these patients must be integrated into primary care. This article discusses some of the tools available for early identification of patients assessment and management of patients with palliative care needs.


Employing mirtazapine to aid benzodiazepine withdrawal.
Insomnia and depression are frequently encountered in patients during withdrawal from substances. While there are no approved medications for treating them, off-label attempts to address these phenomena with mirtazapine have shown some promising results. This case describes the use of mirtazapine as an aid in benzodiazepine withdrawal and its potential benefits in alleviating insomnia and depression in a 32-year-old man. It was found to ameliorate sleep myoclonus that was thought to be associated with his withdrawal syndrome. It is hoped this report will generate interest and stimulate further research in this area of psychopharmacology.


Characterizing tobacco and marijuana use among youth combustible tobacco users experiencing homelessness - considering product type, brand, flavor, frequency, and higher-risk use patterns and predictors.
Cigarette smoking is three times more prevalent among youth experiencing homelessness compared with the general population. Co-use of tobacco and marijuana is also common. The aim of this study is to characterize tobacco and marijuana use among youth experiencing homelessness who use combustible tobacco in a Midwestern city to inform smoking cessation intervention. This study included 96 youth (ages 14-24 years; 52% male, 39% female, 5% transgender/non-binary) attending a homeless drop-in center who had used at least one combustible tobacco product in the past week. We assessed past-month use of tobacco products and marijuana, other product use characteristics (e.g., frequency, brand and flavor), and psychosocial predictors of more frequent (i.e., daily) use of combustible tobacco and marijuana. Most youth experiencing homelessness with past-week combustible tobacco use had used cigarettes (n = 85, 88.5%), cigars (n = 89, 92.7%), and marijuana (n = 82, 85.4%) in the past month. One-third (n = 34) used electronic vapor products (EVPs), 19.8% (n = 19) smoked hookah, and 11.5% (n = 11) used smokeless tobacco (ST). Most marijuana users co-administered with tobacco (n = 67, 69.8%). Daily combustible tobacco smoking was associated with having a child and smoking out of boredom/habit. Daily marijuana use was associated with using substances to cope with one's housing situation. Newport (n = 66, 72.5%) and Black & Mild (n = 48, 51.1%) were the most popular brands of cigarettes and cigars among ever users. Most non-combustible tobacco ever users reported not having a usual brand (EVPs: n = 51, 73.9%; ST: n = 16, 57.1%). Cigar smokers reported the most varied selection of flavors. Young combustible tobacco users experiencing homelessness engage in high-risk use patterns, including poly-tobacco use, co-use of tobacco with marijuana, and frequent combustible product use. Interventions that consider the full context of tobacco and marijuana use are needed to support smoking cessation in this population.


Adherence to and Acceptance of Once-Daily Tacrolimus After Kidney and Liver Transplant: Results From OSIRIS, a French Observational Study.
Adherence to immunosuppressive treatments is a major concern in transplanted patients. This 6-month French observational, longitudinal, prospective study aimed to assess patient adherence to and acceptance of once-daily tacrolimus (Advagraf) initiation in kidney and liver transplant recipients. Data from 1106 patients initiating once-daily tacrolimus during posttransplant follow-up were analyzed. Adherence and acceptance were assessed using self-administered questionnaires at inclusion and at 3 and 6 months. Mean age was 52.4 ± 13.2 years, 61.5% were men. For 94.9% of patients, once-daily tacrolimus was prescribed after switching from twice-daily tacrolimus. At inclusion, 20.9% of patients reported good treatment adherence, 72.0% minor nonadherence, and 7.1% were nonadherent. Mean general acceptance score (range, 0-100) was 77.7 (±24.7). At 3 months, adherence was improved in 21.1%, unchanged in 69.2%, and worsened in 9.7% of patients. Mean general acceptance score was 75.4 (±26.5). General acceptance score was improved in 28.0%, unchanged in 39.4%, and worsened in 32.7% of patients. At 6 months, similar changes in adherence and acceptance were observed. Higher general acceptance score at month 3 was significantly associated with better adherence at month 6. Conversion to once-daily tacrolimus led to an improved rate of adherence at month 3 in more than 20% of patients and a worsened rate of adherence in less than 10% of patients.


Prognostic significance of prostate cancer originating from the transition zone.
Transition zone (TZ) cancers are reported to have better biochemical relapse-free survival (bRFS) after radical prostatectomy (RP) than cancers from the peripheral zone (PZ). To understand the influence of tumor location, we compared bRFS for TZ and PZ cancers stratified for risk using known clinical and pathological prognostic factors. The surgical pathology and outcomes of 494 patients were reviewed. Cancers originating from the TZ and PZ were identified from step sectioning of surgical specimens and tumor mapping. Univariate and multivariate analyses of bRFS after RP were compared. TZ cancers were present in 89 (18%) patients. On univariate analysis, most factors predicted bRFS, although cancer location did not: 5-year bRFS was 85% for TZ vs. 77% for PZ (P = 0.12). However, on multivariate analysis, all factors except SV involvement were significant, including TZ cancer location (P = 0.04, HR = 1.88 [1.02-3.47]). Interestingly, TZ location was correlated with improved 5-year bRFS for cancers > 2 cc (81% for TZ vs. 65% for PZ, P = 0.017), for preop PSA >10 (80% for TZ vs. 59% for PZ, P = 0.027), and for PSAV > 2 (85% for TZ vs. 66% for PZ, P = 0.08). However, TZ cancers showed no difference in outcome for small volumes, low preop PSA, low PSAV, or high Gleason grade. TZ cancers that are large, with high preop PSA, low Gleason scores, and high PSAV show better outcomes than their PZ counterparts. However, high-grade cancer tumor location had no apparent influence on outcome. Tumor location could be considered in subsets for optimal prognostication.


Persistence of asthma medication use in preschool children.
In young children with asthmatic symptoms diagnostic difficulties lead to use of trials of asthma medication as a diagnostic tool. Our aim is to quantify the persistent use of asthma medication, initiated in the first year of life and identify determinants of this persistent use. We identified 165 children within the PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort who used asthma medication before the age of one. Persistent use was investigated during three years after the first prescription. A Cox regression analysis was performed to identify factors associated with persistent use. A total of 58.8% of children continued using asthma medication after the first prescription and 10.3% continued during three years. Children with doctor-diagnosed asthma (Hazard ratio of discontinuation (HR)=0.64, 95% CI: 0.45-0.91) or prescribed inhaled corticosteroids in the first year of life (HR of discontinuation=0.59, 95% CI: 0.40-0.86) were 1.6-1.7 times more likely to continue using asthma medication. Persistence of asthma medication, prescribed in the first year of life is very low and is positively associated with doctor-diagnosed asthma and use of inhaled corticosteroids. Characterizing persistent users of asthma medication is important to understand prescribing of asthma medication in this age group.


Reduced plasma levels of glucagon-like peptide-1 in elderly men are associated with impaired glucose tolerance but not with coronary heart disease.
Besides the insulinotropic effects of glucagon-like peptide-1 (GLP-1) mimetics, their effects on endothelial dysfunction and myocardial ischaemia are of interest. No previous study has investigated associations between plasma levels of GLP-1 and CHD. We investigated longitudinal relationships of fasting GLP-1 with the dynamic GLP-1 response after OGTT (difference between 60 min OGTT-stimulated and fasting GLP-1 levels [DeltaGLP-1]) and CHD in a population-based cohort of 71-year-old men. In the same cohort, we also cross-sectionally investigated the association between stimulated GLP-1 levels and: (1) cardiovascular risk factors (blood pressure, lipids, urinary albumin, waist circumference and insulin sensitivity index [M/I] assessed by euglycaemic-hyperinsulinaemic clamp); and (2) impaired glucose tolerance (IGT) and type 2 diabetes mellitus. During the follow-up period (maximum 13.8 years), of 294 participants with normal glucose tolerance (NGT), 69 experienced a CHD event (13.8 years), as did 42 of 141 with IGT and 32 of 74 with type 2 diabetes mellitus. DeltaGLP-1 did not predict CHD (HR 1.0, 95% CI 0.52-2.28). The prevalence of IGT was associated with DeltaGLP-1, lowest vs highest quartile (OR 0.3, 95% CI 0.12-0.58), with no such association for type 2 diabetes mellitus (OR 1.0, 95% CI 0.38-2.86). M/I was significantly associated with DeltaGLP-1 in the type 2 diabetes mellitus group (r = 0.38, p < 0.01), but not in the IGT (r = 0.11, p = 0.28) or NGT (r = 0.10, p = 0.16) groups. Impaired GLP-1 secretion is associated with IGT, but not with type 2 diabetes mellitus. This finding in the latter group might be confounded by oral glucose-lowering treatment. GLP-1 does not predict CHD. Although DeltaGLP-1 was associated with insulin sensitivity in the type 2 diabetes mellitus group, GLP-1 does not seem to be a predictor of CHD in insulin-resistant patients.


Vacuum-assisted closure for deep infection after spinal instrumentation for scoliosis.
Our aim was to review the efficacy of the wound vacuum-assisted closure (VAC) system in the treatment of deep infection after extensive instrumentation and fusion for spinal deformity in children and adolescents. A total of 14 patients with early deep spinal infection were treated using this technique. Of these, 12 had neuromuscular or syndromic problems. Clinical and laboratory data were reviewed. The mean follow-up was 44 months (24 to 72). All wounds healed. Two patients required plastic surgery to speed up the process. In no patient was the hardware removed and there was no loss of correction or recurrent infection. We believe that the wound VAC system is a useful tool in the armamentarium of the spinal surgeon dealing with patients susceptible to wound infections, especially those with neuromuscular diseases. It allows for the retention of the instrumentation and the maintenance of spinal correction. It is reliable and easy to use.


[Asthma associated with gastroesophageal reflux].
In order to explore the association between poorly controllable asthma and gastroesophageal reflux (GER), a prospective clinical trial is presented. This trial included 28 patients with negative atopic indicators who presented difficulty in the management of their disease. All patients underwent a complete medical history as well as skin tests for common airborne allergens, total serum IgE, peripheral blood eosinophils, spirometry, chest X-ray and esophageal barium films. Additionally, esophageal endoscopy was performed on 9 patients, and esophageal manometry in 1 patient. All were submitted to antireflux therapy and received omeprazole and cisapride for 8 weeks. Complete improvement was observed in 24 patients (85.7%), moderate improvement in 3 patients (10.7%), and no improvement in 1 patient (3.6%). Three patients required antireflux surgery. Symptoms reappeared 2-3 weeks after suspending treatment, which led to the recommendation that antireflux measures become a way of life for these patients.


Characteristics of a line of Eimeria necatrix after 16 successive passages of oocysts collected after peak oocyst production.
A line of Eimeria necatrix was selected by repeated passages of oocysts that were collected after peak oocyst production from feces or cecal contents of previously infected chickens. When compared with the parent strain, the new line of E. necatrix after 16 successive passages had the following characteristics: (1) the peak of oocyst production was delayed by 2 days; (2) the sizes of 9 endogenous development stages became larger; and (3) the reproductive capacity and the immunogenicity were both enhanced. This new line of E. necatrix may be used for the development of new coccidiosis vaccines.


Loads distributed in vivo among vertebrae, muscles, spinal ligaments, and intervertebral discs in a passively flexed lumbar spine.
The load distribution among lumbar spinal structures-still an unanswered question-has been in the focus of this hybrid experimental and simulation study. First, the overall passive resistive torque-angle characteristics of healthy subjects' lumbar spines during flexion-extension cycles in the sagittal plane were determined experimentally by use of a custom-made trunk-bending machine. Second, a forward dynamic computer model of the human body that incorporates a detailed lumbar spine was used to (1) simulate the human-machine interaction in accordance with the experiments and (2) validate the modeled properties of the load-bearing structures. Third, the computer model was used to predict the load distribution in the experimental situation among the implemented lumbar spine structures: muscle-tendon units, ligaments, intervertebral discs, and facet joints. Nine female and 10 male volunteers were investigated. Lumbar kinematics were measured with a marker-based infrared device. The lumbar flexion resistance was measured by the trunk-bending machine through strain gauges on the axes of the machine's torque motors. Any lumbar muscle activity was excluded by simultaneous sEMG monitoring. A mathematical model was used to describe the nonlinear flexion characteristics. The subsequent extension branch of a flexion-extension torque-angle characteristic could be significantly distinguished from its flexion branch by the zero-torque lordosis angle shifted to lower values. A side finding was that the model values of ligament and passive muscle stiffnesses, extracted from well-established literature sources, had to be distinctly reduced in order to approach our measured overall lumbar stiffness values. Even after such parameter adjustment, the computer model still predicts too stiff lumbar spines in most cases in comparison with experimental data. A review of literature data reveals a deficient documentation of anatomical and mechanical parameters of spinal ligaments. For instance, rest lengths of ligaments-a very sensitive parameter for simulations-and cross-sectional areas turned out to be documented at best incompletely. Yet by now, our model well reproduces the literature data of measured pressure values within the lumbar disc at level L4/5. Stretch of the lumbar dorsal (passive) muscle and ligament structures as an inescapable response to flexion can fully explain the pressure values in the lumbar disc. Any further external forces like gravity, or any muscle activities, further increase the compressive load on a vertebral disc. The impact of daily or sportive movements on the loads of the spinal structures other than the disc cannot be predicted ad hoc, because, for example, the load distribution itself crucially determines the structures' current lever arms. In summary, compressive loads on the vertebral discs are not the major determinants, and very likely also not the key indicators, of the load scenario in the lumbar spine. All other structures should be considered at least equally relevant in the future. Likewise, load indicators other than disc compression are advisable to turn attention to. Further, lumbar flexion is a self-contained factor of lumbar load. It may be worthwhile, to take more consciously care of trunk flexion during daily activities, for instance, regarding long-term effects like lasting repetitive flexions or sedentary postures.


Evaluating human cancer cell metastasis in zebrafish.
In vivo metastasis assays have traditionally been performed in mice, but the process is inefficient and costly. However, since zebrafish do not develop an adaptive immune system until 14 days post-fertilization, human cancer cells can survive and metastasize when transplanted into zebrafish larvae. Despite isolated reports, there has been no systematic evaluation of the robustness of this system to date. Individual cell lines were stained with CM-Dil and injected into the perivitelline space of 2-day old zebrafish larvae. After 2-4 days fish were imaged using confocal microscopy and the number of metastatic cells was determined using Fiji software. To determine whether zebrafish can faithfully report metastatic potential in human cancer cells, we injected a series of cells with different metastatic potential into the perivitelline space of 2 day old embryos. Using cells from breast, prostate, colon and pancreas we demonstrated that the degree of cell metastasis in fish is proportional to their invasion potential in vitro. Highly metastatic cells such as MDA231, DU145, SW620 and ASPC-1 are seen in the vasculature and throughout the body of the fish after only 24-48 hours. Importantly, cells that are not invasive in vitro such as T47D, LNCaP and HT29 do not metastasize in fish. Inactivation of JAK1/2 in fibrosarcoma cells leads to loss of invasion in vitro and metastasis in vivo, and in zebrafish these cells show limited spread throughout the zebrafish body compared with the highly metastatic parental cells. Further, knockdown of WASF3 in DU145 cells which leads to loss of invasion in vitro and metastasis in vivo also results in suppression of metastasis in zebrafish. In a cancer progression model involving normal MCF10A breast epithelial cells, the degree of invasion/metastasis in vitro and in mice is mirrored in zebrafish. Using a modified version of Fiji software, it is possible to quantify individual metastatic cells in the transparent larvae to correlate with invasion potential. We also demonstrate, using lung cancers, that the zebrafish model can evaluate the metastatic ability of cancer cells isolated from primary tumors. The zebrafish model described here offers a rapid, robust, and inexpensive means of evaluating the metastatic potential of human cancer cells. Using this model it is possible to critically evaluate whether genetic manipulation of signaling pathways affects metastasis and whether primary tumors contain metastatic cells.


Hepatic steatosis and nonalcoholic fatty liver disease are common and associated with cardiometabolic risk in a primary prevention cohort of people with HIV.
Hepatic steatosis, including nonalcoholic fatty liver disease (NAFLD), is common among people with HIV (PWH). We present baseline steatosis prevalence and cardiometabolic characteristics among REPRIEVE substudy participants. REPRIEVE is an international, primary cardiovascular disease prevention, randomized, controlled trial of pitavastatin calcium vs. placebo among 7769 PWH ages 40-75 years on antiretroviral therapy (ART) and with low-to-moderate cardiovascular risk. A subset of participants underwent noncontrast computed tomography, with hepatic steatosis defined as mean hepatic attenuation less than 40 HU or liver/spleen ratio less than 1.0, and NAFLD defined as steatosis in the absence of frequent alcohol use or viral hepatitis. Of 687 evaluable persons, median age was 51 years, BMI 27 kg/m 2 , CD4 + T-cell count 607 cells/μl; 17% natal female sex, 36% Black, 24% Hispanic, and 98% HIV-1 RNA less than 400 copies/ml. Hepatic steatosis prevalence was 22% (149/687), and NAFLD 21% (96/466). Steatosis/NAFLD prevalence was higher in men and with older age, non-Black race, and higher BMI and waist circumference. Both were associated with BMI greater than 30 kg/m 2 , metabolic syndrome components, higher atherosclerotic cardiovascular disease (ASCVD) risk score, HOMA-IR, LpPLA-2 and hs-CRP, and lower high-density lipoprotein cholesterol. Of HIV-specific/ART-specific characteristics, only history of an AIDS-defining illness was more common among persons with steatosis/NAFLD. After adjusting for age, sex and race/ethnicity, BMI greater than 30 kg/m 2 , HOMA-IR greater than 2.0, Metabolic syndrome and each of its components were associated with NAFLD prevalence. In this cohort with controlled HIV and low-to-moderate cardiovascular risk, hepatic steatosis and NAFLD were common and associated with clinically relevant metabolic and inflammatory disturbances but not current HIV-related or ART-related factors.


TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation.
The biological outcome of TMPRSS2:ERG chromosomal translocations in prostate cancer (PC) remains poorly understood. To address this, we compared the transcriptional effects of TMPRSS2:ERG expression in a transgenic mouse model with those of ERG knockdown in a TMPRSS2:ERG-positive PC cell line. This reveals that ERG represses the expression of a previously unreported set of androgen receptor (AR)-independent neuronal genes that are indicative of neuroendocrine (NE) cell differentiation-in addition to previously reported AR-regulated luminal genes. Cell sorting and proliferation assays performed after sustained ERG knockdown indicate that ERG drives proliferation and blocks the differentiation of prostate cells to both NE and luminal cell types. Inhibition of ERG expression in TMPRSS2:ERG-positive PC cells through blockade of AR signaling is tracked with increased NE gene expression. We also provide evidence that these NE cells are resistant to pharmacological AR inhibition and can revert to the phenotype of parental cells upon restoration of AR/ERG signaling. Our findings highlight an ERG-regulated mechanism capable of repopulating the parent tumor through the transient generation of an anti-androgen therapy-resistant cell population, suggesting that ERG may have a direct role in preventing resistance to anti-androgen therapy.


Role of cyclooxygenase enzymes in a murine model of experimental cholera.
Nonsteroidal anti-inflammatory drugs (e.g., indomethacin) inhibit and reduce the fluid secretion responses elicited by cholera toxin (CT), but it has not been conclusively determined which cyclooxygenase (COX) isoform is involved in CT's action. This study evaluated the role of the COX enzymes and their arachidonic acid metabolites in experimental cholera. Swiss-Webster mice were dosed with celecoxib and rofecoxib and challenged with CT in ligated small intestinal loops, and intestinal segments from mice deficient in COX-1 and COX-2 were challenged with CT. The effects of CT on fluid accumulation, prostaglandin E(2) production, mucosal tissue injury, and markers of oxidative stress were measured. Celecoxib and rofecoxib given at 160 micro g per mouse inhibited CT-induced fluid accumulation by 48% and 31%, respectively, but there was no significant difference among cox-1(-/-) and cox-2(-/-) mice in response to CT compared to wild-type controls. CT elevated tissue levels of oxidized glutathione and lipid peroxides and elicited small intestinal tissue injury in two of five cox-1(-/-) and four of five cox-2(-/-) mice. A role for COX-2 in CT's mechanism of action has previously been suggested by the effectiveness of COX-2 inhibitors in reducing CT-induced fluid secretion, but CT challenge of COX-1 and COX-2 knockout mice did not corroborate the pharmacological data. The results of this study show that CT induced oxidative stress in COX-deficient mice and suggest a tissue-protective role for arachidonic acid metabolites in the small intestine against oxidative stress.


Endogenous testosterone is associated with increased striatal response to audience effects during prosocial choices.
The role of testosterone on cognitive functions in humans remains controversial. One recent hypothesis suggests that this steroid hormone advances social status. As being observed by others is known to modulate a range of behaviors because of image concerns, we hypothesized that such an audience effect might be an important component of status seeking that is under the control of testosterone. Thus, we investigated to which extent testosterone levels are associated with the effect of being observed during prosocial choices and the neural mechanisms underlying this effect. We enrolled twenty-four male participants, aged 22.47 ± 2.62 years, in an fMRI experiment to examine the relationship between testosterone levels and brain activity engaged in deciding whether to accept or reject monetary transfers to two types of organizations (a positively evaluated organization and a negatively evaluated organization) in presence or absence of an audience. When comparing the public to the private condition, the rate of acceptance increased for the positively evaluated organization, while the rate of rejection increased for the negatively evaluated one. Higher testosterone levels were linked to greater activation in the striatum in the public compared to the private condition, regardless of the organization type. These results indicate a relationship between testosterone levels and striatal activity induced by the audience effect. These findings provide new insights on the role of testosterone in human social behavior.


Surgical techniques and adjuvants for the management of primary and recurrent pterygia.
The removal and rate of recurrence of pterygium have been discussed for years. The disorder is highly associated with environmental factors, and recurrence rates can be unacceptably high and cannot be successfully predicted. New techniques and graft preparations and postoperative management strategies are helping to reduce the recurrence rates and provide an ocular surface that is near ideal for future cataract or refractive surgery. This review discusses the advantages and disadvantages of various treatment strategies.


Infantile gastroenteritis in the community: a cost-of-illness study.
Rotavirus infections are the main cause of gastroenteritis in infants and children and it is expected that by the age of 5 years, nearly every child will have experienced at least one episode of rotavirus gastroenteritis. While severe cases are hospitalized, milder disease is either treated at home or by the GP, and as such the true prevalence of rotavirus infection in the community, and the burden of disease, is unknown. This paper reports the results of a cost-of-illness study which was conducted alongside a structured community surveillance study. Forty-eight percent of our sample was found to have rotavirus acute gastroenteritis; and the average total cost of a child presenting with rotavirus gastroenteritis ranged between pound sterling 59 and pound sterling 143 per episode, depending on the perspective. Given the prevalence and severity of the disease, the estimated burden of rotavirus gastroenteritis to society is pound sterling 11.5 million per year.


[Erythrocyte cholesterol content in polycythemia vera: relation to ischemic heart disease].
Relative cholesterol content and its distribution between erythrocytes and plasma were studied in 34 patients with polycythemia vera (PV) both with and without concomitant coronary heart disease (CHD). Deformability of erythrocytes, disturbances of microcirculation (blood flow fragmentation, decrease of capillary density) were also assessed. Erythrocytes cholesterol/phospholipids molar ratios (0.68+/-0.03) in patients was lower than normal value (0.8) in spite of decreased cell deformability. This was associated with some increase of peroxidation products. Blood cholesterol distribution between cell and plasma species had some peculiarities caused by high hematocrit: compared with normal value erythrocytes of patients carried relatively larger portion of total blood cholesterol (23.7+/-0.8% and 27-31%, respectively). However in CHD patients these values were significantly lower with correspondent increase of plasma cholesterol quota. This allowed to suggest possible protective role of blood cholesterol redistribution in polycythemia patients, through erythrocytes trafficking of some part of plasma cholesterol.


Adolescents living with HIV are at higher risk of death and loss to follow up from care: Analysis of cohort data from eight health facilities in Ethiopia.
There are limited data on the treatment outcomes of adolescents living with HIV. Our objective was to compare mortality and loss to follow up (LTFU) rates between adolescent and younger age groups at enrollment in care. This was a retrospective cohort study carried out in eight health facilities in two regions of Ethiopia. Adolescents (age 10-14 and 15-19 year) and children (age 0-9 year) enrolled in chronic HIV care between 2005 and 2013 constituted the study population. We reviewed the individual patient charts between March and June 2014 and updated the data on the status of each patient through December 2015. We used death and loss-to-follow up as primary endpoints and used the Cox-regression analysis where age, categorized as adolescent versus child, was the main predictor variable. Of 2058 participants studied, 52.1% were adolescents. The cohort contributed 2422 person-years of observation (PYO) during the pre-ART follow-up, whereas 1531 patients put on ART contributed 5984 PYO. Of those put on ART, 209 (13.7%) LTFU and 92 (6%) deaths were reported. Adolescents in age group 15-19 yr had the highest risk of LTFU [adjusted hazard ratio, aHR (95% CI) = 3.1 2.1, 5.0 ] followed by those in age group 10-14 yr (aHR = 1.5 [0.9, 2.3]) compared with children aged 0-9 yr. Mortality hazard was significantly higher among younger adolescents (aHR = 2.8 [1.4, 5.4]) and older adolescents (aHR = 2.3 [1.1, 4.9]) compared with children. Adolescents are at higher risk of mortality and LTFU as compared to children ages 0-9. Younger adolescents and children had similar LTFU rates. Narrow age band disaggregated analysis can serve as useful guide for tailoring interventions to the specific needs of different age groups.


Patient opinions regarding surgeon presence, trainee participation, and overlapping surgery.
To explore patient opinions and underlying values regarding overlapping surgery (OS) scenarios, specifically evaluating the effect of attending surgeon presence and availability, as well as trainee participation on patient comfort level and willingness to consent. Mixed methods. Forty adults participated in semi-structured interviews. Interviews included vignettes involving three scenarios of OS (1: attending present; 2: attending absent for wound closure; 3: attending absent and unavailable for wound closure, with covering attending), visual analog scale ratings of participants' comfort with scenarios, and cognitive debriefing. Themes and subthemes were identified using hierarchical coding of transcripts, and quantitative and qualitative analyses were conducted. Quantitative analysis revealed anticipated decreases in comfort with decreasing attending presence/availability (mean comfort level 94% vs. 78% vs. 63% for scenarios 1 vs. 2 vs. 3, P < 0.005), although many patients reported improved comfort with scenario 3 if meeting the covering attending. Participants demonstrated a preference for less trainee involvement (P < 0.005, scenario 1) and greater trainee experience (P < 0.05, all scenarios). However, not all individuals were uncomfortable with attending absence or trainee independence. Themes important for decision making included trust in the surgeon, surgeon experience, trainee involvement, disease severity, cost, and wait time. Patients varied highly in their willingness to consent to OS scenarios. In settings of trainee independence and covering surgeons, many patients desired meeting these members of the treatment team, which improved comfort for some. For some patients, tradeoffs and incentives of timeliness, cost, and convenience modified their willingness to have OS. 4 Laryngoscope, 129:1337-1346, 2019.


Sequencing and functional analysis of styrene catabolism genes from Pseudomonas fluorescens ST.
The nucleotide sequence of the 4,377-bp chromosomal region of Pseudomonas fluorescens ST that codes for the oxidation of styrene to phenylacetic acid was determined. Four open reading frames, named styA, styB, styC, and styD, were identified in this region. Sequence analysis and biotransformation assays, performed with batch and continuous cultures, allowed us to identify the functions of the sequenced genes. styA and styB encode a styrene monooxygenase responsible for the transformation of styrene to epoxystyrene; styC codes for the second enzyme of the pathway, an epoxystyrene isomerase that converts epoxystyrene to phenylacetaldehyde; and the styD gene produces a phenylacetaldehyde dehydrogenase that oxidizes phenylacetaldehyde to phenylacetic acid. StyA, 415-amino-acids long, was found to be weakly homologous to p-hydroxybenzoate hydroxylase from both P. fluorescens and P. aeruginosa and to salicylate hydroxylase from P. putida, suggesting that it might be a flavin adenine dinucleotide-binding monooxygenase. StyB was found to be partially homologous to the carboxyterminal part of the 2,4-dichlorophenol-6-monooxygenase encoded by plasmid pJP4, while the styC product did not share significant homology with any known proteins. The fourth open reading frame, styD, could encode a protein of 502 amino acids and was strongly homologous to several eukaryotic and prokaryotic aldehyde dehydrogenases. The order of the genes corresponds to that of the catabolic steps. The previously suggested presence of the gene for epoxystyrene reductase, which directly converts epoxystyrene to 2-phenylethanol (A.M. Marconi, F. Beltrametti, G. Bestetti, F. Solinas, M. Ruzzi, E. Galli, and E. Zennaro, Appl. Environ. Microbiol. 61:121-127, 1996), has not been confirmed by sequencing and by biotransformation assays performed in continuous cultures. A copy of the insertion sequence ISI162, belonging to the IS21-like family of elements, was identified immediately downstream of the styrene catabolic genes.


Sex differences in taste aversion learning: an analysis of the minimal effective dose.
Male and female rats injected with various doses of LiCl following the consumption of a novel saccharin solution subsequently avoided consumption of saccharin, with the degree of the aversion directly related to the dose of LiCl. Although this dose-response relationship was evident for both males and females, the minimal effective dose for inducing an aversion was lower for males, an effect consistent with previous work examining sex differences in taste aversion learning. The necessity of considering sex as a variable when comparing the relative sensitivity of behavioral measures of toxicity was discussed.


Vaccines that facilitate antigen entry into dendritic cells.
Although vaccines have been highly successful in preventing and treating many infectious diseases (including smallpox, polio and diphtheria) diseases prevalent in the developing world such as malaria and HIV, that suppress the host immune system, require new, multiple strategies that will be defined by our growing understanding of specific immune activation. The definition of adjuvants, previously thought of as any substance that enhanced the immunogenicity of antigen, could now include soluble mediators and antigenic carriers that interact with surface molecules present on DC (e.g. LPS, Flt3L, heat shock protein) particulate antigens which are taken up by mechanisms available to APC but not other cell types (e.g. immunostimulatory complexes, latex, polystyrene particles) and viral/bacterial vectors that infect antigen presenting cells (e.g. vaccinia, lentivirus, adenovirus). These approaches, summarized herein, have shown potential in vaccinating against disease in animal models, and in some cases in humans. Of these, particle-antigen conjugates provide rapid formulation of the vaccine, easy storage and wide application, with both carrier and adjuvant functions that activate DC. Combined vaccines of the future could use adjuvants such as virus-like particles and particles targeted towards a predominant cellular type or immune response, with target cell activation enhanced by growth factors or maturation signals prior to, or during immunization. Collectively, these new additions to adjuvant technology provide opportunities for more specific immune regulation than previously available.


The effect of swimming exercise on lipid peroxidation in the rat brain, liver and heart.
We intended to study the effect of swimming exercise on the brain, liver and heart malondialdehyde (MDA) levels which are the last product of oxidation, and to compare them with the brain, liver and heart MDA levels of controls. The experiments were carried out on 20 Wistar rats which were fed with a standard laboratory chow diet ad libitum. Rats were distributed in two groups, control group (n = 10) and exercise group (n = 10). The exercise group rats were exposed to swimming exercise for 30 minutes. After this animals in each group were sacrificed by decapitation, their brain, liver and heart tissues were quickly removed. MDA levels of the brain, liver and heart were determined according to the method in which MDA reacts with thiobarbituric acid. Results were evaluated by the Mann-Whitney U test. The liver and heart MDA levels in the exercise group were (29.59+/-6.73 and 10.49+/-1.90 nmol/g tissue, respectively) significantly higher than in the control group (21.78+/-3.46 and 8.86+/-1.25 nmol/g tissue, p<0.01 and p<0.05, respectively). However, the brain MDA levels were similar in both groups (exercise group 19.37+/-5.50 nmol/g tissue and control group 16.58+/-2.44 nmol/g tissue; p=0.325). It is concluded that swimming exercise might cause oxidative stress.


Effect of coating using beeswax and sodium nitroprusside on chlorophyll stability and quality factors of lime during cold storage.
Lime (Citrus floridana) is a quickly perishable fruit, limiting its shelf life because of reduced chlorophyll content and post-harvest quality under different storage conditions. To increase chlorophyll stability as well as other quality factors of limes, they were coated with beeswax in 0.1 wt.% and sodium nitroprusside in three various concentrations (0.1, 0.2, and 0.4 mM) at 25 °C for 3 min and then stored at 8 °C for 60 days. In this research, changes in weight loss, juice content, firmness (F), chlorophyll, chlorophyllase activity, polyphenol oxidase activity, color, total acidity (titratable acidity), ascorbic acid (ASA) and sensory evaluation were studied. During storage at low temperatures, BW surface coating (0.1%) alone, sodium nitroprusside alone, and also in combination with each other and a double layer were effective in maintaining chlorophyll and the qualitative characteristics of limes. In our observations, the best treatment was the treatment where the limes were coated by beeswax enriched by sodium nitroprusside coating. This treatment contained the highest content of lime juice and the highest chlorophyll plus the lowest activity of chlorophyllase and polyphenol oxidase, while the amount of green color was maintained to a large extent. As a result, it is possible to use beeswax enriched by sodium nitroprusside coating method to maintain the quality and chlorophyll of cold-stored lime fruits.


The NPH4 locus encodes the auxin response factor ARF7, a conditional regulator of differential growth in aerial Arabidopsis tissue.
Organ bending through differential growth represents a major mechanism by which plants are able to adaptively alter their morphology in response to local changes in the environment. Two plant hormones, auxin and ethylene, have been implicated as regulators of differential growth responses; however, the mechanisms by which they elicit their effects remain largely unknown. Here, we describe isolation of the NPH4 gene of Arabidopsis, which is conditionally required for differential growth responses of aerial tissues, and we report that NPH4 encodes the auxin-regulated transcriptional activator ARF7. The phenotypes of nph4 mutants, which include multiple differential growth defects associated with reduced auxin responsiveness, including impaired auxin-induced gene expression, are consistent with the predicted loss of function of a transcriptional activator, and these phenotypes indicate that auxin-dependent changes in gene transcription are prerequisite for proper organ bending responses. Although NPH4/ARF7 appears to be a major regulator of differential growth, it is not the sole regulator because phenotypes of nph4 null mutants were suppressed by application of ethylene. This latter finding illustrates the intimate connection between auxin and ethylene in the control of growth in higher plants.


Increases in alcohol consumption in women and elderly groups: evidence from an epidemiological study.
In most Western countries, alcohol consumption continues to increase, specifically among women and older adults. Insight into these trends may aid intervention strategies. Here we present data on alcohol consumption by age and sex as well as associations between alcohol use and demographic lifestyle/traits. The data are from a large (N>16,000) population-based Dutch sample, ascertained based on the presence of twins in the family. A set of 16 indicators of normative and problematic alcohol use was assessed in participants of the Netherlands Twin Register between 2009-2012 (ages 18-97; 6,052 men; 10,535 women). Alcohol consumption and demographic/lifestyle traits, including educational attainment, work-related/financial stress, urbanization, religiousness, smoking/cannabis initiation, and BMI were described by age and sex. Associations were examined by regressing aspects of alcohol use on age, sex, their interaction, and demographic/lifestyle variables. Age, sex, and initiation of cigarette and cannabis use were the most important predictors of alcohol use. Frequency of alcohol use was lowest between 18-25 years, with 3.2% of men and .6% of women drinking 6-7 times/week, and highest above age 65 years, with 30.6-32.7% of men and 20.2-22.0% of women drinking 6-7 times/week. Women consumed the lowest quantities of alcohol between 25-45 years, with a 5.7-5.9% prevalence of excessive drinking (>14 glasses/week), and the largest quantities between 55-65 years (15.5% excessive drinkers). Age at alcohol initiation, onset of regular drinking, and first alcohol intoxication were lowest between ages 18-25 years and highest above age 65 years. Among older participants, men initiated alcohol use and regular drinking earlier, and had lower age at first intoxication than women, but among young adults, no sex differences were observed. Alcohol consumption was high in the elderly Dutch population, especially among women. Alcohol initiation, onset of regular drinking, and first alcohol intoxication occur at increasingly younger ages, and the previous gap between men and women in age at alcohol initiation, onset of regular drinking, and first alcohol intoxication has closed almost entirely. Heavy alcohol use was most strongly predicted by older age, sex (male), and initiation of smoking and cannabis use.


The Primary Care Research Object Model (PCROM): a computable information model for practice-based primary care research.
Chronic disease prevalence and burden is growing, as is the need for applicable large community-based clinical trials of potential interventions. To support the development of clinical trial management systems for such trials, a community-based primary care research information model is needed. We analyzed the requirements of trials in this environment, and constructed an information model to drive development of systems supporting trial design, execution, and analysis. We anticipate that this model will contribute to a deeper understanding of all the dimensions of clinical research and that it will be integrated with other clinical research modeling efforts, such as the Biomedical Research Integrated Domain Group (BRIDG) model, to complement and expand on current domain models. We used unified modeling language modeling to develop use cases, activity diagrams, and a class (object) model to capture components of research in this setting. The initial primary care research object model (PCROM) scope was the performance of a randomized clinical trial (RCT). It was validated by domain experts worldwide, and underwent a detailed comparison with the BRIDG clinical research reference model. We present a class diagram and associated definitions that capture the components of a primary care RCT. Forty-five percent of PCROM objects were mapped to BRIDG, 37% differed in class and/or subclass assignment, and 18% did not map. The PCROM represents an important link between existing research reference models and the real-world design and implementation of systems for managing practice-based primary care clinical trials. Although the high degree of correspondence between PCROM and existing research reference models provides evidence for validity and comprehensiveness, existing models require object extensions and modifications to serve primary care research.


Wide Remote-Range and Accurate Wireless LC Temperature-Humidity Sensor Enabled by Efficient Mutual Interference Mitigation.
Inductor-capacitor wireless integrated sensors (LCWISs) featuring untethered and multitarget measurements are promising in health monitoring and human-machine interfaces. However, the lack of a profound understanding of the internal interference hinders the design of the LCWIS, which has a wide remote sensing range and high accuracy. Herein, a mutually exclusive effect of the mutual inductance interferences in LCWIS was revealed and quantified, enabling a design with a wide range of remote sensing (working distance comparable to the single-target device, working radius: 4 mm) and 16% reduced area. As a key to accurate multitarget measurement, a quantified target interference model based on interference decomposition was proposed to understand the target interferences, providing profound guidance for the design of ultra-accurate LCWIS. As a proof, we designed a cellulose-polyacrylate-cellulose LCWIS (CPC-LCWIS) with ultrahigh accuracies (∼1.2% RH and ∼0.18 °C) beyond commercial wired gauges. The CPC-LCWIS with full-coil sensing structures achieved exceptionally high sensitivities (0.36 MHz/°C and 0.25 MHz/% RH). The CPC-LCWIS was validated for health monitoring and human-machine interfaces. The concept studied in this work provides profound guidance for designing a high-performance flexible LCWIS for advanced wearable electronics.


Large Perivascular Spaces Visible on Magnetic Resonance Imaging, Cerebral Small Vessel Disease Progression, and Risk of Dementia: The Age, Gene/Environment Susceptibility-Reykjavik Study.
With advancing age, an increased visibility of perivascular spaces (PVSs) on magnetic resonance imaging (MRI) is hypothesized to represent impaired drainage of interstitial fluid from the brain and may reflect underlying cerebral small vessel disease (SVD). However, whether large perivascular spaces (L-PVSs) (>3 mm in diameter) visible on MRI are associated with SVD and cognitive deterioration in older individuals is unknown. To examine whether L-PVSs are associated with the progression of the established MRI markers of SVD, cognitive decline, and increased risk of dementia. The prospective, population-based Age, Gene/Environment Susceptibility-Reykjavik Study assessed L-PVSs at baseline (September 1, 2002, through February 28, 2006) on MRI studies of the brain in 2612 participants. Participants returned for additional MRI from April 1, 2007, through September 30, 2011, and underwent neuropsychological testing at the 2 time points a mean (SD) of 5.2 (0.2) years apart. Data analysis was conducted from August 1, 2016, to May 4, 2017. The presence, number, and location of L-PVSs. Incident subcortical infarcts, cerebral microbleeds, and progression of white matter hyperintensities detected on MRI; cognitive decline defined as composite score changes between baseline and follow-up in the domains of memory, information processing speed, and executive function; and adjudicated incident dementia cases diagnosed according to international guidelines. Of the 2612 study patients (mean [SD] age, 74.6 [4.8] years; 1542 [59.0%] female), 424 had L-PVSs and 2188 did not. The prevalence of L-PVSs was 16.2% (median number of L-PVSs, 1; range, 1-17). After adjusting for age, sex, and interval between baseline and follow-up scanning, the presence of L-PVSs was significantly associated with an increased risk of incident subcortical infarcts (adjusted risk ratio, 2.54; 95% CI, 1.76-3.68) and microbleeds (adjusted risk ratio, 1.43; 95% CI, 1.18-1.72) and a greater 5-year progression of white matter hyperintensity volume. The presence of L-PVSs was also associated with a steeper decline in information processing speed and more than quadrupled the risk of vascular dementia. All associations persisted when further adjusted for genetic and cerebrovascular risk factors. The associations with cognitive outcomes were independent of educational level, depression, and other SVD MRI markers. Large PVSs are an MRI marker of SVD and associated with the pathogenesis of vascular-related cognitive impairment in older individuals. Large PVSs should be included in assessments of vascular cognitive impairment in the older population and as potential targets for interventions.


[A case of malignant peritoneal mesothelioma without deletion of p16].
The patient was a man in his 60s with a history of 2 operations for the treatment of malignant neurogenic tumors. Partial resection of the stomach and liver was performed in December 2006, followed by chemotherapy with adriamycin and interferon; resection of a recurrent tumor in the left subphrenic space was performed in December 2007. In June 2011, recurrent tumors were detected in the lesser curvature of the stomach body and left inferior quadrant of the abdomen (12 mm [SUVmax 7.9] and 23 mm [SUVmax 10.5], respectively)by using 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET). The tumors resected in August 2011 were diagnosed as malignant peritoneal mesothelioma on immunohistochemical analysis. In February 2013, FDG-PETrevealed a 20-mm tumor of in the mesentery with a SUVmax of 7.6, and the tumor was resected. This secondary tumor had the same features of the previously resected malignant mesothelioma. Fluorescence in situ hybridization revealed no deletion of the p16 gene, and the patient had had no other recurrence during follow-up. Malignant peritoneal mesothelioma is a rare disease, accounting for 10% of all malignant mesothelioma cases, with low rates of p16 gene deletion compared with malignant pleural mesothelioma. Previous studies have reported that the lack of p16 deletion is associated with better prognosis in malignant pleural mesothelioma. Herein, we report of a patient diagnosed with malignant peritoneal mesothelioma, without deletion of the p16 gene, who survived for over 2 years and 10 months after initial diagnosis of malignant mesothelioma.


Synthesis and identification of 3-(4-hydroxy-1-naphthoxy)lactic acid as a metabolite of propranolol in the rat, in man, and in the rat liver 9000 g supernatant fraction.
The formation of 3-(4-hydroxy-1-naphthoxy)lactic acid (4-HO-NLA) from propranolol was investigated. Authentic 4-HO-NLA was synthesized from 4-methoxy-1-naphthol using methods previously used for preparation of naphthoxylactic acid (NLA). Cleavage of the 4-methyl ether was accomplished using iodotrimethylsilane in the presence of cyclopentene. After ip administration of propranolol-3,3-d2 (P-3,3-d2) (20 mg/kg) to rats, 4-HO-NLA-d2 was identified by GC-MS as a urinary metabolite. After administering pseudoracemic propranolol (S-P-d0/R-P-3,3-d2) ip to rats (20 mg/kg), parent ions of 4-HO-NLA-d0 and -d2 as methyl ester-trifluoroacetyl derivatives were monitored by GC-MS. 4-HO-NLA arose stereoselectively from S-propranolol (S/R ratio 2.6). After administering approximately equimolar quantities of 4-HO-P and P-3,3-d2 (10 mg/kg each, ip), only 4-HO-NLA-d2 arising from metabolism of P-3,3-d2 was observed by GC-MS indicating that 4-HO-P is probably not an important metabolic intermediate in vivo. In vitro experiments in the presence of the rat liver supernatant fraction performed with P-3,3-d2, NLA, and 4-HO-P showed that only NLA led to 4-HO-NLA. Incubation of NLA also produced two other hydroxylated NLA regioisomers. Incubation of 4-methoxypropanolol, a more lipophilic congener of 4-HO-P, produced no lactic acid metabolite in the presence of the rat liver supernatant fraction, indicating that poor lipophilicity is not the only deterrent to N-dealkylation of the side chain of 4-HO-P.(ABSTRACT TRUNCATED AT 250 WORDS)


Secondary hyperparathyroidism status in Brazil: Brazilian census of parathyroidectomy.
Secondary hyperparathyroidism (SHP) is a common and serious complication of chronic kidney disease (CKD), with a negative impact on morbidity and mortality. Despite advances in the clinical management of SHP, treatment failure still occurs in a significant number of patients. In such cases, parathyroidectomy (PTx) is indicated. To have an overview of the prevalence of severe SHP and of its surgical treatment in hemodialysis (HD) patients in Brazil. This was an observational and descriptive study. Data were obtained from questionnaires posted to 660 dialysis units (DU). Results are expressed in absolute values and percentages, or means and standard deviation, as appropriate. 226 (34%) DU answered the questionnaire, providing data about 32,264 HD patients. The prevalence rate of severe SHP (PTH > 1,000 pg/mL) was 10.7 % (n = 3,463). 68 hospitals countrywide perform PTX. Around 40% of them are university centers. 49 (21.7%) DU reported not to have a specialized medical center to refer their patients with severe SHP. 74 (33%) DU reported that the time interval between surgery indication and its performance was over 6 months. The main recognized obstacles to surgery performance were: difficulty to perform the preoperative exams, lack of head and neck surgeons and the long waiting time. Although severe SHP is highly prevalent in Brazil, a significant number of patients do not have access to PTx. Better public health policies and liaison between nephrologists and head and neck surgeons are urgently required to change this reality.