Fluvastatin attenuated ischemia/reperfusion-induced autophagy and apoptosis in cardiomyocytes through down-regulation HMGB1/TLR4 signaling pathway.
Fluvastatin, a traditional fat-decreasing drug, is widely used for curing cardiovascular disease. Previous reports demonstrated that fluvastatin pretreatment protected against myocardial ischemia/reperfusion (I/R) by inhibiting TLR4 signaling pathway and/or reducing proinflammatory cytokines. However, whether fluvastatin has a cardioprotective effect against apoptosis and autophagy remains unknown. This study aims to evaluate whether the cardioprotective role of fluvastatin in I/R is mediated by high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) pathway via anti-apoptotic and anti-autophagic functions. Sprague-Dawley rats were anesthetized, artificially ventilated and subjected to 30 min of coronary occlusion, followed by 4 h of reperfusion. The animals were randomized into four groups: (i) Sham operation; (ii) I/R; (iii) I/R + low-dosage fluvastatin (10 mg/kg); and (iv) I/R + high-dosage fluvastatin (20 mg/kg). After reperfusion, the hemodynamic parameters, myocardial infarct size, structural alteration of myocardium, apoptosis index, pro-inflammatory cytokine production, Beclin-1, Light chain 3 (LC3), HMGB1, TLR4 and Nuclear factor kappa B (NF-κB) protein levels were measured and recorded. It was found that fluvastatin preconditioning improved left ventricular dysfunction, reduced HMGB1/TLR4/NF-κB expressions, and inhibited cardiomyocyte apoptosis, autophagy, and inflammation reaction. Moreover, treatment with fluvastatin ameliorated myocardial injury by reducing infarct size, causing less damage to cardiac structure, downregulating autophagy-related protein expression and releasing pro-inflammation mediators. Our findings indicate that fluvastatin exerts beneficial effects on cardiac ischemic damage, which may be associated with its anti-autophagic and anti-apoptotic functions via inhibition of HMGB1/TLR4-related pathway during I/R injury.


Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma.
Mammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients. Eighty-five mRCC patients received everolimus at Helsinki University Hospital (cohort A). Computed tomography (CT) verified pneumonitis was correlated with outcome using Kaplan-Meier, Cox regression and logistic regression. An independent cohort of 148 everolimus treated mRCC patients (cohort B) at Aarhus University Hospital was assessed for validation. In cohort A, CT-verified pneumonitis (N = 29, 34.1%) was associated with improved overall survival (OS) (24.7 versus 8.5 months; P < 0.001), progression-free survival (PFS) (5.5 versus 3.2 months; P = 0.002) and clinical benefit rate (CBR) 57.1% versus 24.1% (P = 0.003). In multivariate analyses pneumonitis was associated with improved OS (hazard ratio [HR], 0.22; 95% confidence interval [CI] 0.12-0.44; P < 0.001), PFS (HR 0.37; 95% CI 0.21-0.66; P = 0.001) and CBR (odds ratio [OR] 4.11; 95% CI 1.42-11.95; P = 0.01). In cohort B, CT-verified pneumonitis (N = 29, 19.6%) was associated with improved OS (12.9 versus 6.0 months; P = 0.02), PFS (6.0 versus 2.8 months; P = 0.02) and CBR (79.3% versus 39.5%; P < 0.001). In multivariate analyses pneumonitis was associated with improved OS (HR 0.58; 95% CI 0.36-0.94; P = 0.03), PFS (HR 0.61; 95% CI 0.39-0.95; P = 0.03) and CBR (OR 5.65; 95% CI 2.10-15.18; P = 0.001). In a combined multivariate analysis (N = 233), with pneumonitis as a time-dependent covariate, CT-verified pneumonitis was associated with longer OS (HR, 0.67; 95% CI 0.46-0.97; P = 0.03). Furthermore, in a landmark analysis, pneumonitis was associated with longer OS (17.4 versus 7.8 months; P = 0.01). Everolimus-induced pneumonitis is associated with improved outcome in patients with mRCC and may serve as a biomarker of everolimus efficacy.


Hypercoagulability in venous and arterial thrombosis.
The term "hypercoagulability" is used to describe patients who are at increased risk for thrombosis because of inherited defects in their anticoagulant pathways or because of various predisposing causes. About one in five patients of European descent who present with venous thromboembolism have a specific genetic defect in their anticoagulant pathway. In these patients, anticoagulant prophylaxis is indicated at times of high risk, such as after surgery. Prolonged anticoagulant therapy may be required in patients with recurrent or life-threatening thromboemboli, but decisions about this are best made on an individual basis. Patients who present with arterial thrombosis usually develop their disease as a complication of atherosclerosis. However, these patients also have a form of hypercoagulability, manifested primarily by high fibrinogen levels and elevated factor VII activity. Evidence increasingly indicates that these and other hemostatic markers may help in the assessment of patients at risk for coronary heart disease.


A proposed methodology to estimate the cumulative life-time UVB exposure using geographic information systems: An application to multiple sclerosis.
The cause of multiple sclerosis (MS) is unknown; multiple risk factors have been implicated, including environmental exposures, such as sunlight. Many studies have relied on latitude alone as a crude proxy for sunlight exposure. We aimed to develop a protocol allowing a more detailed estimate of cumulative ambient ultra-violet B (UVB) exposure at critical time-periods over a patient's life-course. 4010 definite MS patients with a 'movement history' from birth to the study end (2005) were selected from the University of British Columbia, Canada's MS Genetic database. Patient's place of resident from birth were tracked, each place being geocoded (latitude and longitude) and assigned a UVB value using the NASA Total Ozone Mapping Spectrometer (TOMS) dataset. Combined, these data allowed an estimated UVB value for each patient based on year and location. Using this protocol, we provide a potentially more detailed cumulative UVB exposure for critical periods in a patients' life history based on their individual spatial migration through time. This protocol is intended to provide a framework for researchers to more accurately estimate UVB exposures for individuals over the course of their life history and may be useful for understanding etiology of MS and other chronic disease.


Quantitative EEG measures in profoundly deaf and normal hearing individuals while performing a vibrotactile temporal discrimination task.
Challenges in early oral language acquisition in profoundly deaf individuals have an impact on cognitive neurodevelopment. This has led to the exploration of alternative sound perception methods involving training of vibrotactile discrimination of sounds within the language spectrum. In particular, stimulus duration plays an important role in linguistic categorical perception. We comparatively evaluated vibrotactile temporal discrimination of sound and how specific training can modify the underlying electrical brain activity. Fifteen profoundly deaf (PD) and 15 normal-hearing (NH) subjects performed a vibrotactile oddball task with simultaneous EEG recording, before and after a short training period (5 one-hour sessions; in 2.5-3 weeks). The stimuli consisted of 700 Hz pure-tones with different duration (target: long 500 ms; non-target: short 250 ms). The sound-wave stimuli were delivered by a small device worn on the right index finger. A similar behavioral training effect was observed in both groups showing significant improvement in sound-duration discrimination. However, quantitative EEG measurements reveal distinct neurophysiological patterns characterized by higher and more diffuse delta band magnitudes in the PD group, together with a generalized decrement in absolute power in both groups that might reflect a facilitating process associated to learning. Furthermore, training-related changes were found in the beta-band in NH. Findings suggest PD have different cognitive adaptive mechanisms which are not a mere amplification effect due to greater cortical excitability.


A new method for measuring edge tensions and stability of lipid bilayers: effect of membrane composition.
We report a novel and facile method for measuring edge tensions of lipid membranes. The approach is based on electroporation of giant unilamellar vesicles and analysis of the pore closure dynamics. We applied this method to evaluate the edge tension in membranes with four different compositions: egg phosphatidylcholine (eggPC), dioleoylphosphatidylcholine (DOPC), and mixtures of DOPC with cholesterol and dioleoylphosphatidylethanolamine. Our data confirm previous results for eggPC and DOPC. The addition of 17 mol % cholesterol to the DOPC membrane causes an increase in the membrane edge tension. On the contrary, when the same fraction of dioleoylphosphatidylethanolamine is added to the membrane, a decrease in the edge tension is observed, which is an unexpected result considering the inverted-cone shape geometry of the molecule. It is presumed that interlipid hydrogen bonding is the origin of this behavior. Furthermore, cholesterol was found to lower the lysis tension of DOPC bilayers. This behavior differs from that observed on bilayers made of stearoyloleoylphosphatidylcholine, suggesting that cholesterol influences the membrane mechanical stability in a lipid-specific manner.


Morphometric analysis of Th(1) and Th(2) cytokine expression in human pulmonary tuberculosis.
Following infection with Mycobacterium tuberculosis, host cytokine responses influence disease manifestation. Differences in cytokine expression likely determine whether tuberculosis (TB) progresses, resolves, or becomes latent. In particular, the balance between Th(1) and Th(2) cytokine responses influences the expression of disease in individuals with pulmonary TB. Since the cytokine microenvironment in pulmonary TB remains suboptimally defined, we utilized quantitative immunohistochemistry to compare the expression of Th(1) cytokines [interferon-gamma (IFNgamma) and interleukin-12 (IL-12)] and Th(2) cytokines [IL-4, IL-10, transforming growth factor-beta (TGFbeta)] in surgically resected lungs of seven TB patients and four control subjects. We also quantified IFNgamma-inducible protein 10 (IP-10) expression, a CXC chemokine for macrophages and T cells. Morphometric analyses revealed increased IFNgamma, IL-12, IP-10, and TGFbeta in granulomas and in pneumonitis areas of TB lungs. In contrast, IL-10 and IL-4 expressions were globally reduced in TB lung tissues compared to controls. Th(1) cytokines and TGFbeta are increased while Th(2) cytokines are decreased in well-formed pulmonary granulomas of TB patients compared to controls.


Studying the burden of community-acquired pneumonia in adults aged ≥50 years in primary health care: an observational study in rural Crete, Greece.
Community-acquired pneumonia (CAP) is a potentially life-threatening condition that often requires hospitalisation particularly in the elderly population or in patients with comorbidities. The aims of this study were to estimate the CAP frequency and severity in a well-defined primary healthcare setting in rural Crete, to record patient characteristics, their immunisation status and to estimate hospitalisation frequency and determinants. An observational study was designed and implemented in a rural setting within the prefecture of Heraklion in the island of Crete, Greece. Eligible patients were those aged 50 years or above, presenting with CAP based on signs and symptoms and positive X-ray findings. A total of 124 CAP cases were recorded, 40 of which (32.3%) were hospitalised. Τhe age-standardised CAP incidence was estimated to be 236.7 cases per 100,000 persons aged ≥50 years. Forty-three patients (35.2%) were vaccinated against pneumococcus. The most frequent chronic illnesses were heart disease (64.5%), chronic obstructive pulmonary disease (32.5%), and type 2 diabetes (21%). Hospitalisation determinants included advanced age (≥74 years, Odds ratio (OR) 7.13; P value=0.001; 95% confidence interval (CI), 2.23-22.79), obesity (OR 3.36, P=0.037; 95% CI, 1.08-10.52), ≥40 pack-years of smoking (OR 3.82, P value=0.040; 95% CI, 1.07-18.42), presence of multimorbidity (OR 5.77, P value=0.003; 95% CI, 1.81-18.42) and pneumococcal vaccination (OR 0.29, P value=0.041; 95% CI, 0.09-0.95). This study highlighted patient characteristics and aspects of CAP epidemiology in the context of a rural primary care setting in southern Europe where limited data have been published until now.


Factors affecting the preparedness of Helicopter Emergency Medical Services (HEMS) in disasters: a systematic review.
One of the most significant advantages of Helicopter Emergency Medical Service (HEMS) in disaster relief efforts is their ability to reach inaccessible or remote areas quickly. This is especially important in the aftermath of natural disasters such as earthquakes, floods, or hurricanes, where roads may be blocked or damaged, and conventional ground transportation may not be available. There are many factors can affect the performance of Helicopter Emergency Medical Service (HEMS) in disasters. This study aims to investigate the factors affecting the Helicopter Emergency Medical Service (HEMS) in disasters. The systematic search in Cochran Library, PubMed, Scopus, Science Direct, Web of Science, ProQuest, and Google Scholar databases between the first of January in 1975 and the thirty-first of May in 2023. The articles were selected based on the keywords of the authors. At last, the criteria were extracted from the selected ones. The primary search included 839 articles. After studying their title, abstract, and full context, only nine articles, including two qualitative and seven quantitative ones, were chosen for analysis. After analysis and extracting data from the final studies, the preparation factors were categorized into 6 general classes of human resources: training and practicing, management, instructions and standards, equipment, and structure. Among these, the role of training is highlighted by holding practice and maneuvers to improve and prepare the personnel and manage disasters and incidents. The results obtained from this systematic review provide a total view of the factors affecting the preparation of the air ambulance during disasters and incidents. It is recommended that senior managers and policy makers use the findings of the present study to identify the factors which affect preparedness of HEMS in disasters and take the necessary measures to eliminate to obstacles.


Proteasome Inhibitors as a Potential Cause of Heart Failure.
Proteasome inhibitors have become an important drug class in the treatment of multiple myeloma. In addition to its role in myeloma cells, the proteasome plays a critical role in the myocardium, particularly in the context of cardiac stress. The growing awareness of the cardiovascular toxicity of proteasome inhibitors is emerging following the phase 3 trials and the transition into real-world practice. This article reviews the background to this problem and the incidence of the problem in phase 3 trials and subsequent phase 2 trials in new patient cohorts and discusses the strategy to detect and manage this emerging problem.


The epidemiology of domestic violence in Saudi Arabia: a systematic review.
The aim of this study is to review the prevalence, risk factors, and outcomes of domestic violence (DV) in Saudi Arabia. Systematic review utilizing PRISMA guidelines conducted on articles focusing on research related to the epidemiology of domestic violence in Saudi Arabia between 2009 and 2017 were identified through electronic databases (PubMed and Embase) and supplemented by cross-referencing and local journal searches. Eleven studies were conducted in six cities (Riyadh, Jeddah, Madina, Taif, Arar, and Al-Ahsa). Several screening questionnaires were utilized; four studies used the WHO multi-country study questionnaire and found that the lifetime prevalence of DV ranged between 39.3 and 44.5%. The most frequently reported risk factors for DV were the level of education of both the victim and the spouse and alcohol or drug addiction of the spouse. One in every three women in Saudi Arabia is a victim of domestic violence. Strategies to reduce risk factors, prevent DV, care for victims, and mitigate the effects of DV must be adopted by health care agencies in Saudi Arabia.


Presence of M184I/V in minor HIV-1 populations of patients with lamivudine and/or didanosine treatment failure.
The aim of the study was to investigate the presence of M184I/V in minor HIV-1 populations of patients who failed lamivudine (3TC) and/or didanosine (ddI) treatment. Fourteen 3TC-experienced patients who, after switching therapy to a ddI regimen, had a new failure without M184I/V in the major viral population were included in the study. Ninety plasma samples were analysed by direct sequencing and selective real-time polymerase chain reaction (SPCR), which detects GTG/GTA and ATA mutants down to 1 and 0.2% of the population, respectively. In five samples, SPCR detected resistant virus when direct sequencing detected wild-type M184. In patients with mixed viral populations at sequencing, the median proportion of mutants detected by SPCR was 30%. SPCRGTG reactivity dominated, while SPCRATA reactivity only was uncommon. M184I/V disappeared in patients in whom 3TC was stopped but ddI continued. Ten patients with ddI failure had no M184I/V. Minor HIV-1 strains may harbour M184I/V in patients failing ddI therapy, despite direct sequencing showing wild-type virus. Although M184I/V may reduce the genetic barrier of ddI for mutations such as K65R and L74V, the lack of re-emergence of M184I/V in the minor quasispecies of most patients who failed ddI suggests that M184I/V was not a preferred route to ddI resistance in our patient population.


Influences of glutamine administration on response selection and sequence learning: a randomized-controlled trial.
Precursors of neurotransmitters are increasingly often investigated as potential, easily-accessible methods of neuromodulation. However, the amino-acid glutamine, precursor to the brain's main excitatory and inhibitory neurotransmitters glutamate and GABA, remains notably little investigated. The current double-blind, randomized, placebo-controlled study provides first evidence 2.0 g glutamine administration in healthy adults affects response selection but not motor sequence learning in a serial reaction time task. Specifically, glutamine increased response selection errors when the current target response required a different hand than the directly preceding target response, which might indicate enhanced cortical excitability via a presumed increase in glutamate levels. These results suggest glutamine can alter cortical excitability but, despite the critical roles of glutamate and GABA in motor learning, at its current dose glutamine does not affect sequence learning.


Surgical Management of Recurrent Brain Metastasis: A Systematic Review of Laser Interstitial Thermal Therapy.
The incidence of recurrent metastatic brain tumors is increasing due to advances in local therapy, including surgical and radiosurgical management, as well as improved systemic disease control. The management of recurrent brain metastases was previously limited to open resection and/or irradiation. In recent years, laser interstitial thermal therapy (LITT) has become a promising treatment modality. As systemic and intracranial disease burden increases in a patient, patients may no longer be candidates for surgical resection. LITT offers a relatively minimally invasive option for patients that cannot tolerate or do not want open surgery, as well as an option for accessing deep-seated tumors that may be difficult to access via craniotomy. This manuscript aims to critically review the available data regarding the use of LITT for recurrent intracranial brain metastasis. Ten of seventy-two studies met the criteria for review. Generally, the available literature suggests that LITT is a safe and feasible option for the treatment of recurrent brain metastases involving supratentorial and cortical brain, as well as posterior fossa and deep-seated locations. Among all studies, only one directly compared craniotomy to LITT in the setting of recurrent brain metastasis. Prospective studies are needed to better elucidate the role of LITT in the management of recurrent brain metastases.


Associated lymphoma and abdominal aortic aneurysm demonstrated by computed tomography.
In a review of 260 cases of lymphoma, there were 6 patients with an aneurysm of the abdominal aorta. In four cases there was surrounding abdominal lymphadenopathy. The diagnosis was established by computed tomography (CT) because of calcification in the aortic wall was visible on the scans in all 6 cases. This calcification was not sufficiently clear to permit identification of the aneurysm on plain films in three of the cases. In two cases without abdominal lymph-adenopathy, contrast-filled nodes delineated the outer margin of the wall of the aorta.


Transmission electron microscopy at 20 kV for imaging and spectroscopy.
The electron optical performance of a transmission electron microscope (TEM) is characterized for direct spatial imaging and spectroscopy using electrons with energies as low as 20 keV. The highly stable instrument is equipped with an electrostatic monochromator and a C(S)-corrector. At 20 kV it shows high image contrast even for single-layer graphene with a lattice transfer of 213 pm (tilted illumination). For 4 nm thick Si, the 200 reflections (271.5 pm) were directly transferred (axial illumination). We show at 20 kV that radiation-sensitive fullerenes (C(60)) within a carbon nanotube container withstand an about two orders of magnitude higher electron dose than at 80 kV. In spectroscopy mode, the monochromated low-energy electron beam enables the acquisition of EELS spectra up to very high energy losses with exceptionally low background noise. Using Si and Ge, we show that 20 kV TEM allows the determination of dielectric properties and narrow band gaps, which were not accessible by TEM so far. These very first results demonstrate that low kV TEM is an exciting new tool for determination of structural and electronic properties of different types of nano-materials.


[Pulmonary tuberculosis].
Tuberculosis (TB) is a global health problem driven by poverty, HIV infection, etc. In Europe, the problem of multidrug resistance (i.e., resistance to at least rifampin and isoniazid) (MR) develops. The cases come essentially from the former U.S.S.R. In Belgium, the incidence of tuberculosis continues to decline to 9.4/100,000 inhabitants in 2008. The percentage of MR germs is 2.8%. The distribution of cases is not uniform across the country. The incidence is much higher among people recently coming from high prevalence countries than among the Belgian native. The pulmonary forms of TB are more contagious and more common. The clinical signs are frequently non specific. The diagnosis is often mentioned up after performing a chest Xray and must always be confirmed by microbiological examination and culture of several sputum or other respiratory specimens. It is very important to identify the germ, M. tuberculosis complex and to test its sensitivity to anti-TB agents. Standard treatment consists of 4 drugs: isoniazid, rifampin, ethambutol and pyrazinamide for 2 months followed by rifampin and isoniazid for at least 4 additional months. In suspected cases of MR, 5 drugs are prescribed at the outset. Treatment and duration will be adjusted according to the results of susceptibility testing. The potential toxicities of second-line drugs should be well known by the physicians. Compliance of the patient is essential. Screening in the entourage is part of the therapeutic process.


Stakeholder impact on the implementation of integrated care: Opportunities to consider for patient-centered outcomes research.
Nearly half of Americans live with chronic disease. Many have multiple chronic conditions that often present as a combination of physical and mental health conditions. Aligning stakeholder-driven, patient-centered outcomes research with population health strategies such as innovative ways to deliver care management can reduce the burden of multiple chronic conditions. In addition, successfully creating meaningful, inclusive research requires actively engaging stakeholders throughout the lifecycle of a study. This study integrates stakeholder engagement, using a large health plan in western Pennsylvania, to conduct a randomized controlled trial. Three care management strategies, High-Touch, High-Tech, and Usual Care, are compared for effectiveness among members with multiple chronic conditions. Care strategies are delivered via the Community Team, a multidisciplinary community-based team, offering in-person (High-Touch) and digital (High-Tech) care management in 14 counties across Pennsylvania. Participants are followed for 12months, with repeated measurements of self-reported health status and activation in care, while tracking administrative measurements of primary and specialty health service utilization. Quality of life, care satisfaction, engagement in care, and service utilization will be compared using generalized mixed models. Additionally, semi-structured interviews are conducted for both participants and care managers over the course of the study to evaluate feasibility. This manuscript presents implementation strategies, while noting that the implementation of patient-centered outcomes research in a real-world setting requires rapid evaluation, redesign of workflow, and tailored approaches for success.


Multicentre Investigation of Prognostic Factors Incorporating p16 and Tumour Infiltrating Lymphocytes for Anal Cancer After Chemoradiotherapy.
Anal squamous cell carcinomas (ASCC) are strongly associated with human papillomaviruses. Standard of care is chemoradiotherapy at uniform doses with no treatment stratification. Immunohistochemical staining for p16INK4A (p16), a surrogate for human papillomaviruses, is prognostic for outcomes. We investigated this alongside clinical-pathological factors, including tumour infiltrating lymphocyte (TIL) scores. Using an independent, multicentre cohort of 257 ASCC treated with chemoradiotherapy, pretreatment biopsies were stained and scored for p16 and TIL. Kaplan-Meier curves were derived for outcomes (disease-free survival [DFS], overall survival and cancer-specific survival), by stage, p16 and TIL scores and Log-rank tests were carried out to investigate prognostic effect. A multivariate analysis was carried out using Cox regression. Stage, sex, p16 and TILs were independently prognostic. Hazard ratios for death (overall survival) were 2.51 (95% confidence interval 1.36-4.63) for p16 negative versus p16 positive, 2.17 (1.34-3.5) for T3/4 versus T1/2, 2.42 (1.52-3.8) for males versus females and 3.30 (1.52-7.14) for TIL1 versus TIL3 (all P < 0.05). We have refined prognostic factors in ASCC. p16 adds to stratification by stage with respect to DFS in early disease and overall survival/DFS in locally advanced cancers. Our data support the role of the host immune response in mediating outcomes. These factors will be prospectively evaluated in PLATO (ISRCTN88455282).


Does serum CA125 have clinical value for follow-up monitoring of postoperative patients with epithelial ovarian cancer? Results of a 12-year study.
The detection of CA125 has been used in the follow up of ovarian cancer. At present, some scholars believe that serum CA125 has no clinical value for the follow-up monitoring the recurrence for postoperative patients with epithelial ovarian cancer, but in our clinical follow-up found that when the serum CA125 value is <35 U/ml, postoperative patients of epithelial ovarian carcinoma had already showed recurrent lesions in some ecological and imaging examinations or in laparotomy exploration and biopsy, and we given the patients timely treatment, the prognosis were improved. Retrospective analysis the values of serum CA125 of 342 postoperative patients of epithelial ovarian carcinoma, consisting of 296 non-recurrent and 46 recurrent cases, as well as 3175 cases of menopausal women and 603 cases of postoperative patients of gynecological malignant tumor for the follow-up from January 2005 to December 2016. The median value of CA125 for non-recurrent patients of epithelial ovarian carcinoma is 8.9 U/ml, the median value of CA125 for non-recurrent patients of epithelial ovarian carcinoma is 29.7 U/ml; for menopausal women, 8.1 U/ml; and for postoperative patients of gynecological malignant tumor, 7.2 U/ml, whereas the mean ± standard deviation is 9.0 ± 1.9 U/ml, 31.3 ± 16.2U/ml, 8.0 ± 1.1 U/ml, and 6.8 ± 2.1 U/ml, respectively. If the value of the CA125 for postoperative patients of epithelial ovarian carcinoma between 10 and 35 U/ml indicates a relative risk of recurrence. When the value of CA125 is higher than 10 U/ml and continuously increased, need to be vigilant and should be combined with imaging examination (PET-CT). This result may improve the prognosis for recurrent patients because of the early detection of recurrent lesions and early retreatment.


Depression, anxiety, and the COVID-19 pandemic: Severity of symptoms and associated factors among university students after the end of the movement lockdown.
This online cross-sectional study investigated the severity of depressive, anxiety, and stress symptoms among university students and determined the association between various factors and the levels of depressive and anxiety symptoms in response to the coronavirus disease 2019 (COVID-19) pandemic after the movement control order (MCO) was lifted. A total of 316 participants were administered a self-report questionnaire that collected data on sociodemographic attributes, personal characteristics, COVID-19-related stressors, religious coping, and clinical characteristics. In addition, the Multidimensional Scale of Perceived Social Support (MSPSS) and the 21-item Depression, Anxiety and Stress Scale (DASS-21) were administered. Regarding depression, 15.5%, 11.7%, and 9.2% of the participants reported mild, moderate, and severe to extremely severe depression, respectively. For anxiety, 7.0%, 16.5%, and 13.2% of the respondents had mild, moderate, and severe to extremely severe anxiety, respectively. Moreover, 26.3% of participants had mild stress, 9.5% had moderate stress, and 6.6% had severe to extremely severe stress. The multiple linear regression model revealed that frustration because of loss of daily routine and study disruption and having preexisting medical, depressive, and anxiety disorders were associated with elevated depressive symptoms, while a greater degree of family and friends social support was associated with less depressive symptoms after adjusting for age, gender, and marital status. It was also found that frustration because of study disruption and having preexisting medical, depressive, and anxiety disorders were associated with elevated anxiety symptoms, while being enrolled in medicine-based courses and having a greater degree of family support were factors associated with less anxiety symptoms after adjusting for age, gender, and marital status. There is a need to conduct a longitudinal study in the future to confirm the causal relationship between the significant predictive factors and depression and anxiety identified in this study, and maintenance of a persistent flow of academic activities and social interaction may be of utmost importance to safeguard the mental wellbeing of university students.


The pharmacokinetics and safety of lidocaine in liver cancer patients undergoing hepatic resection.
The purpose of this study was to explore the pharmacokinetics (PK) characteristics and safety of continuous lidocaine infusion during hepatectomy in liver cancer patients. This study included thirty-five patients undergoing laparoscopic hepatectomy from January 2021 to December 2021. Patients received a short infusion of 1% lidocaine at a dose of 1.5 mg/kg based on ideal body weight, followed by a continuous infusion of 1 mg/kg/h during the operation. The plasma concentrations of lidocaine and its active metabolites were measured using validated ultra-performance liquid chromatography-tandem mass spectrometry. Safety was evaluated by monitoring and recording all adverse events (AEs). The concentrations of lidocaine were within the safe range, except one patient's concentration of lidocaine which reached the toxic range (> 5 μg/mL). The mean half-life (T1/2), the mean time to maximum observed concentration (Tmax), and the mean maximum observed concentration (Cmax) of lidocaine were 3.96 h, 2.85 h, and 2030 ng/mL, respectively; the mean T1/2, Tmax, and Cmax (n = 32) of MEGX were 6.59 h, 5.05 h, and 333.28 ng/mL, respectively; and the mean T1/2, Tmax, and Cmax of GX (n = 18) were 25.98 h, 7.33 h, and 75.81 ng/mL. Although eight subjects with AEs were reported, there were no serious AEs or deaths. No patients had serious postoperative complications. No deaths occurred within 30 days after the operation. Under the administration regimen of this study, intravenous infusion of lidocaine is safe and tolerable for liver cancer patients with laparoscopic hepatectomy. Fine safety and PK characteristics support the application of lidocaine in such patients and further clinical research. China Clinical Trial Registration Center (ChiCTR2100042730), Registered 27 January 2021.


Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3.
Liver metastasis is the leading cause of death in patients with colorectal cancer (CRC). Surgical resection of the liver metastases increases the incidence of long-term survival in patients with colorectal liver metastasis (CRLM). However, many patients experience CRLM recurrence after the initial liver resection. As an unavoidable pathophysiological process in liver surgery, liver ischemia-reperfusion (IR) injury increases the risk of tumor recurrence and metastasis. Colorectal liver metastasis (CRLM) mouse models and mouse liver partial warm ischemia models were constructed. The levels of lipid peroxidation were detected in cells or tissues. Western Blot, qPCR, elisa, immunofluorescence, immunohistochemistry, scanning electron microscope, flow cytometry analysis were conducted to evaluate the changes of multiple signaling pathways during CRLM recurrence under liver ischemia-reperfusion (IR) background, including SGK1/IL-6/STAT3, neutrophil extracellular traps (NETs) formation, polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) infiltration. Hepatocyte serum/glucocorticoid regulated kinase 1 (SGK1) was activated in response to hepatic ischemia-reperfusion injury to pass hepatocyte STAT3 phosphorylation and serum amyloid A (SAA) hyperactivation signals in CRLM-IR mice, such regulation is dependent on SGK-activated IL-6 autocrine. Administration of the SGK1 inhibitor GSK-650394 further reduced ERK-related neutrophil extracellular traps (NETs) formation and polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) infiltration compared with targeting hepatocyte SGK1 alone, thereby alleviating CRLM in the context of IR. Our study demonstrates that hepatocyte and immune cell SGK1 synergistically promote postoperative CRLM recurrence in response to hepatic IR stress, and identifies SGK1 as a translational target that may improve postoperative CRLM recurrence.


The influence of high and low sodium intakes on post-operative antidiuresis.
There remains some doubt over the influence of intravenous fluid and electrolyte therapy on the development of postoperative hyponatraemia. We believe the effect of varying sodium intakes on fluid balance during both the early antidiuresis phase and the later postoperative period has received insufficient emphasis. Therefore, the effects of intravenous regimens, containing either 450 mmol/24 h of sodium (saline group) or no sodium (dextrose group), on salt and water balance, plasma sodium and plasma water concentrations have been studied in two groups of 6 patients undergoing upper abdominal surgery. Hyponatraemia was not seen in the saline group but marked salt (+ 1023 mmol) and water retention (+ 3509 ml) were seen by day + 4. The dextrose group became relatively hyponatraemic (131.8 mmol/l) by day +1 but, following a phase of fluid retention during the 24 h following surgery, they developed negative fluid balance with some recovery of plasma sodium levels. This study confirms the importance of the sodium content of intravenous fluids both on the early development of hyponatraemia and on water and salt balance during the later postoperative period.


Photoacoustic Imaging and Characterization of Bone in Medicine: Overview, Applications, and Outlook.
Photoacoustic techniques have shown promise in identifying molecular changes in bone tissue and visualizing tissue microstructure. This capability represents significant advantages over gold standards (i.e., dual-energy X-ray absorptiometry) for bone evaluation without requiring ionizing radiation. Instead, photoacoustic imaging uses light to penetrate through bone, followed by acoustic pressure generation, resulting in highly sensitive optical absorption contrast in deep biological tissues. This review covers multiple bone-related photoacoustic imaging contributions to clinical applications, spanning bone cancer, joint pathologies, spinal disorders, osteoporosis, bone-related surgical guidance, consolidation monitoring, and transsphenoidal and transcranial imaging. We also present a summary of photoacoustic-based techniques for characterizing biomechanical properties of bone, including temperature, guided waves, spectral parameters, and spectroscopy. We conclude with a future outlook based on the current state of technological developments, recent achievements, and possible new directions.


Design and dissemination of a multiregional long-term care infection control training program.
Long-term care facilities have only recently begun to receive attention in the area of infection control. A training program was developed in Nebraska to help supply practitioners with knowledge and techniques designed specifically for the long-term care environment. This program's success led to its implementation in other regions. The regional extensions of the program were designed to operate with independent faculty but standardized course materials.


Synthesis of Alkyl and Aryl Boronate Esters via CeO2-Catalyzed Borylation of Alkyl and Aryl Electrophiles Including Alkyl Chlorides.
A recyclable protocol using a CeO2-nanorod catalyst for borylation of alkyl halides with B2pin2 (pin = OCMe2CMe2O) is reported. A wide range of synthetically useful alkyl boronate esters are readily obtained from primary and secondary alkyl electrophiles, including unactivated alkyl chlorides, demonstrating broad utility and functional group tolerance. Preliminary investigation revealed an involvement of in situ formed catalytically active boryl species. The catalyst can be reused for up to six runs without appreciable loss in activity. In addition, we have demonstrated the use of this recyclable catalyst for the borylation of aryl halides with B2pin2, providing valuable aryl boronate esters under neat conditions.


Clinical and radiological outcomes of postoperative septic arthritis after anterior cruciate ligament reconstruction.
Septic arthritis after arthroscopic anterior cruciate ligament (ACL) reconstruction is a rare complication. In the literature, several treatments have been proposed. The aim of the study was to report our results using ambulatory irrigation of the knee and parenteral and oral antibiotics. From January 2001 to December 2008, a total of 12 patients were treated for postoperative septic arthritis of the knee after ACL reconstruction in our hospital. The average age at trauma was 24 years (range 16-43 years). The treatment protocol included irrigation of the knee (for 2 days) and parenteral antibiotics and oral antibiotics subsequently. Repetitive irrigation was performed if necessary. The average duration of follow-up for our series was 38 months (range 6-54 months). Follow-up included International Knee Documentation Committee (IKDC) forms, radiography, Tegner and Lysholm scores, and KT-1000 arthrometric evaluation. In all cases treatment of infection was successful. Neither graft nor hardware removal was needed in any of the cases. At final examination, the pivot shift was negative in 10 of 12 patients, and it was 1+ in the other 2 patients; the Lachman was negative in all cases. The mean postoperative Tegner score was 7.2, and the mean Lysholm score was 98.3. In all, 10 of the 12 patients were graded as group A and the other 2 as group B using the IKDC form. The mean postoperative manual maximum KT-1000 side-to-side difference was 2.3. No significant bone tunnel enlargement was found at radiographic evaluation. The described treatment regimen gives reliable results for this complication. There were no recurrences of septic arthritis or bone infection. No further surgeries were required, and the graft was retained during the treatment of septic arthritis.


Frequent finding of the androgen receptor A645D variant in normal population.
The androgen receptor A645D mutation has been described in one patient with ambiguous genitalia and one boy with normal phenotype. Because of this phenotypic variation, we screened a cohort of men from the general population (n = 293) as well as men with the following disorders of the genital tract for the mutation: men with prostate cancer (n = 89), testicular cancer (n = 87), and infertility (n = 103). We also investigated the influence of the polymorphic CAG and GGN repeats on the phenotypic outcome. The A645D variant was found in three men from the general population (1.0%). These men did not differ regarding testosterone or LH concentrations, compared with the rest of this population. In addition, two men with prostate cancer (2.3%) and one infertile man (1.0%) presented with the mutation. No statistical differences in frequency were noted between the study groups, and none of these individuals had any genital malformations. All men who presented with the mutation carried an extraordinarily short GGN repeat of 10 base triplets in combination with long CAG repeats of 26-28 (average 27.3). In contrast, men with GGN=10, but CAG less than 26 did not have the A645D mutation. A single-nucleotide polymorphism analysis revealed that the A645D variant has emerged from the most common haplogroup in our population. We conclude that the A645D mutation, which is present in 1% of the general Swedish population, is linked to GGN10 and long CAG repeats. Its effect on androgen receptor function is currently unknown.


Optimal dose of succinylcholine for tracheal intubation in patients during inhalation induction with sevoflurane: a randomized controlled trial.
To determine the dose of succinylcholine during inhalation induction of a patient. Prospective, double-blind, randomized study. Operating room of a university hospital. 180 adult, ASA physical status 1 and 2 patients with a suspected difficult airway, who were scheduled for surgery. Nonpremedicated patients were anesthetized with inhalation of 8% sevoflurane, followed by succinylcholine. Group 1 received intravenous (IV) succinylcholine 0.3 mg/kg, Group 2 had IV succinylcholine 0.6 mg/kg, and Group 3 was given IV succinylcholine 1.0 mg/kg. Direct laryngoscopy and tracheal intubation were performed after onset of succinylcholine. Intubation conditions were scored as excellent, good, or poor. The recovery time of spontaneous respiration, end-tidal carbon dioxide partial pressure (PETCO2), and pulse oxygen saturation (SpO2) were recorded. Acceptable conditions (excellent and good) for intubation were rated in 80% of Group 1 patients (0.3 mg/kg succhinylcholine), 91.7% of Group 2 patients (0.6 mg/kg), and 93.3% of Group 3 patients (1.0 mg/kg), respectively. Intubation scores were similar in Groups 2 and 3, and were significantly higher than in Group 1 patients (0.3 mg; P < 0.01). Time to recovery of spontaneous respiration in Group 3 was significantly prolonged compared with Groups 1 and 2 (238 ± 59 sec vs 132 ± 43 sec, P < 0.001; 238 ± 59 sec vs 151 ± 47 sec, P < 0.001, respectively). SpO2 in Group 3 did not differ significantly from Group 1 and 2 values. However, PETCO2 in Group 3 was significantly higher than in Groups 1 or 2. Succinylcholine at a dose of 0.6 mg/kg IV provided intubation conditions similar to succinylcholine at 1.0 mg/kg IV, and recovery of spontaneous respiration following a 0.6 mg/kg dose of succinylcholine was significantly shorter.


Subunit structure of external invertase from Saccharomyces cerevisiae.
Because 50% of the mass of the external invertase of Saccharomyces cerevisiae consists of carbohydrate, it has been extremely difficult to obtain an accurate molecular weight of this enzyme by centrifugal or electrophoretic techniques. However, on removing almost all of the oligosaccharide chains of this enzyme with the endo-beta-N-acetyl-glucosaminidase H from Streptomyces plicatus, it has been possible to show that carbohydrate-free invertase is composed of two 60,000-dalton subunits. Terminal sequence analysis with carboxypeptidases A, B, and Y provided strong evidence that the subunits are identical.


Dietary fibre and health: the story so far.
The present paper reviews progress in research on dietary fibre and human health over the past five decades. There is now convincing evidence from prospective cohort studies that diets low in dietary fibre are associated with increased risk of common non-communicable diseases including CVD, type 2 diabetes and colorectal cancer. These findings provide strong support for hypotheses proposed by Denis Burkitt 50 years ago, based on very limited evidence but with considerable imagination and insight. For the first two to three decades of this period, research on dietary fibre was hampered by the lack of consensus about the definition, and measurement, of this complex and diverse dietary component and by the lack of appropriate tools for investigating the gut microbiome that is central to understanding mechanisms of action. Recent technical and scientific advances in microbiome research (based on fast, low-cost, DNA sequencing) are facilitating investigation of the associations between dietary fibre, the gut microbiome and human health. Current challenges include the need for agreement about the characteristics of a healthy gut microbiome. Although the health benefits attributed to higher dietary fibre intake are likely to be shared with most types of dietary fibre, one should anticipate that different sources of dietary fibre and the other components (resistant starch and non-digestible oligosaccharides) that make up dietary fibre will have characteristically different effects on human physiology and disease risk. In conclusion, population-level intakes of dietary fibre are low and there is a public health priority to develop and implement more effective interventions to increase intake.


Mathematical Modeling to Guide Experimental Design: T Cell Clustering as a Case Study.
Mathematical modeling provides a rigorous way to quantify immunological processes and discriminate between alternative mechanisms driving specific biological phenomena. It is typical that mathematical models of immunological phenomena are developed by modelers to explain specific sets of experimental data after the data have been collected by experimental collaborators. Whether the available data are sufficient to accurately estimate model parameters or to discriminate between alternative models is not typically investigated. While previously collected data may be sufficient to guide development of alternative models and help estimating model parameters, such data often do not allow to discriminate between alternative models. As a case study, we develop a series of power analyses to determine optimal sample sizes that allow for accurate estimation of model parameters and for discrimination between alternative models describing clustering of CD8 T cells around Plasmodium liver stages. In our typical experiments, mice are infected intravenously with Plasmodium sporozoites that invade hepatocytes (liver cells), and then activated CD8 T cells are transferred into the infected mice. The number of T cells found in the vicinity of individual infected hepatocytes at different times after T cell transfer is counted using intravital microscopy. We previously developed a series of mathematical models aimed to explain highly variable number of T cells per parasite; one of such models, the density-dependent recruitment (DDR) model, fitted the data from preliminary experiments better than the alternative models, such as the density-independent exit (DIE) model. Here, we show that the ability to discriminate between these alternative models depends on the number of parasites imaged in the analysis; analysis of about [Formula: see text] parasites at 2, 4, and 8 h after T cell transfer will allow for over 95% probability to select the correct model. The type of data collected also has an impact; following T cell clustering around individual parasites over time (called as longitudinal (LT) data) allows for a more precise and less biased estimates of the parameters of the DDR model than that generated from a more traditional way of imaging individual parasites in different liver areas/mice (cross-sectional (CS) data). However, LT imaging comes at a cost of a need to keep the mice alive under the microscope for hours which may be ethically unacceptable. We finally show that the number of time points at which the measurements are taken also impacts the precision of estimation of DDR model parameters; in particular, measuring T cell clustering at one time point does not allow accurately estimating all parameters of the DDR model. Using our case study, we propose a general framework on how mathematical modeling can be used to guide experimental designs and power analyses of complex biological processes.


SNPD-CRISPR: Single Nucleotide Polymorphism-Distinguishable Repression or Enhancement of a Target Gene Expression by CRISPR System.
A wide range of diseases, including cancer, autoimmune diseases, or neurodegenerative diseases, have been associated with single nucleotide mutations in their causative genes. Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system is a flexible and efficient genome engineering technology widely used for researches and therapeutic applications which offers immense opportunity to treat genetic diseases. The complex of Cas9 and the guide RNA acts as an RNA-guided endonuclease. Cas9 recognizes a sequence motif known as a protospacer adjacent motif (PAM), and then the guide RNA base pairs with its proximal target region of 20 nucleotides with sequence complementarity. Here we describe the procedure named single nucleotide polymorphism-distinguishable (SNPD)-CRISPR system which can suppress or enhance the expression of disease-causative gene with single nucleotide mutation distinguished from its wild-type. In this study, we used HRAS, one of most famous cancer-causative genes, as an example of a target gene.


Pre-clinical Formulation Development of an in situ Meglumine Salt of AZD5991: A Novel Macrocyclic Mcl-1 Inhibitor.
AZD5991 is a potent and selective macrocyclic inhibitor of Mcl-1 in clinical development. Developing an intravenous solution formulation for AZD5991 proved to be challenging primarily due to the poor intrinsic solubility of AZD5991. In this article are described studies performed to select a suitable crystalline form and to assess physicochemical properties of AZD5991 to aid in the design of a solution formulation for preclinical studies. It is preferable that the preclinical formulation has a line of sight for clinical formulation. For AZD5991, a concentration of at least 20 mg/ml was required for toxicology studies. Toward this goal, extensive pre-formulation characterization of AZD5991 including solid form analysis, pH-solubility profiling and solubility determination in cosolvents and other solubilizing media were carried out. Crystalline Form A, which is more stable in aqueous solution and possesses acceptable thermal stability, was selected for preclinical and clinical development of AZD5991. Extensive solubility evaluation revealed an interesting pH-solubility profile that significantly enhances solubilization at pH > 8.5 to allow solution concentrations of at least 30 mg/ml by in situ meglumine salt formation. Developing pre-clinical formulations to support in vivo studies requires a good understanding of the physicochemical properties of the drug candidates. Candidates with challenging pharmaceutic properties like the novel macrocycle molecule AZD5991, demand extensive characterization in its polymorph landscape, solubility profile and suitability evaluation of the excipients. Meglumine, a pH-adjusting and solubilizing agent, was found to be the best choice for formulating AZD5991 into an intravenous product to support preclinical studies.


All-Endoscopic Brachial Plexus Complete Neurolysis for Idiopathic Neurogenic Thoracic Outlet Syndrome: A Prospective Case Series.
To describe an all-endoscopic technique for infra- and supraclavicular brachial plexus (BP) neurolysis and to assess its functional outcomes for patients suffering from nonspecific neurogenic thoracic outlet syndrome (NTOS). Between January 2010 and January 2013, 36 patients presenting an idiopathic nonspecific NTOS benefited from an endoscopic decompression in our institution. The inclusion criteria were a typical clinical NTOS and failure of a 6-month well-conducted nonsurgical treatment. Preoperative findings about other shoulder conditions and complementary procedures were exclusion criteria. Interscalene, costoclavicular, and retropectoralis minor spaces were released endoscopically. The primary endpoint was the Disability of the Arm, Shoulder and Hand (DASH) score improvement 6 months after the surgery. Postoperative criteria such as pain relief, paresthesia, upper limb weakness, and provocative tests were also assessed. Of 36 patients, 10 were excluded and 5 were lost during follow-up. The data of the 21 remaining patients were analyzed after 6 months. Pre- and postoperative mean DASH scores were, respectively, 70 (range 36-98) and 34 (range 2-91). The average improvement was 36 (range -20 to 80), with P = .0002. Pain and paresthesia were relieved in 80% to 90% of the cases. No complication was reported. Although requiring arthroscopic skills and expert knowledge of the anatomy, our technique seems to be safe and reproducible, and it provides significant functional improvements in the selected patients with nonspecific NTOS, with an average postoperative DASH score improvement of 36%. Level IV, therapeutic case series.


[Mechanics of circulation in lowering the blood pressure in different hemodynamic forms of hypertension (author's transl)].
The high blood pressure of essential hypertension sustained by an increased peripheral resistance or by cardiac output, or by both of these magnitudes. To examine the mechanics of lowering the blood pressure in these different forms of hypertension on analysis of circulation was carried out on three patients with a cardiac output hypertension and on seven patients with a resistance hypertension before and after lowering the blood pressure by the compound preparation Briserin. The results showed that the influence on the hemodynamics was different. The therapeutic result was due partly to a decrease of the cardiac output and partly to a reduction in vascular peripheral resistance. The increased parameter of circulation decreased during the treatment. Occasionally however the cardiac output as well as the peripheral resistance were decreased or while one of the parameters decreased the other even increased.


Meat quality of Nguni steers supplemented with Acacia karroo leaf-meal.
The objective of the study was to determine the meat quality of Nguni steers supplemented with Acacia karroo leaf-meal. Thirty 19-month old steers were randomly assigned to A. karroo leaf-meal (AK), sunflower cake (SF) and a control (CN) diets. Steers on the AK and SF diets were given an additional 150 g of protein per day for 60 days. The steers were slaughtered at 21 months and the m.longissimus thoracis et lumborum was sampled for meat quality measurements. Steers that received SF diet had lighter-coloured (L*) (P<0.05) meat than those on AK and CN diets. The highest redness (a*) (17.3+/-0.29) values were recorded in steers supplemented with AK compared to those that received SF and CN diets. Diet had no effect on pH, drip loss, water holding capacity, sarcomere length, muscle bundle areas, myofibrillar fragment length, Warner-Bratzler shear force and cholesterol values. Steers supplemented with AK (22.4+/-0.08%) and SF (22.5+/-0.08%) had higher (P<0.05) meat protein content than those on the CN (20.2+/-0.08%) diet. Highest muscle fibre area (3472.6+/-119.51 microm(2)), fat content (1.2+/-0.11%) and cooking loss (25.2+/-0.73%) of meat aged for 2 days were recorded in steers given the SF diet compared to those on the AK and CN diets. Supplementing Nguni cattle with A. karroo leaf-meal produced beef of comparable quality to natural pasture alone but with a fresher appearance and higher protein content.


The application of fractal dimension to temporomandibular joint sounds.
Researchers have attempted to use mathematical analysis of the sounds produced by symptomatic temporomandibular joints (TMJ) as a diagnostic modality. However, previous studies have generally concluded that such analyses have little diagnostic utility. Previous studies using Fourier transforms and visual inspection were of limited success. This paper reports the results of a preliminary retrospective study using fractal analysis to analyze sounds produced by symptomatic temporomandibular joints previously diagnosed using other clinical modalities as having internal derangements with reducing discs. Multiple mandibular opening and closing cycles were recorded in four subjects. The study revealed that fractal analysis produced a high degree of reproducibility within, and similarity across subjects. The fractual dimension associated with joints having this pathology was found to be 1.266, revealing that fractal analysis shows promise as a noninvasive method for diagnosing interarticular TMJ pathology.


New insight into the impact of biochar during vermi-stabilization of divergent biowastes: Literature synthesis and research pursuits.
Biochar amendment for compost stabilization of divergent biowastes is gaining considerable attention due to environmental, agronomic and economic benefits. Research to date exhibits its favorable physico-chemical characteristics, viz. greater porosity, surface area, amount of functional groups, and cation exchange capacity (CEC), which allow interface with main nutrient cycles, favor microbial activities during composting, and improve the reproduction of earthworms during vermicomposting. Biochar amendment during composting and vermicomposting of biowastes boosts physico-chemical properties of compost mixture, microbial activities and organic matter degradation; and reduces nitrogen loss and emission of greenhouse gases (GHGs). It also improves the quality of final compost by increasing concentration of plant available nutrients, enhancing maturity, decreasing composting duration and reducing the toxicity of compost. Due to these characteristics, biochar could be considered a beneficial additive for the stabilization of different biowastes during composting and vermicomposting processes. Hence, good quality vermicompost, efficient recycling and management of biowastes could be achieved by addition of biochar through composting and vermicomposting.


Designing a nine cysteine-less DNA packaging motor from bacteriophage T4 reveals new insights into ATPase structure and function.
The packaging motor of bacteriophage T4 translocates DNA into the capsid at a rate of up to 2000 bp/s. Such a high rate would require coordination of motor movements at millisecond timescale. Designing a cysteine-less gp17 is essential to generate fluorescently labeled motors and measure distance changes between motor domains by FRET analyses. Here, by using sequence alignments, structural modeling, combinatorial mutagenesis, and recombinational rescue, we replaced all nine cysteines of gp17 and introduced single cysteines at defined positions. These mutant motors retained in vitro DNA packaging activity. Single mutant motors translocated DNA molecules in real time as imaged by total internal reflection fluorescence microscopy. We discovered, unexpectedly, that a hydrophobic or nonpolar amino acid next to Walker B motif is essential for motor function, probably for efficient generation of OH(-) nucleophile. The ATPase Walker B motif, thus, may be redefined as "β-strand (4-6 hydrophobic-rich amino acids)-DE-hydrophobic/nonpolar amino acid".


Mixed ligand monolithic columns for reversed-phase capillary electrochromatography via hydrophobic and π interactions.
Novel mixed ligand monoliths (MLM) for capillary electrochromatography (CEC) of a wide range of solutes differing in both polarity and size were introduced. The MLM capillary columns were based on the different compositions of octadecyl acrylate (ODA) and 2-naphthyl methacrylate (NAPM) monomers in the presence of trimethylolpropane trimethacrylate (TRIM) crosslinker and a ternary porogenic solvent made up of cyclohexanol, ethylene glycol, and water. As expected, the magnitude of the electroosmotic flow (EOF) changed with the composition of the MLM. As the percent of the monomer ODA in the polymerization mixture was increased, the EOF increased to a maximum at 50-mol% ODA and then leveled off at 75-mol% and 100-mol% ODA, an indication that the ODA ligand in general exhibited a higher binding for the mobile-phase ions than the NAPM ligand. This is due to the fact that the ODA is an acrylate-based monomer, whereas the NAPM is a methacrylate-based monomer. While ODA provided solely nonpolar interactions, NAPM exhibited both nonpolar and π interactions with certain solutes. It was found out that columns with a given composition of both ligands yielded a unique selectivity for a given set of solutes that was not matched by columns made by either ODA or NAPM alone. Several test mixtures were used in the evaluation of the MLM columns including polycyclic aromatic hydrocarbons, alkyl phenyl ketones, nitroalkanes, alkylbenzenes, toluene derivatives, peptides, and proteins. Peptide mapping of the tryptic digest of the standard lysozyme protein was also studied.


Inhibition of host Ogr1 enhances effector CD8+ T-cell function by modulating acidic microenvironment.
Immunotherapies for cancer, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to a long-lasting clinical response. But the therapeutic response rate remains low on account of many tumors that have evolved sophisticated strategies to evade immune surveillance. Solid tumors are characterized by the highly acidic microenvironment, which may weaken the effectiveness of antitumor immunity. Here, we explored a promising therapeutic development deployed by pH manipulation for avoiding immunoevasion. The highly acidified microenvironment of melanoma induces the expression of G-protein-coupled receptor (Ogr1) in T cells, which weakened their effective function and promote tumor growth. Ogr1 inhibition reactivate CD8+ T cells and have a cytotoxic role by reducing the activity of high glycolysis, resulting in comparatively low acidification of the tumor microenvironment, and leads to tumor suppression. In addition, the adoptive transfer of Ogr1-/--CD8+ T cells enhanced the antitumor responses, with the potential for immediate clinical transformation.


Future risk of bovine tuberculosis recurrence among higher risk herds in Ireland.
Within the Irish national bovine tuberculosis (bTB) eradication programme, controls are tighter on higher risk herds, known as H-herds. These H-herds are defined as herds that have previously had a bTB restriction (also known as a bTB episode), with at least 2 animals positive to the single intradermal comparative tuberculin test (SICTT) or with a bTB lesion detected at slaughter. Such herds are considered at higher risk of recurrence following the end of the bTB episode. In this study, we examined if, and when, the future bTB risk of H-herds returned to a similar level comparable to herds with no history of bTB. In addition, the proportion of bTB episodes in 2012 that could be attributed to the recent introduction of an infected animal was also estimated, providing an update of earlier work. The study population consisted of all Irish herds that were not bTB restricted at the start of 2012 and with at least one whole-herd SICTT in 2012, with the herd being the unit of interest. The outcome measure was a bTB restriction, defined as any herd where at least 1 standard SICTT reactor or an animal with a bTB lesion at slaughter in 2012 was identified. A logistic regression model was used to model the probability of a herd being restricted in 2012. Herds that were previously restricted had significantly higher odds of being restricted in 2012 compared to herds that had not. Similarly, the odds of being restricted in 2012 decreased as the time since the previous restriction increased, but increased as the severity of the previous restriction increased. Odds of being restricted also increased with an increase (although not linear) in herd size, the number of animals greater than 1 year of age purchased in 2011, the county incidence rate and the proportion of cows in the herd. The recent introduction of an infected animal accounted for 7.4% (6.7-8.2) of herd restrictions. This study confirms the key role of past bTB history in determining the future risk of Irish herds, with the odds related to both the severity of and time since the previous restriction. It also illustrates the difficulty in clearly defining H-herds, noting that risk persists for extended periods following a bTB restriction, regardless of breakdown severity. There is a need for robust controls on H-herds for an extended period post de-restriction.


Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors.
The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.


Remote sensing-based water quality index estimation using data-driven approaches: a case study of the Kali River in Uttar Pradesh, India.
The present study evaluates the water quality status of 6-km-long Kali River stretch that passes through the Aligarh district in Uttar Pradesh, India, by utilizing high-resolution IRS P6 LISS IV imagery. In situ river water samples collected at 40 random locations were analyzed for seven physicochemical and four heavy metal concentrations, and the water quality index (WQI) was computed for each sampling location. A set of 11 spectral reflectance band combinations were formulated to identify the most significant band combination that is related to the observed WQI at each sampling location. Three approaches, namely multiple linear regression (MLR), backpropagation neural network (BPNN) and gene expression programming (GEP), were employed to relate WQI as a function of most significant band combination. Comparative assessment among the three utilized approaches was performed via quantitative indicators such as R 2, RMSE and MAE. Results revealed that WQI estimates ranged between 203.7 and 262.33 and rated as "very poor" status. Results further indicated that GEP performed better than BPNN and MLR approaches and predicted WQI estimates with high R 2 values (i.e., 0.94 for calibration and 0.91 for validation data), low RMSE and MAE values (i.e., 2.49 and 2.16 for calibration and 4.45 and 3.53 for validation data). Moreover, both GEP and BPNN depicted superiority over MLR approach that yielded WQI with R 2 ~ 0.81 and 0.67 for calibration and validation data, respectively. WQI maps generated from the three approaches corroborate the existing pollution levels along the river stretch. In order to examine the significant differences among WQI estimates from the three approaches, one-way ANOVA test was performed, and the results in terms of F-statistic (F = 0.01) and p-value (p = 0.994 > 0.05) revealed WQI estimates as "not significant," reasoned to the small water sample size (i.e., N = 40). The study therefore recommends GEP as more rational and a better alternative for precise water quality monitoring of surface water bodies by producing simplified mathematical expressions.


Prolonged APTT of unknown etiology: A systematic evaluation of causes and laboratory resource use in an outpatient hemostasis academic unit.
A prolonged activated partial thromboplastin time (APTT) of unknown cause is one of the most frequent reasons why outpatients are referred for hemostasis consultation. Nevertheless, very few data are available on the relative contribution of individual causes of this common clinical scenario. Here, we present a systematic evaluation of all causes of APTT prolongation in a consecutive population of outpatients referred for specialized hemostasis consultation during a 14-year period. All cases referred to an academic specialized hemostasis outpatient unit due to APTT prolongation of unknown etiology whose prolonged APTT was confirmed in the first visit were included in the study. Data were obtained from the electronic medical records. Among 187 consecutive patients, the most frequent causes were antiphospholipid antibodies in 22.6%, contact pathway factor deficiencies in 17.4%, other coagulation factor deficiencies in 11.6%, and vitamin K deficiency/liver disease in 11.6%. A definite cause was not identified in 22.1% of patients. Presence of antiphospholipid antibodies, and absence of bleeding symptoms were both associated with significantly longer APTT values compared to other categories/clinical scenarios. The investigation of each case required a mean of 18.2 additional tests per patient, with estimated costs ranging from US$191.60 to US$1055.60. Our results describe the main causes of APTT prolongation in outpatients, as well as estimates of resource use required to investigate this condition, thus providing evidence supporting the importance of measures to minimize the indiscriminate use of this assay.


New analytical approach to calibrate the co-axial HPGe detectors including correction for source matrix self-attenuation.
To calibrate the co-axial HPGe semiconductor detectors, we introduce a new theoretical approach based on the Direct Statistical method proposed by Selim and Abbas (1995, 1996) to calculate the full-energy peak efficiency for cylindrical detectors. The present method depends on the accurate analytical calculation of the average path length covered by the photon inside the detector active volume and the geometrical solid angle Ω, to obtain a simple formula for the efficiency. In addition, the self attenuation coefficient of the source matrix (with a radius greater than the detector's radius), the attenuation factors of the source container and the detector housing materials are also treated by calculating the average path length within these materials. (152)Eu aqueous radioactive sources covering the energy range from 121 to 1408 keV were used. Remarkable agreement between the measured and the calculated efficiencies was achieved with discrepancies less than 2%.


Higher rate of toxicity with no increased efficacy when hydroxyurea is added to a regimen of stavudine plus didanosine and nevirapine in primary HIV infection.
Twenty-four subjects presenting at a single treatment center with primary HIV infection were enrolled in a pilot study aimed to establish the possible role of hydroxyurea in this setting. Study participants were randomly assigned to receive or not to receive hydroxyurea in addition to stavudine (d4T) plus didanosine (ddI) and nevirapine (NVP). Seventy-five percent of patients without hydroxyurea had plasma HIV RNA below 50 copies/mL at 48 weeks by both intention-to-treat (ITT) and on-treatment (OT) analysis in comparison with 50% (ITT) and 67% (OT) of patients with hydroxyurea (p >.1). A median increase of >200 cells/mm3 was observed from baseline to week 48 whether or not hydroxyurea was included in the regimen. Overall, in 12 patients treated with hydroxyurea, 33 adverse events were reported versus 19 reported for 12 patients who did not receive hydroxyurea (p <.05). Our results suggest that that adding hydroxyurea to a regimen of d4T plus ddI and NVP increases toxicity without improving the antiviral effect.


Pathophysiology of seroma in breast cancer.
Seroma is the most common complication of mastectomy. The aim of this systematic review is to clarify the pathophysiology of seroma. A computer-assisted MEDLINE search was conducted, and additional references were found in the bibliographies of these articles. The reference terms ''breast cancer'', ''mastectomy'', ''seroma'', ''lymphocele'' and ''lymphocyst'' were used as both keyword and subject terms. The search was limited to studies published in English. The definition of seroma was highly variable across studies, but was most commonly a seroma large enough to be noticed by the patient or medical staff and affecting the patient's satisfaction in the immediate or acute postoperative period. So far, only limited data are available on the severity of seroma. With respect to the pathophysiology of seroma, the data indicated that several anatomical factors, especially dead space, likely contribute to seroma formation. However, it was obscure whether seroma was due to lymph-like fluid or exudate. There is considerable variability in the way seroma is defined across studies, and its pathophysiology remains uncertain.


The impact of genetic syndromes on children's growth.
Genetic syndromes that include short stature are recognized by their effect on children's growth rates, by their effect on the growth rate and pubertal development in adolescence, and by the presence of stigmata associated with certain syndromes. The effects of Down, Seckel, Turner, Russell-Silver, Prader-Willi, and Noonan syndromes on growth and the growth-inhibiting features of achondroplasia, hypophosphatemic rickets, and Laron dwarfism are reviewed. The terminology used by professionals in discussing genetic alterations should minimize the effects of labeling and stigmatization and should emphasize the normal aspects of a child's life.


Molecular mechanisms involved in lead induced disruption of hepatic and pancreatic glucose metabolism.
Lead (Pb) is a toxic heavy metal known to be associated with pathology of various human chronic diseases. This study has focused on the effect of lead on glucose homeostasis with regard to metabolic function of pancreas and liver. Islets of Langerhans were isolated from the pancreas of rats and exposed to lead for 24h, then insulin release along with markers of ER stress and oxidative stress were evaluated. In another part, lead was administered to rats for 32 days and after evaluating criteria of diabetes, the activity of gluconeogenesis and glycogenolysis enzymes, and markers of oxidative stress and inflammation were measured in the liver. Lead disrupted insulin secretory function of islets through activating GSK-3β and ER stress, and increased activity of gluconeogenic enzymes in the liver featured by glucose intolerance. Chronic exposure to lead can disrupt glucose homeostasis by affecting pancreas and liver mainly through induction of insulin resistance.


Acetoacetate and brain lipogenesis: developmental pattern of acetoacetyl-coenzyme A synthetase in the soluble fraction of rat brain.
The existence of acetoacetyl-CoA synthetase in rat brain cytosol is reported. The coupling of this enzyme with cytosolic acetoacetyl-CoA thiolase can provide acetyl-CoA for lipogenesis and cholesterol synthesis without the need for mitochondrial participation. This new route for acetoacetate utilization may be important in developing brain.


The critical role of dysregulated Hh-FOXM1-TPX2 signaling in human hepatocellular carcinoma cell proliferation.
Aberrant activation of the Hedgehog (Hh) signaling pathway is frequently observed in hepatocellular carcinoma (HCC), nevertheless, the precise molecular mechanism remains unclear. Forkhead box M1 (FOXM1), a target of the Hh pathway, is a key oncofetal transcription factor and a master cell cycle regulator. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is an oncogene critical for mitosis. However, how these molecular events affect HCC progression remains unclear. Realtime PCR, immunohistochemistry, western blotting, and analyses of datasets TCGA and Gene Expression Omnibus (GEO) were conducted to assess the expression of TPX2 and FOXM1 at the mRNA and protein levels in HCC samples or HCC cells. Expression and knockdown of TPX2 and FOXM1 were performed to assess their role in regulating HCC cell proliferation in vitro and in vivo. Dual luciferase report assay and chromosome immunoprecipitation (ChIP) were investigated to seek the FOXM1 binding sites in the promoter of TPX2. Specific antagonists (cyclopamine and GANT61) of the Hh pathway down-regulated TPX2, whereas activation of Hh signaling stimulated TPX2 expression. Furthermore, TPX2 over-expression accelerated HCC cell proliferation when upstream events of Hh signaling were inhibited, and TPX2 knockdown significantly alleviated Sonic Hh ligand (Shh)-induced HCC cell proliferation. Reporter assays and ChIP showed that FOXM1 bound to the TPX2 promoter, confirming that TPX2 is a direct downstream target of FOXM1. Xenograft model further verified the cell function and expression regulation of TPX2 and FOXM1 in vivo. Furthermore, FOXM1 regulated TPX2 activity to drive HCC proliferation. Immunohistochemical (IHC) analysis indicated that FOXM1 and TPX2 were highly-expressed in HCC samples and cohort study revealed that FOXM1 and TPX2 may act as negative predictors for the prognosis of patients with HCC. TPX2 acts as a novel downstream target and effector of the Hh pathway, and Hh signaling contributes to HCC proliferation via regulating the FOXM1-TPX2 cascade, suggesting that this signaling axis may be a novel therapeutic target for HCC.


Is the Kerala Model of Community-Based Palliative Care Operations Sustainable? Evidence from the Field.
The palliative care operation in Kerala, unlike other parts of India, is widespread. Kerala's community-based approach to palliative care is often recognized in the current literature as a sustainable model. However, the sustainability of palliative care operations is not empirically studied, and the domains of sustainability are not clearly explained in the current literature. The present study attempted to explore the following research questions. First, are the community-based palliative care operations in Kerala really sustainable? Second, what are the dimensions of sustainability? To answer these research questions, an empirical field-based investigation was carried out using the case study method. The study was conducted among ten selected palliative care units in the Malappuram and Palakkad districts of Kerala. The records of service delivery, reports, and other available documents were accessed. Interviews were conducted with the key functionaries and other staff of the individual palliative care units. The result of the study indicates that palliative care is delivering uninterrupted and comprehensive care to the needy in the region. Three dimensions were evident as the sustainability of palliative care operation. The replication of this model requires an understanding of these dimensions.


School Nurses as Vital Members of 504 and Individualized Educational Program Teams: Do District-Level Policies Make a Difference in School Nurses' Involvement?
In 2019, 10 to 20 million school-aged youth were identified as having a chronic health condition or disability. However, little is known about U.S. school district policies on school nurses' participation in Individualized Educational Program (IEP) and Section 504 teams to support these youth. Using nationally representative district-level data from the 2016 School Health Policies and Practices Study, we examined whether U.S. school districts have policies on school nurse participation in IEP and 504 development. In addition, we examined the relationship between having such policies and policies on (a) creating and maintaining school teams to assist students with disabilities and (b) the participation of other essential school staff in IEP and 504 development. Among districts with policies regarding school nurse participation in IEP development versus those that did not, a significantly greater proportion had policies on student support teams and counselors' participation on IEP teams (79.2% vs. 44.4%, p < .001, and 98.7% vs. 56.2%, p < .001, respectively). In addition, among districts with policies on school nurse participation in 504 development versus those that did not, a significantly greater proportion also had policies on support teams and counselors' participation on 504 teams (77.5% vs. 43.1%, p < .001, and 97.2% vs. 50.7%, p < .001, respectively). We also examine regional and locale differences in these policies. Findings encourage discussion on student support teams' role in school districts for students with chronic health conditions and disabilities, how school nurses can be essential team members, and better coordination of student care to promote children who are engaged, healthy, and supported within the school community.


Genetic characterization of West Nile virus lineage 2, Greece, 2010.
We conducted a complete genome analysis of a West Nile virus detected in Culex pipiens mosquitoes during a severe outbreak of human West Nile disease in Greece 2010. The virus showed closest genetic relationship to the lineage 2 strain that emerged in Hungary in 2004; increased virulence may be associated with amino acid substitution H249P.


Feasibility of adopting retroperitoneal robotic partial nephrectomy after extensive transperitoneal experience.
Adoption of robotic retroperitoneal surgery has lagged behind robotic surgery adoption in general due to unique challenges of access and anatomy. We evaluated our initial results with robotic retroperitoneal robotic partial nephrectomy (RRPN) after transitioning from exclusively transperitoneal robotic partial nephrectomy (TRPN) to evaluate safety and any identifiable learning curve. We evaluated our single-surgeon (RA) prospective partial nephrectomy database since adopting RRPN routinely for posterior tumors in 2017. The surgeon had previously performed 410 partial nephrectomies by this time. Outcomes were compared after the initial 30 RRPN. Of 137 patients since adopting RRPN, two attempted RRPN were converted to TRPN without complications due to morbid obesity affecting access, and 30 RRPN were completed (107 TRPN). There were no statistically significant differences in demographics, mean tumor size, or RENAL score between groups. Mean blood loss was lower in RRPN (53 mL vs 99 mL, P < 0.05), but there were no transfusions in either group. There was no difference in mean operative (127.8 min vs 141.2 min, P = 0.06) or ischemia time (11.1 min vs 10.8 min, P = 0.98). There were no positive margins in either group. Mean length of stay was lower in RRPN due to more same-day discharges (0.7 vs 0.9 days). There were no 90-day Clavien III-V complications. One RRPN patient was readmitted POD#8 overnight for hypoxia, and one visited the emergency room POD#7 for persistent pain. All three TRPN complications were managed as outpatients. Successful adoption of RRPN can be achieved readily after experience with TRPN. Outcomes were immediately comparable without any identifiable learning curve.


Sleep Characteristics and Cognitive Function in Older Adults Without Dementia: The CABLE Study.
The associations between sleep characteristics and cognition are complicated. Alzheimer's disease (AD) pathologies have been proven to be associated with sleep characteristics. We aimed to investigate the associations between sleep characteristics and cognitive function and examine the roles of AD pathologies in modulating the association of sleep duration with cognition. A total of 974 participants who had measurements of cerebrospinal fluid (CSF) amyloid-β (Aβ), phosphorylated tau (P-tau), total tau proteins (T-tau), cognitive function, and sleep characteristics were included from the Chinese Alzheimer's Biomarker and Lifestyle (CABLE) study. Linear regression analyses were utilized to explore the associations of sleep characteristics with cognition. Non-linear regression analyses were utilized to explore the associations of sleep habits with cognition. Causal mediation analyses were conducted to explore the mediation effects of AD pathologies on cognition. The Pittsburgh Sleep Quality Index (PSQI) total score was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) score (p = 0.0176). Long latency (p = 0.0054) and low efficiency (p = 0.0273) were associated with cognitive impairment. Habitual nap behavior was associated with lower MoCA scores (p = 0.0045). U-shaped associations were observed between sleep habits (bedtime and nocturnal sleep duration) and cognition. A causal mediation analysis indicated that P-tau/Aβ42 mediated the association of sleep duration with cognition. These findings showed sleep characteristics were associated with cognitive functions. Sleep habits (duration, bedtime) had U-shaped associations with cognition. AD core pathologies might partially mediate the influence of sleep duration on cognitive impairments.


Salivary isoamylase in duodenal aspirates.
Salivary isoamylase was measured in duodenal aspirates of 124 consecutive patients during a secretin-pancreozymin test, using an inhibitor method. The isoenzyme was found in 22 patients (17.7%), more often in the patients with abnormal pancreatic function (40.5%) than in those with normal function (8.0%). Before the subtraction of the salivary isoamylase component, total amylase output was falsely normal in three of 37 patients with exocrine pancreatic insufficiency. It is concluded that measurement of amylase isoenzymes rather than of total amylase during the secretin-pancreozymin test may be recommended for scientific purposes. It may also improve discrimination between normal and abnormal exocrine pancreatic function if amylase is chosen as the only parameter for evaluation of pancreatic enzyme secretion.


Sex differences in concomitant medication with benzodiazepines or antidepressants in first-break schizophrenic patients treated with antipsychotic medication.
During a first episode of psychosis, treatment with antipsychotic drugs can improve both positive and negative symptoms. If sufficient amelioration does not occur, adding psychotropic comedication may result in a favorable outcome. To establish sex differences in psychotropic comedication use, we conducted an exploratory retrospective study among first-break patients diagnosed with schizophrenia or schizophreniform disorder. Concerning patient characteristics, no difference in age or antipsychotic drug use was established. At admission, men significantly more often had comorbid substance abuse. Analysis showed that significantly more women than men received benzodiazepines after the onset of psychosis (OR 1.92, 95% CI 1.13-1.27). No sex difference was found in antidepressant comedication (OR 1.22, 95% CI 0.48-3.11). We established a definite sex difference in concomitant benzodiazepine use in first-break patients with schizophrenia. Since women have a better prognosis, we suggest further research to evaluate the efficacy and safety of early benzodiazepine use in the course of schizophrenia. Furthermore, we recommend investigating the possible correlation between benzodiazepine use and substance abuse as a way of treating premorbid symptoms of schizophrenia.


Platelet-Rich stroma from Crohn's disease patients for treatment of perianal fistula shows a higher myeloid cell profile compared to non-IBD controls.
New cell-based therapies are under investigation to improve perianal fistulizing Crohn's disease (pCD) healing. Autologous stromal vascular fraction combined with platelet-rich plasma (referred to as platelet-rich stroma [PRS]) is a new adipose-derived stromal therapy. The effect of Crohn's disease (CD) on adipose tissue, and adipose-derived therapies, is largely unknown. We characterized the cellular composition of subcutaneous lipoaspirate and PRS of pCD patients and non-Inflammatory Bowel Disease (IBD) controls. Consecutive pCD patients (≥18 years) and non-IBD controls, who underwent liposuction for the purpose of autologous PRS therapy, were included (October 2020 and March 2021). Mechanically fractionated lipoaspirate and the combined PRS product were analyzed for cell surface marker expression using fluorescence-activated cell sorting analysis. Twenty-three patients (37.8 [IQR 30.7-45.0] years; 9 [39.1 %] male; 11CD patients) were included. Similar total number of cells were found in CD and non-IBD lipoaspirate (CD 8.23 ± 1.62*105 cells/mL versus non-IBD 12.20 ± 3.39*105). Presence of stromal cells, endothelial like cells, immune cells, T-cells, myeloid cells and M2/M1 macrophage ratio were similar in CD and non-IBD lipoaspirate. In PRS samples, more cells/mL were seen in CD patients (P = 0.030). Myeloid cells were more abundant in CD PRS samples (P = 0.007), and appeared to have a higher regulatory M2/M1 ratio. Interdonor variation was observed between lipoaspirate and PRS samples. The composition of CD and non-IBD lipoaspirate were found to be similar and interdonor variation was observed. However, PRS from CD patients showed more myeloid cells with a regulatory phenotype. Crohn's disease does not appear to alter the immunological composition of adipose-derived products.


Factors Associated With Use of an Online Telemedicine Service to Access Self-managed Medical Abortion in the US.
People in the US have been seeking self-managed abortions outside the formal health care system using medications obtained through online telemedicine. However, little is known about this practice, including potential motivating factors. To examine individual reasons for accessing medication abortion through an online telemedicine service as well as associations between state- and county-level factors and the rate of requests. This population-based cross-sectional study examined all requests for self-managed medication abortion through an online consultation form available from Aid Access, a telemedicine service in the US, between March 20, 2018, and March 20, 2020. Individual-level reasons for accessing the telemedicine service were examined as well as the rate of requests per 100 000 women of reproductive age by state. Zip code data provided by individuals making requests were used to examine county-level factors hypothesized to be associated with increased demand for self-managed abortion: distance to a clinic (calculated using location data for US abortion clinics) and the population proportion identifying as a member of a racial/ethnic minority group, living below the federal poverty level, and having broadband internet access (calculated using census data). During the 2-year study period, 57 506 individuals in 2458 counties in 50 states requested self-managed medication abortion; 52.1% were aged 20 to 29 years (mean [SD] age, 25.9 [6.7] years), 50.0% had children, and 99.9% were 10 weeks' pregnant or less. The most common reasons cited by individuals making requests were the inability to afford in-clinic care (73.5%), privacy (49.3%), and clinic distance (40.4%). States with the highest rate of requests were Louisiana (202.7 per 100 000 women) and Mississippi (199.9 per 100 000 women). At the county level, an increase of 1 SD (47 miles) in distance to the nearest clinic was significantly associated with a 41% increase in requests (incidence rate ratio, 1.41; 95% CI, 1.31-1.51; P < .001), and a 10% increase in the population living below the federal poverty level was significantly associated with a 20% increase in requests (incidence rate ratio, 1.20; 95% CI, 1.13-1.28; P < .001). In this cross-sectional study, clinic access barriers were the most commonly cited reason for requesting self-managed medication abortion using an online telemedicine service. At the county level, distance to an abortion clinic and living below the federal poverty level were associated with a higher rate of requests. State and federal legislation could address these access barriers.


Low serum allopregnanolone levels in children with attention deficit hyperactivity disorder.
Attention deficit hyperactivity disorder (ADHD) has increasing evidence for the role of neurohormones in its etiopathogenesis. It has been suggested that the effects of neurosteroids on the brain in the early developmental period may predispose to neurodevelopmental pathologies. In our study, we examined serum dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and allopregnanolone levels in children with ADHD and whether these neurosteroids differ in the presence of specific learning disorder (SLD) and oppositional defiant disorder (ODD) comorbidities (ADHD+SLD and ADHD+ODD). We also investigated the relationship between neurosteroid levels and the severity of ADHD symptoms. Thirty-five prepubertal children with ADHD and 33 prepubertal healthy children, all aged 6-10 years, were included in this study. The severity of ADHD symptoms was assessed with the parent-rated and teacher-rated Turgay DSM-IV Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S). Serum allopregnanolone levels were significantly lower in the ADHD group compared to healthy controls. When analyzed according to comorbidity status, serum allopregnanolone levels were lower in ADHD+SLD and ADHD+ODD groups compared to healthy controls. However, when compared to healthy children, serum DHEA and DHEA-S levels in children with ADHD were not significantly different. Serum allopregnanolone levels were negatively associated with teacher-rated T-DSM-IV-S hyperactivity/impulsivity scores for all participants only. These findings suggest that allopregnanolone may play a role in the pathophysiology of ADHD, especially in the presence of ODD and SLD comorbidities.


DARTS: An Algorithm for Domain-Associated Retrotransposon Search in Genome Assemblies.
Retrotransposons comprise a substantial fraction of eukaryotic genomes, reaching the highest proportions in plants. Therefore, identification and annotation of retrotransposons is an important task in studying the regulation and evolution of plant genomes. The majority of computational tools for mining transposable elements (TEs) are designed for subsequent genome repeat masking, often leaving aside the element lineage classification and its protein domain composition. Additionally, studies focused on the diversity and evolution of a particular group of retrotransposons often require substantial customization efforts from researchers to adapt existing software to their needs. Here, we developed a computational pipeline to mine sequences of protein-coding retrotransposons based on the sequences of their conserved protein domains-DARTS (Domain-Associated Retrotransposon Search). Using the most abundant group of TEs in plants-long terminal repeat (LTR) retrotransposons (LTR-RTs)-we show that DARTS has radically higher sensitivity for LTR-RT identification compared to the widely accepted tool LTRharvest. DARTS can be easily customized for specific user needs. As a result, DARTS returns a set of structurally annotated nucleotide and amino acid sequences which can be readily used in subsequent comparative and phylogenetic analyses. DARTS may facilitate researchers interested in the discovery and detailed analysis of the diversity and evolution of retrotransposons, LTR-RTs, and other protein-coding TEs.


Identification of intrinsically disordered regions in PTEN and delineation of its function via a network approach.
Intrinsically disordered proteins (IDPs) are proteins that lack stable higher order structures for the entire protein molecule or a significant portion of it. The discovery of IDPs evolved as an antithesis to the conventional structure-function paradigm wherein a higher order structure dictates protein function. Over the last decade, a number of proteins with functionally relevant unstructured regions have been discovered, which includes tumor suppressor PTEN. The protein domains that lack structure provide "hot-spots" for post-translational modifications (PTMs) and protein-protein interactions (PPIs), which facilitate their regulation and participation in multiple cellular processes. Consequently, dysregulation in IDPs contribute to aberrant cellular pathophysiology. Herein, we present PTEN and its translational isoform PTEN-L as a hybrid protein possessing ordered domain and intrinsically disordered C-terminal and an N-terminal tails. We review the role of intrinsic disorder in PTEN function and propose a methodology for the use of intrinsic disorder to study PTEN-regulated higher order protein-networks by associating basic principles of network biology to functional pathway analysis at the systems level.