Influenza B-induced refractory cardiogenic shock: a case report.
An association between influenza A viruses and myocarditis was noted during the 1918 influenza pandemic. Since then, the link between the influenza B virus and fulminant myocarditis or cardiogenic shock has been rarely reported. In February 2013, a 50 year-old-woman without known heart disease presented in profound cardiogenic shock with a left ventricular ejection fraction of 10%. Her presentation was preceded by six days of fever, chills, myalgia and fatigue. She had a junctional tachycardia, a troponin I of 12.6 ng/ml and her coronary angiography demonstrated normal coronary arteries. Percutaneous extracorporeal membrane oxygenation was required. An endotracheal aspirate at admission was positive for influenza B. All other respiratory, blood and urine cultures were negative. On day 7, a repeat echocardiography demonstrated significant recovery of left ventricular function with an ejection fraction of 50%. She was later discharged home in good condition. Influenza B infection can be complicated by fulminant cardiomyopathy leading to cardiogenic shock in adults without preexisting cardiac disease.


Scanning ultrafast electron microscopy.
Progress has been made in the development of four-dimensional ultrafast electron microscopy, which enables space-time imaging of structural dynamics in the condensed phase. In ultrafast electron microscopy, the electrons are accelerated, typically to 200 keV, and the microscope operates in the transmission mode. Here, we report the development of scanning ultrafast electron microscopy using a field-emission-source configuration. Scanning of pulses is made in the single-electron mode, for which the pulse contains at most one or a few electrons, thus achieving imaging without the space-charge effect between electrons, and still in ten(s) of seconds. For imaging, the secondary electrons from surface structures are detected, as demonstrated here for material surfaces and biological specimens. By recording backscattered electrons, diffraction patterns from single crystals were also obtained. Scanning pulsed-electron microscopy with the acquired spatiotemporal resolutions, and its efficient heat-dissipation feature, is now poised to provide in situ 4D imaging and with environmental capability.


[Cell transplantation: current treatments and future prospects].
Regenerative medicine aims to replace a body function or specific cell loss. It includes therapies at the forefront of modem medicine, issuing from translational biomedical research. Transplantation of organs and cells has revolutionized the management of patients for whom medical treatment is a failure. Unfortunately, organ shortage is limiting treatment possibility. As an example, among the 15,000 patients with type I diabetes in Switzerland, only approximately 30 can receive a pancreas or an islet transplant per year. Second example, 500 patients die each year in Switzerland from alcoholic cirrhosis because no treatment is available. Transplantation of islet cells, hepatocytes, mesenchymal stem cells or dopaminergic neurons represents hope fora therapy available for large populations of patients.


Efficacy of Psychological Intervention for Children with Concurrent Posttraumatic Stress Disorder and Mild Traumatic Brain Injury.
Posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are common conditions following motor vehicle accidents (MVAs). Mild TBI and PTSD not only share similar features but may also coexist and interact. Nonetheless, research on psychotherapeutic interventions for PTSD in patients with a history of mTBI, particularly regarding pediatric populations, is limited. The present study compared the efficacy of the prolonged exposure treatment protocol for children and adolescents (PE-A) with PTSD and mTBI (n = 16) versus PTSD alone (n = 21); treatment commenced at least 3 months following an MVA. Emotional status and cognitive functioning were assessed pre- and postintervention using questionnaires and standardized neuropsychological tests. Participants from both groups benefitted from the intervention, as reflected in their emotional status via increased ratings of well-being and decreased ratings of PTSD, anxiety, depression, and postconcussive symptoms, η2 = .21-.50. Ratings of cognitive function also improved for cognitive flexibility, η2 = .30; executive function in everyday life, η2 = .27; and attention and inhibition, η2 = .16. Parental PTSD was the strongest predictor of improvement after intervention, sr2 = .35. Thus, it appears that PE-A is an effective intervention for children with MVA-related PTSD regardless of its comorbidity with mTBI.


Assessment of nerve damage in the feet of long-distance runners.
To answer the question, "Does long-distance running injure nerves of the feet and legs?" we invited the 25 members of the Rochester Track Club who had run the greatest number of miles in their lifetime to participate in a study that involved neurologic examination, determination of detection thresholds of touch-pressure, vibratory, and cooling sensations of the foot, and evaluation of nerve conduction. None of the runners had clinical symptoms or signs of peripheral neuropathy. Most of them reported having had toe and foot injuries, sometimes associated with short-lived sensory symptoms. A computer-assisted sensory evaluation of the detection threshold for vibratory sensation of the toe revealed slightly, but significantly, higher values in the runners in comparison with age- and sex-matched control subjects. Similarly, small, but statistically significant, differences were also observed for some attributes of nerve conduction in the leg and foot nerves of the runners. These results suggest that long-distance running causes multiple small injuries to the toes and feet, which lead to measurable differences in the detection threshold for vibratory sensation and in nerve conduction but not to overt neuropathy. The trivial subclinical neuropathic deficits we noted are readily offset by the assumed health and recreational benefits of running.


Inverse Association between Metformin and Amiodarone-Associated Extracardiac Adverse Events.
Background: The association between metformin and amiodarone-induced adverse events was examined using spontaneous adverse event database. Additionally, the association between other antidiabetic drugs and amiodarone-induced adverse events were also examined. Methods: A total of 6,153,696 reports from the first quarter of 2004 through the fourth quarter of 2015 were downloaded from the US Food and Drug Administration adverse event reporting system. Reporting odds ratio (ROR) and information component (IC) were used to detect associations between antidiabetic drugs and amiodarone-associated adverse events. Additionally, subset data analysis was performed to investigate whether the use of antidiabetic drugs further increased or decreased the risk of adverse events in patients receiving amiodarone therapy. Next, the RORs were adjusted for coadministered antidiabetic drugs using logistic regression analysis. Results: By whole dataset analysis, significant inverse associations were found between metformin and interstitial lung disease (ROR 0.84, 95% confidence interval [CI] 0.79-0.90; IC -0.24, 95% CI -0.33 to -0.15). In the subset data analysis, metformin (ROR 0.62, 95%CI 0.43-0.89; IC -0.63, 95%CI -1.14 to -0.11), sulfonylureas (ROR 0.53, 95%CI 0.32-0.85; IC -0.85, 95%CI -1.53 to -0.17), and dipeptidyl peptidase-4 (DPP-4) inhibitors (ROR 0.25, 95%CI 0.08-0.78; IC -1.66, 95%CI -3.08 to -0.23) were inversely associated with hyperthyroidism. Additionally, metformin (ROR 0.43, 95%CI 0.33-0.57; IC -1.09, 95%CI -1.49 to -0.69), sulfonylureas (ROR 0.64, 95%CI 0.48-0.86; IC -0.59, 95%CI -1.00 to -0.17), and DPP-4 inhibitors (ROR 0.47, 95%CI 0.27-0.81; IC -0.99, 95%CI -1.76 to -0.22) were inversely associated with interstitial lung disease. In the logistic regression analyses, DPP-4 inhibitors (adjusted ROR 0.32, 95% CI 0.10-1.00) and metformin (adjusted ROR 0.46, 95% CI 0.34-0.62) were inversely associated with amiodarone-associated hyperthyroidism and interstitial lung disease, respectively. Conclusion: Metformin is a candidate drug to reduce the risk of amiodarone-induced hyperthyroidism and interstitial lung disease.


Cigarette smoking negatively affects healing response following flap debridement surgery.
The purpose of the present parallel design, controlled clinical trial was to evaluate the treatment outcome following flap debridement surgery (FDS) in cigarette smokers compared to non-smokers. After initial therapy, 57 systemically healthy subjects with moderate to advanced periodontitis who presented with one area (at least 3 teeth) where surgery was required were selected. Twenty-eight patients (mean age: 39.6 years, 20 males) were smokers (> or = 10 cigarettes/day); 29 patients (mean age: 43.9 years, 7 males) were non-smokers. Full-mouth plaque (FMP) and bleeding on probing (BOP) scores, probing depth (PD), clinical attachment level (CAL), and recession depth (RD) were assessed immediately before and 6 months following surgery. Only sites with presurgery PD > or = 4 mm were used for statistical analysis. Presurgery FMP and BOP were similar in smokers and non-smokers and significantly decreased postsurgery in both groups. Overall, PD reduction and CAL gain were greater, although not significantly, in non-smokers (2.4 +/- 0.9 mm and 1.6 +/- 0.7 mm, respectively) than in smokers (1.9 +/- 0.7 mm and 1.2 +/- 0.7 mm, respectively). For moderate sites (PD 4 to 6 mm), no significant differences in PD and CAL changes were found between groups. For deep sites (PD > or = 7 mm), PD reduction was 3.0 +/- 1.0 mm in smokers and 4.0 +/- 0.8 mm in non-smokers, and CAL gain amounted to 1.8 +/- 1.1 mm in smokers and 2.8 +/- 1.0 mm in non-smokers (P = 0.0477). In smokers, 16% of deep sites healed to postsurgery PD values < or = 3 mm as compared to 47% in non-smokers (P = 0.0000); 58% of deep sites in smokers showed a CAL gain > or = 2 mm, as compared to 82% in non-smokers (P = 0.0000). Results of the study indicated that: 1) FDS determined a statistically significant PD reduction and CAL gain in patients with moderate to advanced periodontitis; 2) smokers exhibited a trend towards less favorable healing response following FDS compared to non-smokers, both in terms of PD reduction and CAL gain; and 3) this trend reached clinical and statistical significance at sites with initial deep PD.


Leptospirosis Cases among Outpatients with Non-Malaria Fever Attending Primary Care Clinics during the Rainy Season in Bobo Dioulasso, Burkina Faso.
Leptospirosis is presumably an important cause of non-malarial fever in West Africa. In this study, outpatients consulting in primary care clinics during the rainy season were tested for leptospirosis, and clinical characteristics associated with leptospirosis cases were explored. Patients with fever ≥ 39°C were recruited in nine primary health care centers in Bobo Dioulasso (Burkina Faso). Diagnosis of malaria was ruled out using a rapid diagnostic test (RDT; SD Bioline Malaria®). Leptospirosis cases were defined as patients who tested positive for Leptospira IgM (Leptocheck-WB RDT and Leptospira IgM ELISA assay, Panbio) or DNA in plasma (LipL32 polymerase chain reaction [PCR]). Among 350 patients, 202 tested positive for malaria and were excluded, and 148 met the eligibility criteria and were included. Among these, 26 subjects were considered to be leptospirosis cases: 23 tested positive for Leptospira IgM (15.5%) and three tested positive by PCR (2.2%). Headaches, abdominal symptoms, and myalgia were frequently reported without any difference between leptospirosis cases and negative cases. Cough was more frequently observed among subjects testing positive for leptospirosis (P = 0.02). Water exposure, presence of a skin injury, and walking barefoot were associated with a Leptospira-positive test. All leptospirosis cases recovered without sequelae. A significant portion of outpatients with non-malarial febrile illness during the rainy season in Burkina Faso had epidemiological factors associated with leptospirosis and tested positive for Leptospira. The favorable outcome of leptospirosis cases was reassuring; this could be due in particular to the young age of the patients.


FnCpf1: a novel and efficient genome editing tool for Saccharomyces cerevisiae.
Cpf1 is a new class II family of CRISPR-Cas RNA-programmable endonucleases with unique features that make it a very attractive alternative or complement to Cas9 for genome engineering. Using constitutively expressed Cpf1 from Francisella novicida, the present study demonstrates that FnCpf1 can mediate RNA-guided DNA cleavage at targeted genomic loci in the popular model and industrial yeast Saccharomyces cerevisiae. FnCpf1 very efficiently and precisely promoted repair DNA recombination with efficiencies up to 100%. Furthermore, FnCpf1 was shown to introduce point mutations with high fidelity. While editing multiple loci with Cas9 is hampered by the need for multiple or complex expression constructs, processing itself a customized CRISPR array FnCpf1 was able to edit four genes simultaneously in yeast with a 100% efficiency. A remarkable observation was the unexpected, strong preference of FnCpf1 to cleave DNA at target sites harbouring 5'-TTTV-3' PAM sequences, a motif reported to be favoured by Cpf1 homologs of Acidaminococcus and Lachnospiraceae. The present study supplies several experimentally tested guidelines for crRNA design, as well as plasmids for FnCpf1 expression and easy construction of crRNA expression cassettes in S. cerevisiae. FnCpf1 proves to be a powerful addition to S. cerevisiae CRISPR toolbox.


A consecutive preparation method based upon accelerated solvent extraction and high-speed counter-current chromatography for isolation of aesculin from Cortex fraxinus.
A consecutive preparation method based upon accelerated solvent extraction (ASE) coupled with high-speed counter-current chromatography (HSCCC) was presented and aesculin was obtained from Cortex fraxinus. The extraction condition of ASE was optimized with response surface methodology; some significant parameters such as the solvent system and its stability, the amount of loading sample in HSCCC were also investigated. The original sample was first extracted with methanol at 105°C and 104 bar for 7 min using ASE, then the extracts were consecutively introduced into the HSCCC system and separated and purified with the same ethyl acetate/n-butanol/water (7:3:10, v/v/v) solvent system for five times without further exchange and equilibrium. About 3.1 ± 0.2 mg/g in each time and total of 15.4 mg/g aesculin with purity over 95% was isolated from Cortex fraxinus. The results demonstrated that the consecutive preparation method was time and solvent saving and high throughput, it was suitable for isolation of aesculin from Cortex fraxinus, and also has good potential on the separation and purification of effective compounds from natural product.


A randomized trial of behavioral physical therapy interventions for acute and sub-acute low back pain (NCT00373867).
Psychological factors consistent with fear-avoidance models are associated with the development of chronic low back pain (LBP). As a result, graded activity (GA) and graded exposure (GX) have been suggested as behavioral treatment options. This clinical trial compared the effectiveness of treatment-based classification (TBC) physical therapy alone to TBC augmented with GA or GX for patients with acute and sub-acute LBP. Our primary hypothesis was that GX would be most effective for those with elevated pain-related fear. In total, 108 patients enrolled in this clinical trial and were randomly assigned to receive TBC, GA, or GX. Outcomes were assessed by a blinded evaluator at 4 weeks and by mail at 6 months. The primary outcomes for this trial were disability and pain intensity, and the secondary outcomes were fear-avoidance beliefs, pain catastrophizing, and physical impairment. There were no differences in 4-week and 6-month outcomes for reduction of disability, pain intensity, pain catastrophizing, and physical impairment. GX and TBC were associated with larger reductions in fear-avoidance beliefs at 6 months only. Six-month reduction in disability was associated with reduction in pain intensity, while 6-month reduction in pain intensity was associated with reductions in fear-avoidance beliefs and pain catastrophizing. This trial suggests that supplementing TBC with GA or GX was not effective for improving important outcomes related to the development of chronic LBP.


Interleukin-37 protects against acinar cell pyroptosis in acute pancreatitis.
Acute pancreatitis (AP) is a local and/or systemic inflammatory disease that starts with acinar cell injury and necrosis; it has no effective medical treatment and thus remains a life-threatening condition. Interleukin-37 (IL-37), a natural immunomodulator, has demonstrated an antiinflammatory effect; however, the role of IL-37 in AP remains unknown. The serum IL-37 levels of 39 healthy controls and 94 patients with AP were measured. Cholecystokinin was applied to induce pancreatic acinar cell injury in vitro. Classical experimental AP models, such as caerulein, l-arginine, and taurolithocholic acid 3-sulfate disodium salt, were included in the in vivo study. A transgenic mouse model with the IL-37 gene and administration of recombinant IL-37 were used to further investigate the function of IL-37 in AP. Pancreas-specific gasdermin D-knockout (GSDMD-knockout) mice were used to explore the protective mechanism of IL-37. Our results showed that serum IL-37 levels in humans were negatively correlated with the severity of AP. Furthermore, IL-37-transgenic mice and supplementation with recombinant IL-37 could both protect against AP. Mechanistically, IL-37 was able to suppress pyroptosis of injured acinar cells, and specific depletion of GSDMD in the pancreas counteracted the protective effect of IL-37. Our study demonstrates that IL-37 protects against acinar cell pyroptosis in AP.


Diagnostic application of genotypic identification of mycobacteria.
This study evaluated conventional methods, GLC and three molecular tests, including 16S rRNA sequencing, for the identification of mycobacteria, and the experiences of the authors with the integration of these methods into a diagnostic clinical laboratory were also recorded. Of 1067 clinical isolates of mycobacteria identified by conventional tests, 365 were tested by Accuprobe hybridization assays and PCRs specific for Mycobacterium tuberculosis (MTB) complex or Mycobacterium avium complex (MAC), 202 were tested by 16S rRNA sequencing, and 142 were tested by GLC. Three runs of all tests were performed on a weekly basis. The identifications for 209 MTB complex and 118 MAC isolates obtained by species-specific PCR were in complete agreement with AccuProbe hybridization and conventional test results. The 16S rRNA sequence-based identification, at a similarity of > or =99 %, for 132 of 142 isolates was concordant with the identifications made by the biochemical methods, and for 134 isolates was concordant with the identifications made by GLC at species, group or complex level. 16S rRNA sequencing resulted in fewer incorrectly identified or unidentified organisms than GLC or conventional tests. For the slowly growing non-tuberculous mycobacteria, the mean turnaround times for identification were 4-5 days for 16S rRNA sequencing, 14-29 days for GLC and 22-23 days for conventional methods. Considering the large proportion of some species among clinical isolates, a strategy of initial screening with species-specific PCR (or AccuProbe assays) for the MTB complex and MAC, followed by direct sequencing of the strains that yield negative results, should make 16S rRNA sequencing more affordable for routine application in diagnostic laboratories.


Predictive variables of depressive symptoms and anxiety in older adults from primary care: a cross-sectional observational study.
By 2050, the number of people aged 60 years and older will have doubled worldwide and the most common mental disorders in this age group are currently depressive symptoms and anxiety. This study aimed to analyze the Basic and Instrumental Activities of Daily Living (BADLs and IADLs, respectively) in older adults; socio-demographic, clinical, lifestyle, and environmental variables; and cognitive impairment related to the appearance of depressive symptoms and anxiety. A cross-sectional observational study was conducted with 327 participants aged ≥65 years in primary care. The variables were Yesavage's Geriatric Depression Scale, the Goldberg Anxiety Subscale, socio-demographic, clinical, lifestyle, environmental variables, BADLs, IADLs, and the Spanish version of the Mini-Mental State Examination. An analysis of variance was carried out for the predictive multiple linear regression models. '≥ 1 chronic pathology' and 'low dependency' in BADL are negatively associated with anxiety, while 'physical activity' and 'low dependency' in BADL are associated with positive factors for depressive symptoms. Predictor variables could improve the early detection of anxiety and depressive symptoms by general practitioners and serve as a basis for future studies and personalised-adapted cognitive stimulation programs.


[Evaluation of microcirculatory disorders in shock patients].
The microcirculatory status depicts an indicator of organ perfusion in hemodynamic shock. Distribution pattern of microcirculatory disturbances reflects the underlying cause of shock: In septic shock, organ perfusion is severely impaired via arteriolo-venous shunting with shutting up small vessel perfusion; however, cardiogenic shock is characterized by a global impairment of microcirculation, involving all vascular beds. Hence, a differentiated evaluation of microcirculatory disturbances not only supports an early diagnosis of an imminent multiorgan dysfunction syndrome (MODS), but also allows a more accurate evaluation of severity of hemodynamic compromise in critical care medicine. Bedside sidestream darkfield (SDF) technique offers the opportunity to describe the microcirculatory status quo semiquantitatively and to evaluate the effect of novel therapeutic approaches on microcirculation. Further technical improvements of this technique may open new fields of diagnostic and therapeutic applications in intensive care medicine by supporting an early diagnosing of MODS, evaluating prognosis, and optimizing therapeutic measures .


Genotyping of hepatitis C virus isolates using CLIP sequencing.
Determination of hepatitis C virus (HCV) genotypes and subtypes has become increasingly important for the clinical management and prognosis of HCV infections. The aim of the present study was to assess the specificity and reliability of a newly developed, commercially available HCV genotyping kit (TRUGENE HCV 5'NC genotyping kit). This technique utilizes PCR fragments previously generated by the diagnostic Roche AMPLICOR HCV test, which are subsequently subjected to simultaneous PCR amplification and direct sequencing (CLIP sequencing) of the 5' noncoding region (5'NCR). HCV isolates from 100 randomly chosen patients were genotyped by both the TRUGENE HCV 5'NC genotyping kit and DNA enzyme immunoassay (DEIA). Typing results obtained by both methods were in complete concordance in 91% of the cases. HCV RNA from the samples with discordant genotype assignment in both assays was additionally amplified with primers from the HCV core and NS5B regions. Phylogenetic analysis of the obtained sequences supported the results obtained from DEIA in six cases and CLIP sequencing in two cases. In the former six cases, the TRUGENE HCV 5'NC genotyping kit could not correctly differentiate between subtypes of genotypes 1 and 2 due to the high conservation of the 5'NCR. However, since there was not any misclassification between HCV genotypes 1 and non-1 types, the results obtained with this system are, in general, reliable and can be used in clinical practice. The TRUGENE HCV 5'NC genotyping kit in our hands proved to be a fast and convenient technique that might be an attractive option for HCV genotyping in laboratories already using the Roche AMPLICOR HCV test for diagnostic reverse transcription-PCR.


Neuroprotection and Beyond: The Central Role of CB1 and CB2 Receptors in Stroke Recovery.
The endocannabinoid system, with its intricate presence in numerous cells, tissues, and organs, offers a compelling avenue for therapeutic interventions. Central to this system are the cannabinoid receptors 1 and 2 (CB1R and CB2R), whose ubiquity can introduce complexities in targeted treatments due to their wide-ranging physiological influence. Injuries to the central nervous system (CNS), including strokes and traumatic brain injuries, induce localized pro-inflammatory immune responses, termed neuroinflammation. Research has shown that compensatory immunodepression usually follows, and these mechanisms might influence immunity, potentially affecting infection risks in patients. As traditional preventive treatments like antibiotics face challenges, the exploration of immunomodulatory therapies offers a promising alternative. This review delves into the potential neuroprotective roles of the cannabinoid receptors: CB1R's involvement in mitigating excitotoxicity and CB2R's dual role in promoting cell survival and anti-inflammatory responses. However, the potential of cannabinoids to reduce neuroinflammation must be weighed against the risk of exacerbating immunodepression. Though the endocannabinoid system promises numerous therapeutic benefits, understanding its multifaceted signaling mechanisms and outcomes remains a challenge.


Accuracy of intensity and inclinometer output of three activity monitors for identification of sedentary behavior and light-intensity activity.
Purpose. To examine the accuracy of intensity and inclinometer output of three physical activity monitors during various sedentary and light-intensity activities. Methods. Thirty-six participants wore three physical activity monitors (ActiGraph GT1M, ActiGraph GT3X+, and StepWatch) while completing sedentary (lying, sitting watching television, sitting using computer, and standing still) light (walking 1.0 mph, pedaling 7.0 mph, pedaling 15.0 mph) intensity activities under controlled settings. Accuracy for correctly categorizing intensity was assessed for each monitor and threshold. Accuracy of the GT3X+ inclinometer function (GT3X+Incl) for correctly identifying anatomical position was also assessed. Percentage agreement between direct observation and the monitor recorded time spent in sedentary behavior and light intensity was examined. Results. All monitors using all thresholds accurately identified over 80% of sedentary behaviors and 60% of light-intensity walking time based on intensity output. The StepWatch was the most accurate in detecting pedaling time but unable to detect pedal workload. The GT3X+Incl accurately identified anatomical position during 70% of all activities but demonstrated limitations in discriminating between activities of differing intensity. Conclusions. Our findings suggest that all three monitors accurately measure most sedentary and light-intensity activities although choice of monitors should be based on study-specific needs.


The hip labrum reconstruction: indications and outcomes--a systematic review.
With further understanding of the function and the importance of the hip labrum, greater attention has been paid to preserve and repair the damaged labrum. Hip labrum reconstruction has been described to optimize hip preservation when the labrum is deficient. This systematic review aimed to explore and identify the reported indications and outcomes in patients who undergo labral reconstruction of the hip joint. The electronic databases EMBASE, MEDLINE, and PubMed were searched for all available dates up to July 2013. Further hand search of the reference sections of the included studies was done. Two reviewers searched, screened, and evaluated the included studies for data quality using the Methodological Index for Non-Randomized Studies (MINORS) Scale. Data were also abstracted in duplicate, and agreement and descriptive statistics are presented. There were 5 eligible studies (3 case series, 1 prospective cohort, and 1 retrospective chart review) with a total of 128 patients, and an average 11/16 quality on the MINORS score included in this review. All patients were diagnosed with femoroacetabular impingement and underwent labral reconstruction. Ninety-four patients were assessed at follow-up (73.4 % survivorship) between a reported mean range of 10 and 49 months. There was variability between the studies with regard to the graft types utilized (ilio-tibial band, Gracilis tendon, Ligamentum teres), surgical approaches [open (18.7 %) vs. arthroscopic (81.3 %)], and the reported outcome measures. Overall, improvement was observed in the patient-reported outcomes and functional scores (mHHS, HOS, UCLA, NASH, and SF-12). The failure rate or conversion to THA rate in all available patients was 20 %. The most common indication for labrum reconstruction was a young, active patient with minimal arthritis and non-salvageable or deficient labrum. Other indications included instability, pain, and hypotrophic dysfunctional labrum. Based on the current available evidence, hip labrum reconstruction is a new technique that shows short-term improvement in patient-reported outcomes and functional scores post-operatively. The main indication for reconstruction was a deficient labrum due to previous surgical excision or irreparable tears in young patients with no significant arthritis. Long-term follow-up results with higher quality studies are still lacking based on this review.


NMR use to quantify phlorotannins: the case of Cystoseira tamariscifolia, a phloroglucinol-producing brown macroalga in Brittany (France).
Among the most renowned natural products from brown algae, phlorotannins are phloroglucinol polymers that have been extensively studied, both for their biotechnological potential and their interest in chemical ecology. The accurate quantification of these compounds is a key point to understand their role as mediators of chemical defense. In recent years, the Folin-Ciocalteu assay has remained a classic protocol for phlorotannin quantification, even though it frequently leads to over-estimations. Furthermore, the quantification of the whole pool of phlorotannins may not be relevant in ecological surveys. In this study, we propose a rapid (1)H qNMR method for the quantification of phlorotannins. We identified phloroglucinol as the main phenolic compound produced by the brown macroalga Cystoseira tamariscifolia. This monomer was detected in vivo using (1)H HR-MAS spectroscopy. We quantified this molecule through (1)H qNMR experiments using TSP as internal standard. The results are discussed by comparison with a standard Folin-Ciocalteu assay performed on purified extracts. The accuracy and simplicity of qNMR makes this method a good candidate as a standard phlorotannin assay.


Biosecurity's unruly spaces.
This paper is about the geopolitics of animal health governance. Through a biosecurity event in South Africa's pig sector we examine changes in the way the governance of disease risk is configuring intra-national spaces. Our case suggests an emerging geopolitics of animal health, one that is defined not by differences between nations but by a more complex patchwork of 'secure' and 'unruly spaces'.


Bladder irrigation after transurethral resection of superficial bladder cancer: a systematic review of the literature.
The vast majority of bladder cancer is non-muscle invasive with transurethral resection (TURBT) as the gold standard for surgical treatment. There is a high recurrence of bladder cancer post surgery, which adds to the frustration in current urologic practice. Current standard of care to further reduce bladder cancer recurrence is instillation of intravesical chemotherapy (ICT), a practice that is not routinely followed. Several studies point to similar effects with normal saline or water irrigation alone. Our objective is to review the current available literature and provide practicing urologist with an alternative to ICT. A systematic search was performed through December 2017. Peer reviewed studies, which evaluated recurrence free survival (RFS) after bladder irrigation with saline or sterile water (SW) post-TURBT were included. Outcomes were analyzed in three groups: ICT, saline and sterile water. Six studies out of 981, including 1515 patients, were eligible. There was no significant difference between ICT, saline and SW groups regarding to the median RFS at 1 year [ICT: 81%, IQR (77.70, -81.00), SW: 74%, IQR (63.3-74.9), saline: 76.7% IQR (76.0, 77.7), p = 0.21]. While saline irrigation showed the highest median RFS among the groups, there was no statistically significant difference between the three groups [ICT: 70%, IQR (66.25, 73.75), SW: 64.1%, IQR (63.05, 65.15), saline: 73%, IQR (66.85, 74.50), p = 0.49]. Adverse events were more frequent amongst patients in the ICT group in comparison to the saline or water groups. Saline and sterile water irrigation provide an alternative to ICT with equivalent recurrence rate and lower incidence of adverse events.


The Severe Deficiency of the Somatotrope GH-Releasing Hormone/Growth Hormone/Insulin-Like Growth Factor 1 Axis of Ghrh-/- Mice Is Associated With an Important Splenic Atrophy and Relative B Lymphopenia.
A debate is still open about the precise control exerted by the somatotrope GH-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor 1 axis on the immune system. The objective of this study was to directly address this question through the use of Ghrh-/- mice that exhibit a severe deficiency of their somatotrope axis. After control backcross studies and normalization for the reduced global weight of transgenic mice, no difference in weight and cellularity of the thymus was observed in Ghrh-/- mice when compared with C57BL/6 wild-type (WT) control mice. Similarly, no significant change was observed in frequency and number of thymic T cell subsets. In the periphery, Ghrh-/- mice exhibited an increase in T cell proportion associated with a higher frequency of sjTREC and naïve T cells. However, all Ghrh-/- mice displayed an absolute and relative splenic atrophy, in parallel with a decrease in B cell percentage. GH supplementation of transgenic mice for 6 weeks induced a significant increase in their global as well as absolute and relative splenic weight. Interestingly, the classical thymus involution following dexamethasone administration was shown to recover in WT mice more quickly than in mutant mice. Altogether, these data show that the severe somatotrope deficiency of Ghrh-/- mice essentially impacts the spleen and B compartment of the adaptive immune system, while it only marginally affects thymic function and T cell development.


In vivo dose estimations through transit signal measured with thimble chamber positioned along the central axis at electronic portal imaging device level in medical linear accelerator in carcinoma of the middle-third esophagus patients undergoing three-dimensional conformal radiotherapy.
This study presents a method to estimate midplane dose (Diso, transit) in vivo from transit signal (St) measured with thimble ionization chamber in cancer of the middle-third esophagus patients treated with three-dimensional radiotherapy (RT). This detector is positioned at the level of electronic portal imaging device in the gantry of a medical linear accelerator. Efficacy of inhomogeneity corrections of three dose calculation algorithms available in XiO treatment planning system (TPS) for planned dose (for open fields) (Diso, TPS) was studied with three heterogeneous phantoms. Diso, transit represents measured signal at transit point (St) far away correlating to dose at isocenter. A locally fabricated thorax phantom was used to measure the in vivo midplane dose (Diso, mid) which was also estimated through St. Thirteen patients with carcinoma of the middle-third esophagus treated with three-dimensional conformal RT were studied. St was recorded (three times, with a gap of 5-6 fractions during the treatment) to estimate Diso, transit, which was compared with the doses calculated by TPS. The dose predictions by superposition algorithm were superior compared to the other algorithms. Percentage deviation of Diso, transit, Diso, mid with Diso, TPS combined all fields was 2.7 and -2.6%, respectively, with the thorax phantom. The mean percentage deviation with standard deviation of estimated Diso, transit with Diso, TPS observed in patients was within standard deviation -0.73% ±2.09% (n = 39). Midplane dose estimates in vivo using this method provide accurate determination of delivered dose in the middle-third esophagus RT treatments. This method could be useful in similar clinical circumstances for dose confirmation and documentation.


Primary Triple Arthrodesis for Management of Rigid Flatfoot Deformity.
Primary triple arthrodesis is a powerful and reliable procedure for stabilizing and correcting painful rigid flatfoot deformities with a low rate of complications. Pay careful attention to the history, physical examination, and weight-bearing radiographic studies as they are critical for selecting patients who will benefit from a triple arthrodesis. Position the patient supine on the operating table with the toes pointing straight up to the ceiling. For a standard triple arthrodesis, use 2 incisions: a lateral sinus tarsi incision, which allows exposure of the subtalar joint, CC joint, and lateral aspect of the TN joint, and a medial incision, which provides exposure of the TN joint. Ensure that joint preparation is thorough as this is critical for the success of any hindfoot arthrodesis. Reduce the TN joint first, followed by the subtalar joint, restoring a plantigrade foot and approximately 5° of hindfoot valgus alignment. Perform rigid fixation of the subtalar joint first, followed by fixation of the TN and CC joints. Accessory procedures are often required in addition to the triple arthrodesis to ensure that appropriate hindfoot alignment and a plantigrade foot are achieved. Perform a staged wound closure, taking care to maximize soft-tissue coverage over the involved hindfoot joints. Ensure that the patient follows strict non-weight-bearing precautions in the immediate postoperative period to limit micromotion at the arthrodesis sites and allow for timely fusion. In one of the largest published series of patients managed with triple arthrodesis (111 patients), Pell et al. reported a union rate of 98% at a minimum follow-up of 2 years, with 91% of patients indicating that they would be willing to repeat the procedure under similar circumstances4.


Perspectives of identity by descent (IBD) mapping in founder populations.
In a founder population patients with a genetic disease are likely to share predisposing genes from a common ancestor. We show that, depending on the distance of the relationship, patients are expected to share extended segments of DNA around the disease gene. Because of the size of the shared segment, a genomic search with DNA markers for such shared segments, identity by descent (IBD) mapping, can efficiently find the map position of genes, particularly due to genetic drift leading to reduction of heterogeneity and the large number of meioses that is implicitly observed. The statistical power of this method and the approximate cost are given as a function of the density of the map of tested markers and the number of generations since a common ancestor. Initial marker spacings between 5 and 15 centiMorgans are shown to be optimal. IBD mapping is applicable to many genetic diseases, because it does not presuppose a specific genetic model.


Controversies associated with the evaluation of elderly men with localized prostate cancer when considering radical prostatectomy.
The incidence of prostate cancer in Japan is increasing due to both the spread of screening and the rapid aging of the population. Most of this increase is expected to be attributable to the increase in the elderly male population. The management of various types of cancers in elderly patients is of growing interest, but several problems are encountered when evaluating elderly patients with localized prostate cancer, especially when radical prostatectomy (RP) is under consideration. First, life expectancy, health status, lifestyle, and available treatment modalities differ between regions, countries, and individuals, which potentially affects the choice of treatment options by both physicians and patients. Second, life expectancy is key when considering indications for RP. Many tools are available for predicting life expectancy, but their utilization varies greatly among physicians. Third, the malignant potential of latent or incidentally detected prostate cancer in Japanese men might be higher than those in other countries, and elderly men with prostate cancer are likely to have high-risk or locally advanced tumors, which may in turn support the more frequent use of radical treatments in elderly men. Fourth, patients treated with RP are likely to have fewer and less severe comorbidities than those treated with other treatments, which would complicate the comparison of outcomes. Fifth, the balance between survival benefits and adverse effects is an important influence on indications for RP. If robot-assisted laparoscopic RP can reduce the risk of adverse effects, indications for RP could be altered. Sixth, although several general health status screening tools such as the Geriatric 8 are available, no screening tools specialized for localized or Japanese prostate cancer patients exist. In conclusion, further study is needed to clarify the management of elderly Japanese patients with localized prostate cancer, because prostate cancer often requires different considerations to other types of cancer.


Oral or parenteral administration of replication-deficient adenoviruses expressing the measles virus haemagglutinin and fusion proteins: protective immune responses in rodents.
The genes encoding the measles virus (MV) haemagglutinin (H) and fusion (F) proteins were placed under the control of the human cytomegalovirus immediate early promoter in a replication-deficient adenovirus vector. Immunofluorescence and radioimmune precipitation demonstrated the synthesis of each protein and biological activity was confirmed by the detection of haemadsorption and fusion activities in infected cells. Oral as well as parenteral administration of the H-expressing recombinant adenovirus elicited a significant protective response in mice challenged with MV. While the F-expressing adenovirus failed to protect mice, cotton rats immunized with either the H- or F-expressing recombinant showed reduced MV replication in the lungs. Antibodies elicited in mice following immunization with either recombinant had no in vitro neutralizing activity, suggesting a protective mechanism involving a cell-mediated immune response. This study demonstrates the feasibility of using oral administration of adenovirus recombinants to induce protective responses to heterologous proteins.


Mating, ovulation and corpus luteum function in the vole, Microtus agrestis.
A study of the relationship between the mating vehaviour of the vole and the induction of ovulation and CL function is described. A single intromission or an injection of LH-RF constitute stimuli which induce ovulation, but normally give rise to CL that degenerate soon after formation. More prolonged mating, or mechanical stimulation of the vagina and cervix given after a separate ovulatory stimulus, result in the maintenance of the CL. Mechanical genital stimulation is effective in inducing CL MAINTENANCE WHEN GIVEN UP TO 48 HR AFTER AN LH-RF injection. Similarities, therefore, are apparent between the vole, an induced oculator, and spontaneous ovulator, and spontaneous ovulators such as the rat, mouse and hamster.


Outcome Measures in Critical Care Nutrition Interventional Trials: A Systematic Review.
Historically, randomized controlled trials (RCTs) in critical care have used mortality as the primary outcome, yet most show no effect on this outcome. Therefore, there has been a shift in the literature to focus on alternative outcomes. This review aimed to describe primary outcomes selected in RCTs of nutrition interventions in critical illness. Systematic search of the literature identified RCTs of nutrition interventions in critically ill adults published between January 2007 and December 2018. Primary outcomes were documented and categorized as mortality, morbidity, health service/cost-effectiveness, or nutrition outcome. The direction of effect of the intervention on the primary outcome (positive, neutral, or negative) was extracted. Of 1163 citations identified and assessed for eligibility, 125 articles were included. However, 52 articles (42%) did not provide a sample-size calculation, leaving 73 articles (58%) for data extraction. The primary outcomes reported were morbidity (n = 24, 32.9%); health service/cost-effectiveness (n = 21, 28.8%); nutrition outcomes (n = 16, 21.9%); mortality (n = 11, 15.1%); and other (n = 1, 1.4%). No RCTs with mortality as the primary outcome reported a difference between intervention and control. Trials that included other primary outcomes frequently reported a difference (n = 27 of 62; 43.5%). Morbidity was the most frequently reported outcome category in RCTs that evaluated a nutrition intervention in critically ill adults, with mortality least frequent. Power calculations were only reported in 58% of included studies. Trials were more likely to show a significant result when an outcome other than mortality was the primary outcome.


An Update on the Emerging Role of Wnt/β-catenin, SYK, PI3K/AKT, and GM-CSF Signaling Pathways in Rheumatoid Arthritis.
Rheumatoid arthritis is an untreatable autoimmune disorder. The disease is accompanied by joint impairment and anomalies, which negatively affect the patient's quality of life and contribute to a decline in manpower. To diagnose and treat rheumatoid arthritis, it is crucial to understand the abnormal signaling pathways that contribute to the disease. This understanding will help develop new rheumatoid arthritis-related intervention targets. Over the last few decades, researchers have given more attention to rheumatoid arthritis. The current review seeks to provide a detailed summary of rheumatoid arthritis, highlighting the basic description of the disease, past occurrences, the study of epidemiology, risk elements, and the process of disease progression, as well as the key scientific development of the disease condition and multiple signaling pathways and enumerating the most current advancements in discovering new rheumatoid arthritis signaling pathways and rheumatoid arthritis inhibitors. This review emphasizes the anti-rheumatoid effects of these inhibitors [for the Wnt/β-catenin, Phosphoinositide 3-Kinases (PI3K/AKT), Spleen Tyrosine Kinase (SYK), and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) signaling pathways], illustrating their mechanism of action through a literature search, current therapies, and novel drugs under pre-clinical and clinical trials.


A system for converting print into braille.
This paper describes a method for converting text into braille, in the form in which it is stored as in a computer. The system has been designed to be configurable for a wide range of languages and character sets, and uses a predominantly table driven method to achieve this. The algorithm is explained in the context of the conversion of text into Standard English Braille (British), and the tables for this transformation are given. Particular importance has been attached to enabling braille specialists, who are not experts in computer algorithms, to be able to modify the system for either slight modifications to an existing braille code translator, or for producing a braille code translator for a new language.


Characteristics and regulatory mechanisms of the amiloride-blockable Na+ channel.
Studies of active Na+ transport across intact amphibian skin and bladder epithelia and, more recently, epithelial cells in culture have served as prototypes for understanding transport function in other experimentally less accessible epithelia such as renal tubules, lung, and sweat glands. Epithelia of diverse phylogenetic origin contain amiloride-blockable Na+ channels that are undoubtedly involved in the regulation of transepithelial Na+ transport and electrolyte homeostasis. With the advent of the techniques of tissue culture, patch clamp, isotope flux measurements in native vesicles and liposomes, and planar lipid bilayer reconstitution, it has now become possible for the first time to explore the functional operation and regulation of this widespread and important transport protein at the molecular level. Epithelial transport physiology has now reached a point where investigators can embark on studies concerning the cellular and molecular biology of epithelial Na+ channels. In our opinion, concentrated experimental efforts should be directed in three general areas. First, detailed kinetic information concerning the molecular mechanisms of Na+ movement through this channel is required. For example, it is necessary to elucidate the nature (i.e., site and location) of channel block by amiloride and structurally related compounds, the structural determinants of its ion selectivity, the voltage dependence of amiloride and ion blockage, and the minimal number of polypeptide subunits required for channel activity. The second area of study concerns the nature of the regulation of this ion channel. What are the mechanisms of channel regulation and, specifically, how does cAMP and aldosterone activate or recruit these Na+ channels? Does regulation occur at the level of channel synthesis, through posttranslational modifications, or via noncovalent interactions with small molecules or peptides? Third, we feel that the isolation and purification of the Na+ channel is important because it will eventually enable investigators to establish the molecular details of ion movement through individual channels, i.e., structural correlates of ion selectivity, binding and blockade by amiloride, and ion flow. The isolation of the Na+ channel will allow the development of molecular probes of the channel protein. These probes will be useful for immunocytochemical localization studies and, ultimately, will lead to sequencing and site-directed mutagenesis studies. Also, questions concerning the homology between Na+ channels found in different tissues and organisms as well as between the different modes of amiloride-sensitive transporters can be addressed.


Alpha/beta T-cell antigen receptor gene and protein expression occurs at early stages of thymocyte differentiation.
Alterations in gene expression that orchestrate eukaryotic cellular differentiation often require appropriate interactions between differentiating cells and a specialized microenvironment. During T-lymphocyte differentiation, immature thymocytes undergo a stringent intrathymic selection process that requires intimate contact with thymic stromal elements. Since this selection process generates T cells that are self-tolerant and recognize nominal antigen only within the context of self-major histocompatibility antigen complex molecules, it is possible that thymocyte/stromal cell interactions are mediated, in part, by antigen-specific receptors expressed on differentiating thymocytes. However, the developmental stage at which alpha/beta antigen-specific receptors are expressed during T-cell maturation has been a matter of debate. To address this issue, we have studied alpha/beta T-cell antigen receptor gene and protein expression on normal thymocyte subsets of AKR/J mice, as well as on a panel of AKR/J primary thymic lymphomas characterized for CD4 (L3T4) and CD8 (Lyt-2) differentiation antigen expression. The data unequivocally demonstrate that alpha/beta heterodimers are expressed not only on phenotypically mature thymocytes but also on the majority of CD4+8+ double-positive cells that comprise the predominant nonmature thymocyte subset. Furthermore, a fraction of thymocytes in the CD4-8- double-negative compartment, known to contain progenitor cells, also expresses readily detectable cell-surface alpha/beta receptors. Therefore, during the process of intrathymic selection, interactions between nonmature thymocytes and stromal cells via the antigen-receptor complex may play a pivotal role in T-cell differentiation and should be considered in formulating schemes for functional T-cell selection.


Shared Decision-Making for Patients with Advanced Urological Malignancies: Evaluation of a Joint Urological-Oncological Clinic Model.
To provide rapid evaluation of patients with advanced urological malignancies, a joint urological-oncological clinic was initiated at our institution in January 2015. We present the first 3-year evaluation of this joint urological-oncological clinic in Switzerland. We performed a retrospective analysis of the characteristics and treatment of all patients reviewed at the joint clinic between January 2015 and December 2017. Statistical analysis was performed by survival analysis. A patient satisfaction questionnaire was handed out to new patients (from April to September 2017). A total of 135 new patients were counseled in the joint clinic and 563 consultations were performed in the period from January 2015 to December 2017. The majority were men with prostate cancer (85%), followed by bladder cancer (9%), and renal cell carcinoma (4%). Men with newly diagnosed metastatic prostate cancer (n = 69) received ADT alone (57%), ADT with docetaxel or abiraterone (33%), and metastasis-directed therapy (10%). High rates of patient satisfaction were reported based on the questionnaire. The joint clinic model has been successfully implemented at our institution and continues on a weekly basis. The clinic is increasingly used, not only for newly diagnosed metastatic prostate cancer, but also for other complex uro-oncological cases. The clinic allows optimized oncological treatment without delay and with a reduced effort for patients.


The worm has turned: unexpected similarities between the transcription of enhancers and promoters in the worm and mammalian genomes.
Our understanding of biological processes in humans is often based on examination of analogous processes in other organisms. The nematode worm Caenorhabditis elegans has been a particularly valuable model, leading to Nobel prize winning discoveries in development and genetics. Until recently, however, the worm has not been widely used as a model to study transcription due to the lack of a comprehensive catalogue of its RNA transcripts. A recent study by Chen et al. uses next-generation sequencing to address this issue, mapping the transcription initiation sites in C. elegans and finding many unexpected similarities between the transcription of enhancers and promoters in the worm and mammalian genomes. As well as providing a valuable resource for researchers in the C. elegans community, these findings raise the possibility of using the worm as a model to investigate some key, current questions about transcriptional regulation that remain technically challenging in more complex organisms.


Temozolomide (Temodal) for treatment of primary brain tumours.
Although the outlook for patients with malignant gliomas continues to be very poor, progress in neurosurgery and radiotherapy, supported by new development in chemotherapy, offer some hope for the future. Temozolomide has recently been introduced by Schering-Plough Ltd (Welwyn Garden City, UK) as a new treatment which merits further investigation in this situation.


Enhancing employee creativity: Effects of choice, rewards and personality.
We conducted a quasi-experimental field study of an organization-wide suggestion program and a follow-up laboratory experiment to examine the effects of choice of rewards on employee creativity. As hypothesized, the results of both studies showed that choice had positive, significant effects on the number of creative ideas employees generated and the creativity level of those ideas. Results of the quasi-experiment also showed that creative self-efficacy (CSE) mediated the effects of reward choice. Two general categories of rewards were examined in our studies-those that directly benefited the idea generator (Self) and those that directly benefited charities (Other). We explored the effects of these reward categories on employee creativity and whether employee creative personality interacted with the reward categories to affect employee creativity. Results showed that the reward categories did not have a significant impact on employee creativity. However, both studies demonstrated that in the Other reward condition, employees with a creative personality produced ideas higher in creativity than those with a less creative personality. The quasi-experiment also showed that CSE mediated the effects of the Reward × Creative Personality interaction. We discussed the implications of these results for the future research and practice. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


From chronic liver disorders to hepatocellular carcinoma: Molecular and genetic pathways.
Hepatocarcinogenesis is a process attributed to progressive genomic changes that alter the hepatocellular phenotype producing cellular intermediates that evolve into hepatocellular carcinoma (HCC). During the preneoplastic phase, the liver is often the site of chronic hepatitis and/or cirrhosis, and these conditions induce liver regeneration with accelerated hepatocyte cycling in an organ that is otherwise proliferatively at rest. Hepatocyte regeneration is accelerated by upregulation of mitogenic pathways involving molecular and genetic mechanisms. Hepatic growth factors, inhibitors and triggers may also play a role. This process leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that have telomerase re-expression, microsatellite instability, and occasionally structural aberrations in genes and chromosomes. Development of dysplastic hepatocytes in foci and nodules and the emergence of HCC are associated with the accumulation of irreversible structural alterations in genes and chromosomes even if the genomic basis of the malignant phenotype is largely heterogeneous. Therefore, a malignant hepatocyte phenotype may be produced by changes in genes acting through different regulatory pathways, thus producing several molecular variants of HCC. On these bases, a key point for future research will be to determine whether the deletions are specific, due to particular loci in the minimally deleted regions of affected chromosome arms, or whether they are non-specific with loss of large portions of chromosomes or entire chromosome arms leading to passive deletion of loci. The final aim is the possibility of identifying a step where carcinogenetic processes could be terminated.


Effectiveness of GeneXpert® in the diagnosis of tuberculosis in people living with HIV/AIDS.
To identify and synthesize the scientific knowledge produced regarding the effectiveness of the GeneXpert test in the diagnosis of pulmonary tuberculosis (TB) in people living with HIV/AIDS. Integrative literature review, which was searched on Embase, Scopus, PubMed, Cinahl, Academic Search Premier, Socindex, and LILACS platforms, in December 2019. The studies surveyed went through two stages of selection: reading of titles and abstracts by two reviewers independently; using the Rayyan platform and reading. Nineteen primary studies in English, Portuguese, and Spanish that answered the study's guiding question were included: How effective is the GeneXpert test in the diagnosis of pulmonary TB in people living with HIV/AIDS? The use of GeneXpert substantially increased the detection of TB cases among the population co-infected with HIV/AIDS, with sensitivity ranging from 68% to 100%, superior to sputum smear microscopy. Specificity ranged from 91.7% to 100%; the positive predictive value from 79.2% to 96.1%; and the negative predictive value from 84.6% to 99.3%. These values were considered similar to sputum smear microscopy by most studies. We also compared these results with different ways of performing culture and other molecular tests, being considered inferior only to the Xpert Ultra. It is possible to affirm that places with a high incidence of HIV/AIDS would benefit from the implementation of the GeneXpert test, entailing effectiveness in diagnosing pulmonary TB in this population when compared to sputum smear microscopy, a widely used test for detection of cases.


Compliance of children and youngsters in the use of mouthguards.
The purpose of the study was to examine the compliance of children wearing their mouthguards, and to evaluate socio-environmental factors that impact upon the usage of the device. Eighty children attending the student clinic of the Hadassah School of Dental Medicine received mouthguards free of charge. One year later, 69 participants and their parents answered a survey aimed at gaining information regarding compliance and comfort when wearing the mouthguard correlated with gender, ages of parents and child, number of siblings, position of child in the family, socio-economic status, education of parents and past dental injuries of siblings or parents. Twenty-nine percent of the children never wore the mouthguard, 32% wore it sometimes, 15.9% wore it when necessary at the beginning but stopped after one month and 23.2% wore the mouthguard whenever needed. About 68% of the participants still possessed the mouthguard one year after receiving it, 44.9% reported that they did not wear the mouthguard because they forgot and 42% reported that the reason for not wearing the appliance was because it was not comfortable. Seventy-seven percent of the parents were not aware of the existence of this appliance prior to this study. In addition, 47.9% stated that dentists had not offered such treatment to them in the past, 20.8% indicated that their child had never possessed a mouthguard before due to its significant expense and 39.6% stated that they would not invest in this treatment in the future because their child would not wear the appliance. Boys were more comfortable wearing the mouthguard than girls. The younger the child and the later s/he was in the sibling order of the family, the more likely s/he was to lose the mouthguard.


Patient perceptions of orthognathic surgery.
A retrospective study of ninety orthognathic surgery patients was conducted to investigate (1) their presurgical concerns and motivations, (2) their preoperative preparation for surgery, and (3) their perceptions of the postsurgical outcome. All subjects completed a twenty-three-item questionnaire and Rotter's Locus of Control Inventory. Statistical date analyses were performed by means of frequency distributions, chi-square, Spearman's r, and Fisher's exact probability tests. The results are presented as thirteen tentative conclusions categorized into three broad areas: motivations and concerns, presurgical preparation, and postsurgical outcome. In the area of motivations and concerns, those with primarily esthetic motivations have less initial reticence toward having orthognathic surgery and less difficulty adjusting to their new appearance than those with strong functional incentives. Younger patients and those patients with strong cosmetic motivations are less concerned about surgical risks. Under the category of presurgical preparation, more females than males desire to speak to a previous orthognathic surgery patient. Patients who receive inadequate explanation of the surgical procedure are more likely to be emotionally unprepared. One of the leading factors in patient dissatisfaction with surgery is the patient's experience of postoperative "surprises." In the area of postsurgical outcome, two-jaw operations precipitate more pain complaints than single-arch procedures. With time, however, patients tend to forget the degree of postoperative pain. Maxillary surgical procedures lead to less severe pain complaints than mandibular procedures, but there are more initial complaints of breathing difficulties and sinus problems following maxillary procedures. Surgical goal fulfillment does not guarantee that a patient would re-elect to have the treatment.


A novel blue luminescent material Na2[Co(C2O4)2(H2O)2]·6H2O: synthesis, structure, luminescence and magnetic properties.
The synthesis, crystal structure and physical properties of new disodium trans-diaquabis(oxalato)cobaltate(ii)hexahydrate {Na2[Co(C2O4)2(H2O)2]·6H2O} crystals have been investigated. Single crystal X-ray analysis reveals that this compound crystallizes in the triclinic system with the space group P1[combining macron]. The structure of this complex consists of [Co(C2O4)2(H2O)2](2-) anionic units with a slightly distorted octahedral geometry of cobalt surrounded by four oxygen atoms of two oxalate groups. The anionic units are interlinked by two Na(+) ions with different octahedral and distorted octahedral environments. The electronic absorption spectra of the compound exhibit bands at 208, 246 and 526 nm in the UV and visible regions. A strong blue luminescence was observed at room temperature when excited at 355 nm. The M(H) curve at 2 K shows a significant nonlinear behaviour with almost zero coercivity which clearly indicates an extremely weak antiferromagnetic/ferromagnetic state of the complex.


Aspergillus fumigatus mycovirus causes mild hypervirulent effect on pathogenicity when tested on Galleria mellonella.
Mycoviruses are a specific group of viruses that naturally infect and replicate in fungi. The importance of mycoviruses was revealed after their effects were identified not only in economically important fungi but also in the human pathogenic fungus Aspergillus fumigatus. The latter was shown recently to harbor at least three different types of mycoviruses including a chrysovirus, a partitivirus and an as yet uncharacterized virus. Assessment of virulence in the presence and absence of mycoviruses in A. fumigatus is pivotal to understanding its pathogenicity. Here, we have investigated, for the first time, the effects of mycoviruses on the pathogenicity of A. fumigatus as assessed using larvae of the greater wax moth Galleria mellonella. In order to observe the effects of mycoviruses on pathogenicity, G. mellonella were injected with virus-free and virus-infected isolates of A. fumigatus and post-infection survival times were analyzed along with the fungal burden. Neither chrysovirus nor partitivirus infection affected fungal pathogenicity when survival rates were assessed which, for the chrysovirus, agreed with a previous study on murine pathogenicity. However statistically significant differences were observed in survival rates and fungal burden in the presence of the uncharacterized A78 virus. Here we show, for the first time, the effects of a partitivirus and an uncharacterized A78 virus on the pathogenicity of A. fumigatus.


No effect of anti-TNF-α agents on the surgical stress response in patients with inflammatory bowel disease undergoing bowel resections: a prospective multi-center pilot study.
TNF-α plays a role in angiogenesis and collagen synthesis, both essential in the wound healing process. There are concerns that pre-operative anti-TNF-α treatment may influence the surgical stress response and increase the risk of surgical complications. The aim of this study was to describe the surgical stress response in patients with inflammatory bowel disease (IBD) and to investigate whether the pre-operative administration of anti-tumor necrosis factor alpha (anti-TNF-α) agents modify the surgical stress response. This was a prospective, multi-center cohort pilot study. The primary outcome was the change in concentration of immunological biomarkers of the surgical stress response (TNF-α, IL-6, and IL-10). Secondary outcome measures were changes in IL-8, IL-17A, C-reactive protein, white blood cells, cortisol, transferrin, ferritin, and D-Dimer in addition to 30 days' post-operative complications and length of post-operative stay in the hospital (LOS). Forty-six patients with IBD undergoing major abdominal surgery were included, and 18 received anti-TNF- α treatment pre-operatively. Peak increase of most of the immunological biomarkers occurred 6 hours after surgical incision. Then the concentration decreased after 24 h followed by a plateau at 48 h. After adjusting for confounders including detectable blood concentrations, no difference in the concentrations of immunological, endocrinological or haematological biomarkers of stress was found between anti-TNF-α treated and anti-TNF-α naïve patients. No increase in post-operative complications or LOS was noticed in patients who received anti-TNF-α treatment. Anti-TNF-α did not affect surgical stress response in this pilot study. Withdrawal of anti-TNF-α drugs prior to surgical intervention in IBD patients might not be justified without measurement of drug concentration and drug antibodies. Clinicaltrails.gov.: NCT01974869 .


Homozygous/compound heterozygote RYR1 gene variants: Expanding the clinical spectrum.
The ryanodine receptor 1 (RYR1) is a calcium release channel essential for excitation-contraction coupling in the sarcoplasmic reticulum of skeletal muscles. Dominant variants in the RYR1 have been well associated with the known pharmacogenetic ryanodinopathy and malignant hyperthermia. With the era of next-generation gene sequencing and growing number of causative variants, the spectrum of ryanodinopathies has been evolving with dominant and recessive variants presenting with RYR1-related congenital myopathies such as central core disease, minicore myopathy with external ophthalmoplegia, core-rod myopathy, and congenital neuromuscular disease. Lately, the spectrum was broadened to include fetal manifestations, causing a rare recessive and lethal form of fetal akinesia deformation sequence syndrome (FADS)/arthrogryposis multiplex congenita (AMC) and lethal multiple pterygium syndrome. Here we broaden the spectrum of clinical manifestations associated with homozygous/compound heterozygous RYR1 gene variants to include a wide range of manifestations from FADS through neonatal hypotonia to a 35-year-old male with AMC and PhD degree. We report five unrelated families in which three presented with FADS. One of these families was consanguineous and had three affected fetuses with FADS, one patient with neonatal hypotonia who is alive, and one individual with AMC who is 35 years old with normal intellectual development and uses a wheelchair. Muscle biopsies on these cases demonstrated a variety of histopathological abnormalities, which did not assist with the diagnostic process. Neither the affected living individuals nor the parents who are obligate heterozygotes had history of malignant hyperthermia.


Human DnaJB6 Antiamyloid Chaperone Protects Yeast from Polyglutamine Toxicity Separately from Spatial Segregation of Aggregates.
Polyglutamine (polyQ) aggregates are associated with pathology in protein-folding diseases and with toxicity in the yeast Saccharomyces cerevisiae Protection from polyQ toxicity in yeast by human DnaJB6 coincides with sequestration of aggregates. Gathering of misfolded proteins into deposition sites by protein quality control (PQC) factors has led to the view that PQC processes protect cells by spatially segregating toxic aggregates. Whether DnaJB6 depends on this machinery to sequester polyQ aggregates, if this sequestration is needed for DnaJB6 to protect cells, and the identity of the deposition site are unknown. Here, we found DnaJB6-driven deposits share characteristics with perivacuolar insoluble protein deposition sites (IPODs). Binding of DnaJB6 to aggregates was necessary, but not enough, for detoxification. Focal formation required a DnaJB6-Hsp70 interaction and actin, polyQ could be detoxified without sequestration, and segregation of aggregates alone was not protective. Our findings suggest DnaJB6 binds to smaller polyQ aggregates to block their toxicity. Assembly and segregation of detoxified aggregates are driven by an Hsp70- and actin-dependent process. Our findings show sequestration of aggregates is not the primary mechanism by which DnaJB6 suppresses toxicity and raise questions regarding how and when misfolded proteins are detoxified during spatial segregation.


Unicompartmental Knee Arthroplasty: Survivorship and Risk Factors for Revision: A Population-Based Cohort Study with Minimum 10-Year Follow-up.
Operative management for end-stage knee osteoarthritis (OA) primarily consists of arthroplasty. Total knee arthroplasty (TKA) is the so-called gold standard for multicompartmental OA. In selected patients, specifically those with unicompartmental OA and no definite contraindications, realignment osteotomies and unicompartmental knee arthroplasty (UKA) are viable options. UKA offers several advantages over TKA, including preservation of both cruciate ligaments, faster recovery, and less osseous resection. The purpose of this study was to determine the survivorship of UKAs and risk factors for all-cause revision surgery in patients with a minimum follow-up of 10 years in a large population-based database. We performed a population-based cohort study using linked administrative databases in Ontario, Canada. We identified all UKAs performed from January 2002 through December 2006. All patients had a minimum 10-year follow-up. Demographic data and outcomes were summarized using descriptive statistics. We used a Cox proportional hazards model with the Fine and Gray method accounting for competing risks such as death to analyze the effect of surgical and patient factors on the risk of revision of UKA. A total of 4,385 patients were identified as having undergone primary UKA from 2002 through 2006 in Ontario. Of these patients, 779 underwent revision surgery, for a cumulative risk for all-cause revision of 16.5% at 10 years (95% confidence interval [CI]: 15.4% to 17.7%). Mechanical loosening was the reason for 83.4% of all revisions. Male sex, diabetes, an age younger than 50 years, and cementless implants were significant risk factors for revision surgery. Residence in a rural or urban setting, income quintile, discharge destination, and type of OA were not associated with the risk of revision. Survivorship at 1, 5, 10, and 15 years was 97.2%, 90.5%, 83.5%, and 81.9%, respectively. This study demonstrated a >80% long-term survivorship for UKA based on a large administrative database sample and identified important risk factors for failure including male sex, younger age, diabetes, and cementless fixation. This study found rates of survivorship similar to those previously reported in the literature, while identifying key risk factors for failure. Patient selection has always been identified as a key factor in ensuring successful UKA, and the risk factors identified in this study may help guide decision-making for surgeons and patients dealing with unicompartmental knee OA. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


The laryngeal primordium and epithelial lamina. A new interpretation.
The laryngeal primordium is present in both the laryngotracheal sulcus (LTS) and the primitive pulmonary sac (PPS). Its early period of development may be subdivided into two phases. The first phase (Stage 11) is represented by what is traditionally referred to as the LTS, located directly beneath the PP4 on the ventral wall of the foregut (primary segment), and by the PPS which is situated at its caudal end. The LTS will represent the primordium of the upper or membranous infraglottic cavity region; whereas the PPS, will give rise not only to the bronchial tree, but also to the primordium of the trachea and the lower or cartilaginous region of the infraglottic cavity. The second phase (Stages 13 and 14) is distinguished by the cranial growth of the LTS above the PP4 and therefore by its absorption into the floor of the primitive pharynx in the mesobranchial area (secondary segment), which will develop into the primordium of the vestibule of the larynx. Similarly, we observed that in the development of the laryngeal cavity there are two temporally and spatially separate epithelial structures: the epithelial septum and the epithelial lamina. In this respect we differ from other authors who are of the opinion that there is a single structure (the epithelial lamina). The epithelial septum is a primary structure responsible for the final configuration of the LTS, as it contributes to the development of the lower end of the primary segment of the LTS and also to the creation of the secondary segment. The epithelial lamina is a secondary structure which appears inside the LTS as a result of pressure exerted by the mesenchyme on its lateral walls, without having any effect on the morphogenesis of the LTS.


Numerical simulations of vorticity banding of emulsions in shear flows.
Multiphase shear flows often show banded structures that affect the global behavior of complex fluids e.g. in microdevices. Here we investigate numerically the banding of emulsions, i.e. the formation of regions of high and low volume fractions, alternated in the vorticity direction and aligned with the flow (shear bands). These bands are associated with a decrease of the effective viscosity of the system. To understand the mechanism of experimentally observed banding, we have performed interface-resolved simulations of the two-fluid system. The experiments were performed starting with a random distribution of droplets, which under the applied shear, evolve in time resulting in a phase separation. To numerically reproduce this process, the banded structures are initialized in a narrow channel confined by two walls moving in opposite directions. We find that the initial banded distribution is stable when droplets are free to merge and unstable when coalescence is prevented. In this case, additionally, the effective viscosity of the system increases, resembling the rheological behavior of suspensions of deformable particles. Droplet coalescence, on the other hand, allows emulsions to reduce the total surface of the system and, hence, the energy dissipation associated with the deformation, which in turn reduces the effective viscosity.


Should T-Tube Drainage be Performed for Choledocholithiasis after Laparoscopic Common Bile Duct Exploration? A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Laparoscopic common bile duct exploration (LCBDE) has been verified to be a comparatively effective treatment approach for uncomplicated choledocholithiasis, and it has been previously proposed that the primary duct closure (PDC) technique, in which the bile duct can directly be sutured in only 1 step compared with the T-tube drainage (TTD), can be deemed a choice after LCBDE; however, the conventional TTD performance is controversial in the minimally invasive surgery era. On the basis of the above-mentioned point, this meta-analysis was conducted to assess the different effects between TTD and PDC after LCBDE. In PubMed, EMBASE, and the Cochrane Library, literature search was conducted to screen out randomized controlled trials (RCTs) to compare PDC with TTD. The analyzed outcome variables included overall morbidity, biliary-specific morbidity (retained stones, biliary leak, biliary peritonitis), other morbidities, operating time, postoperative hospital stay, reintervention (surgery, endoscopy/radiology), and median hospital expenses. In this meta-analysis, there are 4 RCTs qualifying for inclusion, including 396 patients in all (222 in PDC and 214 in TTD). With respect to postoperative overall morbidity (P<0.05), biliary peritonitis (P<0.05), surgery time (P<0.05), length of stay (P<0.05), and median hospital expenses (P<0.05), PDC presented remarkably better results than TTD (P<0.05). Statistically, no remarkable distinction was found between the 2 groups as to biliary-specific morbidity, retained stones, biliary leak, other morbidities, or reintervention (radiology/endoscopy, surgery). In this meta-analysis, there was no evidence provided for clinical benefits of using TTD after LCBDE. Therefore, TTD should not routinely be performed after LCBDE. However, multicenter, large sample size, RCTs should be conducted to clarify this issue.


Current state of craniofacial prosthetic rehabilitation.
This study aimed to review the current state of the techniques and materials used to rehabilitate maxillofacial defects. The MEDLINE and EMBASE databases were searched for articles pertinent to maxillofacial prostheses published from January 1990 to July 2011. The main clinical stages were the subject of analysis. A multidisciplinary approach is preferred when rehabilitating maxillofacial defects. Surgical reconstruction can be used for smaller defects, but larger defects require a prosthesis to achieve an esthetic rehabilitation. Implant retained prostheses are preferred over adhesive prostheses. Silicone elastomer is currently the best material available for maxillofacial prostheses; however, longevity and discoloration, which are greatly influenced by ultraviolet radiation, microorganisms, and environmental factors, remain significant problems. In the near future, the widespread availability and cost effectiveness of digital systems may improve the workflow and outcomes of facial prostheses. Patients report high satisfaction with their prostheses despite some areas that still need improvement. Maxillofacial prostheses are a reliable treatment option to restore maxillofacial defects and improve quality of life. Significant progress has been made in the application of implants for retention and digital technology for designing surgical guides, suprastructures, and craniofacial prostheses. Further improvements are necessary to enhance longevity of prostheses.


[Retracted] Downregulation of ROS‑FIG inhibits cell proliferation, colony‑formation, cell cycle progression, migration and invasion, while inducing apoptosis in intrahepatic cholangiocarcinoma cells.
Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the western blotting data shown in Fig. 9 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to International Journal of Molecular Medicine, or were under consideration for publication at around the same time. In view of the fact that certain of these data had already apparently been published previously, the Editor of International Journal of Molecular Medicine has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 34: 661‑668, 2014; 10.3892/ijmm.2014.1823].


Web-Based Privacy-Preserving Multicenter Medical Data Analysis Tools Via Threshold Homomorphic Encryption: Design and Development Study.
Data sharing in multicenter medical research can improve the generalizability of research, accelerate progress, enhance collaborations among institutions, and lead to new discoveries from data pooled from multiple sources. Despite these benefits, many medical institutions are unwilling to share their data, as sharing may cause sensitive information to be leaked to researchers, other institutions, and unauthorized users. Great progress has been made in the development of secure machine learning frameworks based on homomorphic encryption in recent years; however, nearly all such frameworks use a single secret key and lack a description of how to securely evaluate the trained model, which makes them impractical for multicenter medical applications. The aim of this study is to provide a privacy-preserving machine learning protocol for multiple data providers and researchers (eg, logistic regression). This protocol allows researchers to train models and then evaluate them on medical data from multiple sources while providing privacy protection for both the sensitive data and the learned model. We adapted a novel threshold homomorphic encryption scheme to guarantee privacy requirements. We devised new relinearization key generation techniques for greater scalability and multiplicative depth and new model training strategies for simultaneously training multiple models through x-fold cross-validation. Using a client-server architecture, we evaluated the performance of our protocol. The experimental results demonstrated that, with 10-fold cross-validation, our privacy-preserving logistic regression model training and evaluation over 10 attributes in a data set of 49,152 samples took approximately 7 minutes and 20 minutes, respectively. We present the first privacy-preserving multiparty logistic regression model training and evaluation protocol based on threshold homomorphic encryption. Our protocol is practical for real-world use and may promote multicenter medical research to some extent.


Depression and heart failure: an overview of what we know and don't know.
Depression is prevalent in patients with heart failure, and the two conditions share underlying physiologic mechanisms. The prevalence of depression increases sharply with the severity of heart failure symptoms, an important consideration when confronting patients with worsening heart failure. Depression leads to poorer outcomes in patients with heart failure, including increased risk of poor functional status, hospital readmission, and death. Although beta-blockers are often implicated in the development and exacerbation of depression, evidence for this association is lacking, so withholding beta-blocker therapy is not recommended for patients with heart failure and depression. Evidence on whether therapy for depression also improves cardiac outcomes in heart failure patients is inconclusive, and further research on this question is needed. Nevertheless, early identification of depression in heart failure patients is imperative, as it can facilitate intervention attempts.


Brachial Plexopathy After Cervical Spine Surgery.
Retrospective, multicenter case-series study and literature review. To determine the prevalence of brachial plexopathy after cervical spine surgery and to review the literature to better understand the etiology and risk factors of brachial plexopathy after cervical spine surgery. A retrospective case-series study of 12 903 patients at 21 different sites was performed to analyze the prevalence of several different complications, including brachial plexopathy. A literature review of the US National Library of Medicine and the National Institutes of Health (PubMed) database was conducted to identify articles pertaining to brachial plexopathy following cervical spine surgery. In our total population of 12 903 patients, only 1 suffered from postoperative brachial plexopathy. The overall prevalence rate was thus 0.01%, but the prevalence rate at the site where this complication occurred was 0.07%. Previously reported risk factors for postoperative brachial plexopathy include age, anterior surgical procedures, and a diagnosis of ossification of the posterior longitudinal ligament. The condition can also be due to patient positioning during surgery, which can generally be detected via the use of intraoperative neuromonitoring. Brachial plexopathy following cervical spine surgery is rare and merits further study.


Immunocompetent Mice As a Model for Preclinical Studies of mRNA Vaccine Immunogenicity.
Conducting preclinical studies of mRNA vaccines is complicated by the lack of relevant animal models of the human immune system. Immunocompetent mice are widely used in biomedical research. However, critical differences in the genetics and immune system of mice and humans prevent the study of unique human immune responses in mice. Within the framework of this work, the possibility of modeling the cytotoxic T-cell response to mRNA vaccines encoding the S-protein of the SARS-CoV-2 virus was investigated. High-affinity peptides from S-protein were analyzed for the most frequent allelic variants of human MHC-I, two immunocompetent mouse lines (C57BL/6, BALB/c) and an outbred mouse model of IRC. The results of computer modeling have shown that mouse models can be used in preclinical studies of mRNA vaccines against SARS-CoV-2. Mouse MHC-I is able to present virus peptides that are highly affine for human MHC-I. Moreover, the immunogenicity of some of them has already been confirmed by examining blood samples from patients who have had COVID-19.


High Plant Protein Diet Ameliorated Hepatic Lipid Accumulation Through the Modulation of Gut Microbiota.
Substituting plant protein for animal protein has emerged as a promising strategy for managing atherogenic lipids. However, the impact of long-term intake of a high plant protein diet (HPD) on hepatic lipid disorder remains unclear. Eight-week-old apolipoprotein E deficient (apoE-/- ) mice are fed with either a normal protein diet (NCD) or HPD for 12 weeks. HPD intervention results in decreased body weight accompanied by increased energy expenditure, with no significant effect on glycemic control. Long-term intake of HPD improves the serum and hepatic lipid and cholesterol accumulation by suppressing hepatic squalene epoxidase (SQLE) expression, a key enzyme in cholesterol biosynthesis. Integrated analysis of 16S rDNA sequencing and metabolomics profiling reveals that HPD intervention increases the abundance of the Lachnospiraece family and serum levels of 12,13-DiHOME. Furthermore, in vivo studies demonstrate that 12,13-DiHOME significantly inhibits lipid accumulation, as well as SQLE expression induced by oleic acid in HepG2 cells. Diet rich in plant protein diet alleviates hyperlipidemia via increased microbial production of 12,13-DiHOME.


Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites.
The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration-response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials.


Worldwide scientific efforts on nursing in the field of SARS-CoV-2: a cross-sectional survey analysis.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been a global public health issue. This study aimed to characterize global nursing research on SARS-CoV-2. Nursing-related publications through December 31, 2022, were identified using Scopus. The number of studies, study types, countries, institutions, journals, authors, h-index, total confirmed cases, total deaths, and the highest-cited studies were investigated. In total, 12,427 studies were identified. The number of studies increased rapidly, particularly between 2020 and 2021, with a 2.36-fold increase. The United States published the most studies (3,289, 26.47%), followed by the United Kingdom (1,059, 8.52%) and China (877, 7.06%). Scientific productivity significantly correlated with the total confirmed cases (r = 0.701, p = 0.024) and total deaths (r = 0.804, p = 0.005). The United States had the highest h-index (80), followed by China (59), and the United Kingdom (57). The University of Toronto published the most studies (181), followed by Harvard Medical School (165), and the University of São Paulo (107). Gravenstein S (23) was the most prolific author, followed by Mor V (22), and Rosa WE (19). The International Journal of Environmental Research and Public Health published the most papers (436), followed by PLOS ONE (219), and BMJ Open (185). Several countries, institutions, journals, and authors contributed greatly to SARS-CoV-2-related nursing studies. Countries with larger numbers of confirmed cases and deaths tended to publish more nursing studies. The United States, United Kingdom, and China had the highest quantity and quality of studies.


Pulsatile antagonism on bradykinin 2-receptor (BK2R) by icatibant triggers the most effective kinin-dependent post-conditioning on rat hearts.
Pharmacological post-conditioning (PC) by intermittent but not continuous administration of exogenous bradykinin (BK) reduces ischemia/reperfusion (I/R) injury via the Reperfusion Injury Salvage Kinase (RISK) pathway activation. We evaluated whether intermittent administration with icatibant (HOE140), a BK2R antagonist, may represent an effective PC strategy, with the advantage of limiting the potential risks of supra-physiologic BK activity. Hearts from male Sprague-Dawley (SD) rats on a Langendorff system were exposed to I/R injury (30/120 min). BK (100 nM) and HOE140 (1 µM) were administered post-ischemically during the first 3 min of reperfusion, under continuous or intermittent infusion (10 s/each). Hearts were randomly assigned to 5 groups: 1) I/R alone (n=5); 2) continuous HOE140 (cHOE n=6); 3) intermittent HOE140 (iHOE n=6); 4) continuous BK (cBK n=6); 5) intermittent BK (iBK n=6). End-diastolic left ventricular pressure (LVEDP), developed left ventricular pressure (dLVP) and coronary flow (CF) were monitored throughout reperfusion. Left ventricular infarct mass (IM) was quantified together with the phosphorylated levels of Akt and GSK3β (RISK pathway kinases) at the end of reperfusion. IM was not significantly changed in cBK or cHOE groups (vs. I/R). Conversely, both iBK and iHOE groups showed a significant limitation in IM (vs. I/R, p<0.05, p<0.01, respectively). Akt and GSK3β phosphorylation levels were higher in iBK and iHOE groups (vs. I/R, p<0.05). When compared to I/R group, both LVEDP values (p<0.05, first 60-min reperfusion), as well as dLVP values (p<0.01) were improved only in iHOE group. CF values did not vary among all groups. In isolated rat hearts, intermittent modulation of the endogenous kallikrein-kinin system by a selective BK2R antagonist mediates PC cardioprotection via RISK signaling.


Correlation between UV dose requirement for lambda bacteriophage induction and lambda repressor concentration.
Escherichia coli K-12 wild type and a uvrA mutant derivative were used to construct isogenic strains bearing one, two, three, or more phage lambda cI genomes and containing increasing concentration of lambda repressor as measured by in vitro operator DNA-binding assays. The survival and phage induction in response to UV irradiation were determined. In both strains, dose-response relationships were obtained as a function of the cellular repressor concentration. The uvrA lysogens required one-tenth the UV fluence of the wild-type counterparts for induction. Lysogenic strains containing plasmids that overproduce the lambdaind+ repressor and the same lysogens with plasmids overproducing the lambdaind- repressor displayed the same survival curves as the nonlysogenic parental strain; however, only the former produced infectious centers (at a frequency of 2 x 10(-3) to 5 x 10(-4) in response to radiation.


Immune regulatory properties of multipotent mesenchymal stromal cells: Where do we stand?
Multipotent mesenchymal stromal cells (MSC) can be isolated and efficiently expanded from almost every single body tissue and have the ability of self-renewal and differentiation into various mesodermal cell lineages. Moreover, these cells are considered immunologically privileged, related to a lack of surface expression of costimulatory molecules required for complete T cell activation. Recently, it has been observed that MSC are capable of suppressing the immune response by inhibiting the maturation of dendritic cells and suppressing the function of T lymphocytes, B lymphocytes and natural killer cells in autoimmune and inflammatory diseases as a new strategy for immunosuppression. The understanding of immune regulation mechanisms by MSC is necessary for their use as immunotherapy in clinical applications for several diseases.