Long-term Recurrence and Progression Patterns in a Contemporary Series of Patients with Carcinoma In Situ of the Bladder With or Without Associated Ta/T1 Disease Treated with Bacillus Calmette-Guérin: Implications for Risk-adapted Follow-up.
Limited data are available on patients with carcinoma in situ (CIS) of the bladder managed according to current clinical practice guidelines. To assess the patterns of recurrence, progression to muscle-invasive bladder cancer (MIBC), and upper tract urothelial carcinoma (UTUC) in patients with CIS, and to compare the effectiveness of adequate versus inadequate bacillus Calmette-Guérin (BCG) immunotherapy. A retrospective analysis of 386 patients with CIS of the bladder with or without associated pTa/pT1 disease treated with BCG between 2008 and 2015. Kaplan-Meier estimations and an inverse probability of treatment weighting (IPTW)-Cox regression were performed to compare recurrence-free survival (RFS) and progression-free survival (PFS) and UTUC incidence over time for patients who received adequate versus inadequate BCG treatment. The median follow-up was 70.5 mo. At 5 and 10 yr, RFS was 82% and 52%, PFS was 93.6% and 75.8%, and UTUC incidence was 1.7% and 2.9%, respectively. Most recurrence (73.6%) and progression (69.1%) events occurred in the first 3 yr of follow-up, while 38.7% of UTUC incident events were recorded after 5 yr of follow-up. IPTW-Cox regression revealed that patients who received BCG treatment had a lower risk of recurrence (hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.13-0.34), progression (HR 0.46, 95% CI 0.25-0.87), and UTUC incidence (HR 0.24, 95% CI 0.09-0.64). Limitations include the retrospective design and potential selection bias. Patients with CIS of the bladder show a high risk of recurrence, progression, and UTUC incidence. Most of these outcomes occur during the first 3 yr of follow-up, but a significant proportion of the events occur at long-term follow-up. Although receipt of adequate BCG treatment improves outcomes, intensive and long-term surveillance may be warranted. We investigated the long-term cancer control outcomes for patients with carcinoma in situ (CIS; cancerous cells that have not spread from where they first formed) of the bladder. Patients with CIS have a high risk of cancer recurrence and progression. Treatment with bacillus Calmette-Guérin (BCG) improves outcomes.


Glial-mesenchymal tropism of in vivo avian sarcoma virus neuro-oncogenesis in rats.
Intracerebral inoculation of avian sarcoma virus (ASV) in postnatal animals induces gliomas and sarcomas but no neuronal tumors. High titer Bratislava-77 strain ASV was inoculated intracerebrally in fetal F-344 rats between 17 and 20 days of gestation: a time of active neuronal proliferation. Following birth inoculated rats developed gliomas and sarcomas but no neuronal tumors. The results are evidence that the glial-mesenchymal tropism of in vivo ASV neuro-oncogenesis is independent of stage of neurocytodifferentiation at inoculation.


Correlates of consistent condom use among recently initiated and traditionally circumcised men in the rural areas of the Eastern Cape Province, South Africa.
Consistent use of condoms is the most effective method of preventing STIs including HIV. However, recent evidence suggests that limited knowledge about HIV prevention benefits from male circumcision leads to inconsistent condom use among traditionally circumcised men. The aim of this paper is to report on the prevalence of consistent condom use and identify its psychosocial correlates to inform future HIV prevention strategies among traditionally circumcised men in rural areas of the Eastern Cape Province of South Africa. A cross-sectional study using interviewer administered fully structured questionnaires was conducted among 1656 men who had undergone initiation and traditional male circumcision in rural areas of the Eastern Cape Province of South Africa. Logistic regression was used to evaluate univariate and multivariate relationships of psychosocial correlates with consistent condom use. The mean age of the participants was 21.4 years. About 45% belonged to the amaXhosa ethnic group, followed by 15.1% of the amaMpondo, 11.6% of the amaHlubi, and 27.9% from other ethnic groups. A total of 72.3% reported having a main sexual partner and of those 44.8% indicated having other sexual partners as well. About 49% reported consistent condom use and 80% used free government issued condoms, varies among ethnic groups. A total of 35.1% indicated having tested for HIV. Of those who tested for HIV, 46% reported inconsistent condom use when having sex with their sexual partners. Univariate and multivariate analyses showed a positive association between consistent condom use and the general knowledge of condom use, attitude towards condom use with main and casual sexual partners, subjective norm towards condom use with the main sexual partner, perceived self-efficacy towards condom use, positive self-esteem, beliefs about traditional male circumcision and STI protection, attitude towards gender based violence, and cultural alienation. The study findings reveal important target points for future cultural sensitive health education aimed at increasing consistent condom use among initiated and traditionally circumcised men in the Eastern Cape Province.


Exercise, diet and stress as modulators of gut microbiota: Implications for neurodegenerative diseases.
The last decade has witnessed an exponentially growing interest in gut microbiota and the gut-brain axis in health and disease. Accumulating evidence from preclinical and clinical research indicate that gut microbiota, and their associated microbiomes, may influence pathogenic processes and thus the onset and progression of various diseases, including neurological and psychiatric disorders. In fact, gut dysbiosis (microbiota dysregulation) has been associated with a range of neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and motor neuron disease, as well as multiple sclerosis. The gut microbiota constitutes a dynamic microbial system constantly challenged by many biological variables, including environmental factors. Since the gut microbiota constitute a changeable and experience-dependent ecosystem, they provide potential therapeutic targets that can be modulated as new interventions for dysbiosis-related disorders, including neurodegenerative diseases. This article reviews the evidence for environmental modulation of gut microbiota and its relevance to brain disorders, exploring in particular the implications for neurodegenerative diseases. We will focus on three major environmental factors that are known to influence the onset and progression of those diseases, namely exercise, diet and stress. Further exploration of environmental modulation, acting via both peripheral (e.g. gut microbiota and associated metabolic dysfunction or 'metabolopathy') and central (e.g. direct effects on CNS neurons and glia) mechanisms, may lead to the development of novel therapeutic approaches, such as enviromimetics, for a wide range of neurological and psychiatric disorders.


Potent and specific peptide inhibitors of human pro-survival protein Bcl-xL.
The Bcl-2 family of proteins plays a critical role regulating apoptosis, and pro-survival Bcl-2 family members are important therapeutic targets due to their overexpression in different cancers. Pro-apoptotic Bcl-2 homology 3 (BH3)-only proteins antagonize pro-survival Bcl-2 protein functions by binding directly to them, and a sub-class of BH3-only proteins termed sensitizers can initiate apoptosis via this mechanism in response to diverse signals. The five pro-survival proteins Bcl-xL, Mcl-1, Bcl-2, Bcl-w and Bfl-1 differ in their binding preferences, with Bcl-xL, Bcl-2 and Bcl-w sharing similar interaction profiles for many natural sensitizers and small molecules. Peptides that bind selectively to just one or a subset of family members have shown utility in assays that diagnose apoptotic blockades in cancer cells and as reagents for dissecting apoptotic mechanism. Combining computational design, combinatorial library screening and rational mutagenesis, we designed a series of BH3 sensitizer peptides that bind Bcl-xL with sub-nanomolar affinity and selectivity up to 1000-fold over each of the four competing pro-survival proteins. We demonstrate the efficacy of our designed BH3 peptides in assays that differentiate between cancer cells that are dependent on different pro-survival proteins.


Capillary electrophoretic separation between Fe(II) and Ni(II) precomplexed with 1,10-phenanthroline in a high concentration buffer of n-butyric acid/ n-butyrate and its application.
The capillary electrophoretic separation was accomplished for Fe(II) and Ni(II) precomplexed with 1,10-phenanthroline (phen) in 2 M n-butyric acid/ n-butyrate buffer at pH 4.5 with direct UV detection at 260 nm. The applied voltage was 5 kV. The high concentration buffer of the n-butyrate resulted in a similar separation mechanism to that of ion-pair reversed-phase high-performance liquid chromatography. The separation would be due to the hydrophobic interaction between the ionic associates, [Fe(phen)(3)]( n-butyrate)(+) and [Ni(phen)(3)]( n-butyrate)(+), with the n-butyrate ion and n-butyric acid as background electrolyte. Linear calibration ranges were obtained for Fe(II) and Ni(II) from 100 to 500 ng ml(-1). The relative standard deviations ( n=10) for 3 g mL(-1) Fe(II) and Ni(II) were 0.090 and 0.086, respectively. Detection limits ( S/ N=3) for Fe(II) and Ni(II) were 20 ng mL(-1). The method was applied to the determination of nickel in aluminium and duralumin alloys.


Action threshold for applying insect growth regulators to tomato for management of irregular ripening caused by Bemisia argentifolii (Homoptera: Aleyrodidae).
The whitefly Bemisia argentifolii Bellows & Perring is a major pest of tomatoes, causing an irregular ripening disorder characterized externally by incomplete or inhibited reddening of fruit, especially in longitudinal sections, and internally by an increase in the amount of white tissue. Experiments were undertaken during the spring and fall of 1997 and 1998 and the spring of 1999 to develop an action threshold for applying the insect growth regulators (IGRs) buprofezin and pyriproxyfen to manage B. argentifolii and irregular ripening. The IGRs were applied when predetermined thresholds were reached and were compared with a high rate of the systemic insecticide imidacloprid, which was applied at transplanting and provided season-long whitefly control. Only plots treated when the numbers of sessile nymphs (second through fourth instars) reached five per 10 leaflets consistently had both external and internal irregular ripening severity ratings similar to the imidacloprid standard. Results were similar for buprofezin and pyriproxyfen even though the modes of action differ. The five nymphs per 10 leaflets threshold lends itself to field scouting because nymphal counts completed in the field using the unaided eye supplemented with a 10x hand lens were linearly and significantly related to counts completed in the laboratory with a dissecting microscope.


Protein unbound pharmacokinetics of ambroxol in the blood and brains of rats and the interaction of ambroxol with Polygala tenuifolia by multiple microdialysis.
Ambroxol elevates glucocerebrosidase (GCase) activity and reduces nigrostriatal alpha-synuclein burden to better ameliorate motor function in Parkinson's disease (PD). Polygala tenuifolia is a potential alternative botanical medicine for the treatment of many nonmotor symptoms of PD commonly used in Taiwanese patients. Co-administration of these two medicines pose potential herb-drug interaction. Our hypothesis is that ambroxol and P. tenuifolia may potentially possess herbal drug synergetic effects in the blood and brain. To investigate this hypothesis, a multiple microdialysis system coupled with validated ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for rat blood and brain samples. Experimental rats were divided into three groups: low-dose and high-dose ambroxol alone (10 mg/kg, i.v. and 30 mg/kg, i.v., respectively) and ambroxol (10 mg/kg, i.v.) pretreated with P. tenuifolia extract (1 g/kg, p.o. for 5 consecutive days). Ambroxol easily penetrated into the brain and reached a maximum concentration in the striatum at approximately 60 min after low- and high-dose treatment. The area under the concentration curve (AUC) ratio increased proportionally at the doses of 10 and 30 mg/kg, which suggested a linear pharmacokinetic manner of ambroxol. The brain penetration of ambroxol was approximately 30-34%, which was defined as the ambroxol AUC blood-to-brain distribution ratio (AUCbrain/AUCblood). The P. tenuifolia extract did not significantly alter the pharmacokinetics of ambroxol in the blood and brain of rats. The present study suggests that it is safety without pharmacokinetic interactions for this dosing regimen to use P. tenuifolia extract and ambroxol together.


Verapamil improves the pacing-induced vasodilatation in symptomatic patients with hypertrophic cardiomyopathy.
The purpose of the study was to assess the effect of verapamil on the response of diastolic coronary flow velocity and coronary vascular resistance to pacing in symptomatic patients with hypertrophic cardiomyopathy. In 14 patients with hypertrophic cardiomyopathy, the coronary flow velocity was detected in the left anterior descending coronary artery using transthoracic Doppler echocardiography. The peak diastolic coronary flow velocity and coronary vascular resistance was measured at baseline and during pacing. Changes of these parameters induced by the pacing (expressed as the percentage of baseline values) were compared on verapamil treatment and after verapamil withdrawal. The same measurements were obtained in ten control subjects. The results show that, in hypertrophic cardiomyopathy patients, increase in coronary flow velocity during pacing was significantly higher on than off verapamil therapy (64.8+/-32.5 vs. 41.1+/-21.3%, P<0.05). In control subjects, pacing-induced increase in coronary flow velocity was comparable to changes in coronary flow velocity in hypertrophic cardiomyopathy patients receiving verapamil (80.2+/-18.4 vs. 64.8+/-32.5%, P>0.05). After verapamil withdrawal in hypertrophic cardiomyopathy patients, coronary flow velocity increase during pacing was significantly lower than in control subjects (41.1+/-21.3 vs. 80.2+/-18.4%, P<0.05). During pacing the coronary vascular resistance decreased more on verapamil than after drug withdrawal (-34.7+/-11.7 vs. -24.6+/-12.9%, P<0.05). In control subjects the coronary vascular resistance decreased during pacing -38.6+/-6.3% to similar extent as in hypertrophic cardiomyopathy patients on verapamil. We can conclude that endothelium-dependent vasodilatation during pacing was impaired in symptomatic patients with hypertrophic cardiomyopathy. Verapamil treatment was able to restore adequate vasodilator response to pacing stress.


ANKRD26 is a new regulator of type I cytokine receptor signaling in normal and pathological hematopoiesis.
Sustained ANKRD26 expression associated with germline ANKRD26 mutations causes thrombocytopenia 2 (THC2), an inherited platelet disorder associated with a predisposition to leukemia. Some patients also present with erythrocytosis and/or leukocytosis. Using multiple human-relevant in vitro models (cell lines, primary patients' cells and patient-derived induced pluripotent stem cells) we demonstrate for the first time that ANKRD26 is expressed during the early steps of erythroid, megakaryocyte and granulocyte differentiation, and is necessary for progenitor cell proliferation. As differentiation progresses, ANKRD26 expression is progressively silenced, to complete the cellular maturation of the three myeloid lineages. In primary cells, abnormal ANKRD26 expression in committed progenitors directly affects the proliferation/differentiation balance for the three cell types. We show that ANKRD26 interacts with and crucially modulates the activity of MPL, EPOR and G-CSFR, three homodimeric type I cytokine receptors that regulate blood cell production. Higher than normal levels of ANKRD26 prevent the receptor internalization that leads to increased signaling and cytokine hypersensitivity. These findings afford evidence how ANKRD26 overexpression or the absence of its silencing during differentiation is responsible for myeloid blood cell abnormalities in patients with THC2.


Optical measurements of eardrum vibrations and sound propagation in the ear canal for the fitting of active middle ear implants.
Middle ear implants (MEI) are for the medical rehabilitation of the hearing function in case of sound conduction hearing losses as well as cochlear hearing losses and their combinations. An objective tool to reach the best fitting of the external worn sound processors is essential for patients who do not want or cannot participate in the fitting process. In addition to Laser-Doppler-Vibrometry (LDV) measurement, the sound pressure was measured distant to the eardrum to attain additional information for comparison. Three groups of patients with different middle ear characteristics were examined. Because of the large spreading of measuring results even within a patient group with similar eardrum and middle ear conditions it is difficult to develop characteristic diagrams which represent the mean values of eardrum displacements with different sound processor adjustments being the base for normative data courses. The LDV measurements can be used as a tool for fitting sound processors by finding individual maximum eardrum velocities in the frequency range 125 Hz to 8 kHz. In comparison to acoustical measurements the optical measurements have advantages concerning lower variations of measurement values, higher spectral resolution, and robustness against disturbing acoustic noise, especially at low frequencies.


Prevalence of sexual abuse among patients with functional disorders of the lower gastrointestinal tract.
To evaluate the links between gastrointestinal disorders and sexual abuse, we asked 344 patients consulting in a specialized tertiary care university hospital or a gastroenterologist in private practice, if they had been sexually abused. Forty per cent of patients suffering from lower functional digestive disorder gave a history of having been victims of sexual abuse in contrast to only 10% of patients with organic diseases (P < 0.0003). The prevalence was similar in private practice and in the university hospital. Abused patients were more likely to complain of constipation (P < 0.03) and diarrhoea (P < 0.04). Anismus was more frequent in patients who had been sexually abused (P < 0.02). The prevalence of abuse was four times greater in patients with lower than with upper functional motor disorders of the gastrointestinal tract (P < 0.002). This study confirms the large prevalence of a past history of sexual abuse among patients consulting for gastrointestinal tract functional disorder, and this whatever the kind of recruitment may be. It shows the association to be much stronger in patients who have a lower rather than an upper gastrointestinal dysfunction, the major complaint of abused patients being constipation and diarrhoea.


Metallothionein, copper and zinc in fetal and neonatal human liver: changes during development.
Total and cytosolic zinc (Zn) and copper (Cu), cytosolic metallothionein (MT) and the Cu-load of MT were investigated in fetal (22, 24 and 32 gestational weeks) and neonatal (2-15 months) human liver. Whereas the fraction of cytosolic Zn remained constant at 66% of the total independent of the stage of development, the fraction of cytosolic Cu increased from 26% in preterm liver to about 100% within 12 months postnatally. The MT content was higher in fetal than in neonatal liver. There was a linear correlation (r = 0.996) between cytosolic MT and Zn in both fetal and neonatal liver but not between MT and Cu. In contrast to fetal liver, the Cu-load of MT in neonatal liver seems to be determined by the Zn/Cu ratio in the cytosol. The results suggest that MT is involved in the regulation of Cu and Zn metabolism during fetal and neonatal development.


Genes and traits associated with chromosome 2H and 5H regions controlling sensitivity of reproductive tissues to frost in barley.
Frost at flowering can cause significant damage to cereal crops. QTL for low temperature tolerance in reproductive tissues (LTR tolerance) were previously described on barley 2HL and 5HL chromosome arms. With the aim of identifying potential LTR tolerance mechanisms, barley Amagi Nijo x WI2585 and Haruna Nijo x Galleon populations were examined for flowering time and spike morphology traits associated with the LTR tolerance loci. In spring-type progeny of both crosses, winter alleles at the Vrn-H1 vernalization response locus on 5H were linked in coupling with LTR tolerance and were unexpectedly associated with earlier flowering. In contrast, tolerance on 2HL was coupled with late flowering alleles at a locus we named Flt-2L. Both chromosome regions influenced chasmogamy/cleistogamy (open/closed florets), although tolerance was associated with cleistogamy at the 2HL locus and chasmogamy at the 5HL locus. LTR tolerance controlled by both loci was accompanied by shorter spikes, which were due to fewer florets per spike on 5HL, but shorter rachis internodes on 2HL. The Eps-2S locus also segregated in both crosses and influenced spike length and flowering time but not LTR tolerance. Thus, none of the traits was consistently correlated with LTR tolerance, suggesting that the tolerance may be due to some other visible trait or an intrinsic (biochemical) property. Winter alleles at the Vrn-H1 locus and short rachis internodes may be of potential use in barley breeding, as markers for selection of LTR tolerance at 5HL and 2HL loci, respectively.


Strategies to Address COVID-19 Vaccine Hesitancy Among Ohio Nursing Home Staff.
Despite federal legislation requiring nursing home (NH) staff members to be vaccinated against coronavirus disease 2019 (COVID-19), unvaccinated staff pose an ongoing public health risk. The research question guiding this study is as follows: What is the relationship between strategies to address vaccine hesitancy and vaccination rates among staff? We used the diffusion of innovation (DOI) theory as a theoretical framework. The sample (N = 627) included Ohio-based NHs. Using national and state NH data, multivariable linear regression techniques demonstrated the relationship between strategies to address vaccine hesitancy and vaccination rates among NH staff. Peer counseling and providing sick time or time off for vaccine symptoms were both statistically significant strategies. Compared to facilities that did not engage in peer counseling, those that did saw an average increase of 3.2% of their staff vaccinated. Those that provided sick time or time off saw an average increase of 3.9% of their staff vaccinated. There was no statistically significant relationship between hiring full- or part-time facility infection preventionists and vaccination rates. In order to foster vaccine confidence among long-term services staff, peer counseling, and providing sick time or time off are examples of strategies that can affect vaccination rates among staff. According to DOI, these strategies target the communication channels and social systems of an organization. While this study focuses on NHs, results remain critically important to the remainder of the long-term services system, which does not have vaccine requirements similar to the NH industry.


Neuroprotective effect of mitochondrial translocator protein ligand in a mouse model of tauopathy.
The translocator protein (TSPO) has been identified as a positron emission tomography (PET)-visible biomarker of inflammation and promising immunotherapeutic target for the treatment of Alzheimer's disease (AD). While TSPO ligands have been shown to reduce the accumulation of the toxic Alzheimer's beta-amyloid peptide, their effect on tau pathology has not yet been investigated. To address this, we analyzed the effects of TSPO ligand, Ro5-4864, on the progression of neuropathology in rTg4510 tau transgenic mice (TauTg). Brain atrophy, tau accumulation, and neuroinflammation were assessed longitudinally using volumetric magnetic resonance imaging, tau-PET, and TSPO-PET, respectively. In vivo neuroimaging results were confirmed by immunohistochemistry for markers of neuronal survival (NeuN), tauopathy (AT8), and inflammation (TSPO, ionized calcium-binding adaptor molecule 1 or IBA-1, and complement component 1q or C1q) in brain sections from scanned mice. TSPO ligand treatment attenuated brain atrophy and hippocampal neuronal loss in the absence of any detected effect on tau depositions. Atrophy and neuronal loss were strongly associated with in vivo inflammatory signals measured by TSPO-PET, IBA-1, and levels of C1q, a regulator of the complement cascade. In vitro studies confirmed that the TSPO ligand Ro5-4864 reduces C1q expression in a microglial cell line in response to inflammation, reduction of which has been shown in previous studies to protect synapses and neurons in models of tauopathy. These findings support a protective role for TSPO ligands in tauopathy, reducing neuroinflammation, neurodegeneration, and brain atrophy.


Dichlorvos exposure and human cancer risk: results from the Agricultural Health Study.
We evaluated cancer risk from DDVP (2,2-Dichloroethenyl dimethylphosphate) exposure among pesticide applicators enrolled in the Agricultural Health Study (AHS) cohort. The AHS is a cohort of 57,311 pesticide applicators in North Carolina and Iowa, enrolled from 1993 to 1997 and followed for cancer through 2004. A comprehensive questionnaire collected information on exposure to DDVP and potential confounders. Among the 49,762 licensed pesticide applicators eligible for analysis, 4,613 reported use of DDVP. DDVP exposure was classified as intensity-weighted cumulative exposure days (IWED), calculated as [years of use x days per year x intensity level]. Poisson regression analysis was used to calculate rate ratios (RR) and 95% confidence intervals (CI) to evaluate the association of DDVP exposure among 2,943 incident cases of cancer. DDVP exposure was not associated with any cancer studied here. We observed no elevation in risk among lymphohematopoietic cancers, RR = 1.00 (95% CI 0.51, 1.96) and a small excess risk associated with exposure among those with a family history of prostate cancer (RR = 1.18 (95% CI 0.73, 1.82). We find little evidence of an association between cumulative lifetime use of DDVP and risk of any cancer at this stage of follow up of the AHS.


Ni(OH)2 nanosheets grown on porous hybrid g-C3N4/RGO network as high performance supercapacitor electrode.
A porous hybrid g-C3N4/RGO (CNRG) material has been fabricated through a facile hydrothermal process with the help of glucose molecules, and serves as an efficient immobilization substrate to support ultrathin Ni(OH)2 nanosheets under an easy precipitation process. It was found that the g-C3N4 flakes can uniformly coat on both sides of the RGO, forming sandwich-type composites with a hierarchical structure. It is worth noting that the introduction of the g-C3N4 can effectively achieve the high dispersion and avoid the agglomeration of the nickel hydroxide, and significantly enhance the synthetically capacitive performance. Owning to this unique combination and structure, the CNRG/Ni(OH)2 composite possesses large surface area with suitable pore size distribution, which can effectively accommodate the electrolyte ions migration and accelerate efficient electron transport. When used as electrode for supercapacitor, the hybrid material exhibits high supercapacitive performance, such as an admirable specific capacitance (1785 F/g at a current density of 2 A/g), desirable rate stability (retain 910 F/g at 20 A/g) and favorable cycling durability (maintaining 71.3% capacity after 5000 cycles at 3 A/g). Such desirable properties signify that the CNRG/Ni(OH)2 composites can be a promising electrode material in the application of the supercapacitor.


Acute dystonia following epileptic seizure after bupropion intoxication.
Bupropion is an effective treatment for major depressive disorder and smoking cessation. In this paper, we present a case report about dystonia in the head and the neck after epileptic seizures due to 4200 mg of extended-release bupropion intake, and we aim to take attention to the rare neuropsychiatric side effects that may occur after the use of high doses of bupropion.


Hemophagocytosis exacerbated by G-CSF/GM-CSF treatment in a patient with myelodysplasia.
We describe a 75-year-old man with neutropenia in whom bone marrow aspirate and biopsy demonstrated hemophagocytosis associated with myelodysplasia (MDS). Therapy with granulocyte-colony stimulating factor (G-CSF) and granulocyte-monocyte-colony stimulating factor (GM-CSF) caused splenomegaly and severe thrombocytopenia, which recurred upon rechallenge. We propose that myeloid growth factors may be detrimental in patients with MDS-associated hemophagocytosis.


Expression of LAT1 and 4F2hc in Gastroenteropancreatic Neuroendocrine Neoplasms.
Little is known about the expression of L-type amino acid transporter 1 (LAT1) and 4F2hc in gastroenteropancreatic-neuroendocrine neoplasms (GEP-NENs). Hence, we conducted a study to verify the clinicopathological significance of LAT1 and 4F2hc. Tissues from 126 patients with GEP-NENs were collected between August 2007 and August 2019 at our institution. We evaluated LAT1 and 4F2hc expression by immunohistochemistry, and examined their clinical significance. No statistically significant associations were observed between LAT1 expression and the different NENs. Expression of 4F2hc was significantly different between neuroendocrine tumour (NET)-G1, NET-G2, and NET-G3 (p=0.029), and was significantly associated with vascular invasion (p=0.044) and the Ki-67 index (p=0.042). No association between LAT1 expression and malignant features in GEP-NENs was observed. However, an association between 4F2hc expression and the potential of malignancy in GEP-NENs was evident.


To PARP or not to PARP?-Toward sensitizing acute myeloid leukemia stem cells to immunotherapy.
A new study reveals that leukemia stem cells (LSCs) in acute myeloid leukemia downregulate natural killer cell-activating receptor ligands to evade immune surveillance via the transcriptional co-factor PARP1. The inhibition of PARP1 sensitizes LSCs to immunotherapy, highlighting its potential as a therapeutic target.


Medical Student Engagement in a Virtual Learning Environment Positively Correlates with Course Performance and Satisfaction in Psychiatry.
There has been a move to a "flipped classroom" (FC) in medical education. The FC promotes active learning and utilizes independent preparation prior to in-class sessions. Few studies have evaluated the effectiveness of the FC approach in medical education, specifically via virtual learning. The purpose of this study evaluates student and faculty perceptions of the FC approach and relationships between student engagement and performance. The first-year medical student psychiatry curriculum was redesigned with an FC approach and subsequently altered by COVID-19 to a virtual learning environment. A mixed-method approach was used to examine both qualitative assessment and quantitative performance data. Students and facilitators were invited to participate in surveys regarding the curriculum changes. Student performance data was collected via quizzes and examinations. Engagement was evaluated by student participation in National Board of Medical Examiners-style multiple-choice questions delivered via Top Hat®. Correlational analyses were used to evaluate associations between engagement and performance. T-tests were used to compare student satisfaction across 2019 and 2020. Performance on in-class questions was positively associated with class rank and performance (p < 0.005). More students were either satisfied or strongly satisfied (91.5%) in 2020 compared to 85.7% in 2019 (two-tailed t-test, p = 0.04). Most students (81.3%) preferred in-class questions to lectures. In 2020, 62.6% of student comments were positive regarding the psychiatry curriculum vs 33.3% in 2019. Over 61.5% of facilitators felt positive towards the changes. Our results demonstrate a positive relationship between engagement and class performance. Students and facilitators positively perceived the approach, with students preferring in-class questions compared to lectures. Future research should evaluate overall performance on standardized tests, third-year clerkships, and number of students matching into psychiatry. The online version contains supplementary material available at 10.1007/s40670-021-01287-x.


Effects of bioreductive agents, tirapazamine and mitomycin C, on quiescent cell populations in solid tumors, evaluated by micronucleus assay.
Mice bearing transplantable solid tumors received 10 intraperitoneal administrations of 5-bromo-2'-deoxyuridine (BrdU) to label the proliferating (P) tumor cells, and were then irradiated with 60Co gamma-rays or injected with cis-diamminedichloroplatinum (II) (cisplatin). The tumor cells were isolated and incubated with cytochalasin-B (a cytokinesis blocker). The micronucleus (MN) frequency in the cells without BrdU labeling, which were regarded as quiescent (Q) cells in the tumor, was determined using immunofluorescence staining for BrdU. The MN frequency in the total (P + Q) tumor cell population was determined from tumors that were not pretreated with BrdU. Pretreatment with tirapazamine, a bioreductive agent, could enhance the sensitivity of tumor cells, including Q cells, to radiation more markedly than mitomycin C pretreatment as judged from an in vivo assay immediately after irradiation. Post-irradiation administration of tirapazamine produced a large post-irradiation radiosensitizing effect on both the total and Q tumor cell populations in vivo. Cisplatin treatment combined with tirapazamine demonstrated that tirapazamine also has a chemosensitizing potential for both the total and Q tumor cell populations. We confirmed that the sensitivity of Q cell populations to radiation and chemotherapy using cisplatin can be enhanced by combined treatment with tirapazamine.


Extracellular matrix changes following blunt trauma to rat skeletal muscles.
Myofiber injury-repair was studied in the rat following blunt trauma to the lower leg in order to understand how the inflammatory and regenerative responses of muscles are altered when myofiber rupture is accompanied by bleeding and clotting reactions. A contusion injury to the muscles of the lower hindlimb of the rat was induced by applying an impact force of 4.7 N-m/cm2 to one leg. The gastrocnemius and soleus muscles were removed bilaterally and evaluated by histochemical and immunohistochemical techniques to document myofiber, vascular, and connective tissue alterations for several days following insult (6-120 hr). A significant increase in wet weight of the gastrocnemius muscle was noted 24 hr postinjury as fluid accumulation and bruising were evident in the muscles resulting from bleeding and inflammation. Vascular disruption was confirmed by the localization of some plasma constituents (fibrinogen, albumin, and complement C3) throughout the interstitial space and even inside some of the damaged myofibers. Inflammation was present and persisted for 5 days as evidenced by continued mast cell degranulation and increased vascular permeability. Using antibodies to identify specific proteoglycans which appear or disappear at various times during muscle regeneration, muscle repair could be followed. The repair process required approximately 10 days for restoration of morphologically intact myofibers. Thus, myofiber repair processes appear to be maintained even after disruption of the vascular system and ischemia following blunt trauma.


Reduced growth hormone releasing factor (GHRF)-like immunoreactivity and GHRF gene expression in the hypothalamus of aged rats.
Growth hormone releasing factor-like immunoreactivity (GHRF-LI) and GHRF mRNA levels were evaluated in the hypothalamus of aged (24 months) and young (3 months) rats by semiquantitative immunocytochemistry and slot blot hybridization technique, respectively. Simultaneous detection of reduced GHRF-LI and GHRF mRNA levels in aged rats as compared to young counterparts demonstrates the existence in aged rats of an impaired function of GHRF-producing neurons.


RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis.
N6-methyladenosine (m6A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m6A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m6A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, m6A-sequencing shows that loss of METTL3 impairs the m6A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m6A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m6A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.


Combined preoperative and postoperative immunotherapy for murine C1300 neuroblastoma.
Preoperative treatment of murine C1300-neuroblastoma (C1300) with triple immunotherapy using low-dose cyclophosphamide (CY), retinyl palmitate (RP), and interleukin-2 (IL2), followed by tumor resection leads to significant initial tumor control and prolonged survival. However, because long-term tumor recurrence is 67%, the efficacy of continued postoperative immunotherapy is now evaluated. Thirty-two A/J mice with 1 cm subcutaneous C1300 tumors were treated for 13 days with CY-100 mg/kg, intraperitoneally (IP), on day 2 of treatment then 25 mg/kg on day 9, RP-2500 IU IP 2 x/week, and IL2 1.6 x 10(5) U IP BID on days 4 to 9 and 11 to 13. On day 14, mice were divided into five treatment groups: (1) OP (operated-tumor resection, n = 6); (2) OP+CY (resection and postoperative CY, n = 7); (3) OP+CY+RP (resection and postoperative CY+RP, n = 7); (4) OP+CY+RP+IL2 (resection and postoperative CY+RP+IL2, n = 7); and (5) CY+RP+IL2 (continued CY+RP+IL2 with no resection, n = 5). Survival and postoperative tumor recurrence were followed for 60 days. The cure rates were group 1 33% (2/6), group 2 43% (3/7), group 3 29% (2/7), group 4 71% (5/7), and group 5 20% (1/5). After surgery, tumors that recurred did so in 8 to 22 days, with no statistical difference noted between groups. MHC class I antigenic expression of tumors resected on day 14 and recurrent tumors was determined with monoclonal antibodies and flow cytometry. In tumors resected on day 14, class I expression measured by mean fluorescence, was 374.8 +/- 27.40.(ABSTRACT TRUNCATED AT 250 WORDS)


Composition, function, and timing: exploring the early-life gut microbiota in piglets for probiotic interventions.
The establishment of a robust gut microbiota in piglets during their early developmental stage holds the potential for long-term advantageous effects. However, the optimal timeframe for introducing probiotics to achieve this outcome remains uncertain. In the context of this investigation, we conducted a longitudinal assessment of the fecal microbiota of 63 piglets at three distinct pre-weaning time points. Simultaneously, we gathered vaginal and fecal samples from 23 sows. Employing 16S rRNA gene and metagenomic sequencing methodologies, we conducted a comprehensive analysis of the fluctuation patterns in microbial composition, functional capacity, interaction networks, and colonization resistance within the gut microbiota of piglets. As the piglets progressed in age, discernible modifications in intestinal microbial diversity, composition, and function were observed. A source-tracking analysis unveiled the pivotal role of fecal and vaginal microbiota derived from sows in populating the gut microbiota of neonatal piglets. By D21, the microbial interaction network displayed a more concise and efficient configuration, accompanied by enhanced colonization resistance relative to the other two time points. Moreover, we identified three strains of Ruminococcus sp. at D10 as potential candidates for improving piglets' weight gain during the weaning phase. The findings of this study propose that D10 represents the most opportune juncture for the introduction of external probiotic interventions during the early stages of piglet development. This investigation augments our comprehension of the microbiota dynamics in early-life of piglets and offers valuable insights for guiding forthcoming probiotic interventions.


Addressing data and methodological limitations in estimating catastrophic health spending and impoverishment in India, 2004-18.
Estimates of catastrophic health expenditure (CHE) are counterintuitive to researchers, policy makers, and developmental partners due to data and methodological limitation. While inferences drawn from use of capacity-to-pay (CTP) and budget share (BS) approaches are inconsistent, the non-availability of data on food expenditure in the health survey in India is an added limitation. Using data from the health and consumption surveys of National Sample Surveys over 14 years, we have overcome these limitations and estimated the incidence and intensity of CHE and impoverishment using the CTP approach. The incidence of CHE for health services in India was 12.5% in 2004, 13.4% in 2014 and 9.1% by 2018. Among those households incurring CHE, they spent 1.25 times of their capacity to pay in 2004 (intensity of CHE), 1.71 times in 2014 and 1.31 times by 2018. The impoverishment due to health spending was 4.8% in 2004, 5.1% in 2014 and 3.3% in 2018. The state variations in incidence and intensity of CHE and incidence of impoverishment is large. The concentration index (CI) of CHE was - 0.16 in 2004, - 0.18 in 2014 and - 0.22 in 2018 suggesting increasing inequality over time. The concentration curves based on CTP approach suggests that the CHE was concentrated among poor. The odds of incurring CHE were lowest among the richest households [OR 0.22; 95% CI: 0.21, 0.24], households with elderly members [OR 1.20; 95% CI:1.12, 1.18] and households using both inpatient and outpatient services [OR 2.80, 95% CI 2.66, 2.95]. Access to health insurance reduced the chance of CHE and impoverishment among the richest households. The pattern of impoverishment was similar to that of CHE. In the last 14 years, the CHE and impoverishment in India has declined while inequality in CHE has increased.


Acute suppurative cholangitis secondary to calcific pancreatitis.
In the absence of calculi or carcinoma, the occurrence of acute suppurative cholangitis secondary to calcific pancreatitis is extremely rare. This report describes the successful management of acute suppurative cholangitis by surgical decompression and use of a new aminoglycoside, amikacin.


Autosomal recessive disease in children of consanguineous parents: inferences from the proportion of compound heterozygotes.
This short communication deals with the questions of how to calculate the expected proportion of compound heterozygous patients among affected offspring of consanguineous parents, and how, from an observed proportion of compound heterozygotes, to calculate both the proportion of homozygotes not identical by descent and the frequency of pathogenic alleles in the population. This estimate of allele frequency may be useful when dealing with populations with a considerable number of consanguineous matings.


Suicidal ideation is insensitive to suicide risk after emergency department discharge: Performance characteristics of the Columbia-Suicide Severity Rating Scale Screener.
We describe the Columbia-Suicide Severity Rating Scale (C-SSRS)-Clinical Practice Screener's ability to predict suicide and emergency department (ED) visits for self-harm in the year following an ED encounter. Screening data from adult patients' first ED encounter during a 27-month study period were analyzed. Patients were excluded if they died during the encounter or left without being identified. The outcomes were suicide as reported by the state health department and a recurrent ED visit for suicide attempt or self-harm reported by the state hospital association. Multivariable regression examined the screener's correlation with these outcomes. Among 92,643 patients analyzed, eleven (0.01%) patients died by suicide within a month after ED visit. The screener's sensitivity and specificity for suicide by 30 days were 0.18 (95% confidence interval [CI] = 0.00 to 0.41) and 0.99 (95% CI = 0.99 to 0.99). Sensitivity and specificity were better for predicting self-harm by 30 days: 0.53 (95% CI = 0.42 to 0.64) and 0.97 (95% CI = 0.97 to 0.97), respectively. Multivariable regression demonstrated that screening risk remained associated with both suicide and self-harm outcomes in the presence of covariates. Suicide risk was not mitigated by hospitalization or psychiatric intervention in the ED. The C-SSRS screener is insensitive to suicide risk after ED discharge. Most patients who died by suicide screened negative and did not receive psychiatric services in the ED. Moreover, most patients with suicidal ideation died by causes other than suicide. The screener was more sensitive for predicting nonfatal self-harm and may inform a comprehensive risk assessment. These results compel us to reimagine the provision of emergency psychiatric services.


Comparison of two incision designs for surgical removal of impacted mandibular third molar: A randomized comparative clinical study.
The objective of this study is to investigate the influence of flap design on visibility and accessibility during removal of impacted third molar and hematoma formation, wound gaping and healing of flap post-operatively. The randomized prospective comparative study included 30 patients with impacted mandibular third molars. Two flap designs namely envelope flap (Koener's incision) and 'triangular flap' (Ward's incision) were used. After 7 days, sutures were removed and status of wound, periodontal health, and progress of healing was assessed. Patients were followed through 15 days to judge the incidence of post-operative complications in both groups. No statistical differences were noted between the groups in terms of visibility, accessibility, excessive bleeding during surgery, healing of flap, sensitivity of adjacent teeth, and dry socket. A statistically significant difference was observed in post-operative hematoma, wound gaping, and distal pocket in adjacent tooth, which was significant in Ward's triangular incision group in comparison to Koeiner's envelope incision group. The selection of the flap design is dependent on needs of the case and preference of the operating surgeon and does not seem to have a significant influence on the health of tissues. In order to avoid wide area of exposure of bone, the operating surgeon should clinically and radiographically assess the designing of incision and mucoperiosteal flap, the clinical relevance is still debatable.


Inulin-type fructans modulate intestinal Bifidobacterium species populations and decrease fecal short-chain fatty acids in obese women.
Inulin-type fructans (ITF) prebiotics promote changes in the composition and activity of the gut microbiota. The aim of this study was to determine variations on fecal short chain fatty acids (SCFA) concentration in obese women treated with ITF and to explore associations between Bifidobacterium species, SCFA and host biological markers of metabolism. Samples were obtained in a randomized, double blind, parallel, placebo-controlled trial, with 30 obese women randomly assigned to groups that received either 16 g/day ITF (n = 15) or maltodextrin (n = 15) for 3 months. The qualitative and quantitative analysis of Bifidobacterium spp. was performed in feces by PCR-DGGE and q-PCR, and SCFA profile was analyzed by gas chromatography. Spearman correlation analysis was performed between the different variables analyzed. The species Bifidobacterium longum, Bifidobacterium pseudocatenulatum and Bifidobacterium adolescentis were significantly increased at the end of the treatment in the prebiotic group (p < 0.01) with being B. longum negatively correlated with serum lipopolysaccharide (LPS) endotoxin (p < 0.01). Total SCFA, acetate and propionate, that positively correlated with BMI, fasting insulinemia and homeostasis model assessment (HOMA) (p < 0.05), were significantly lower in prebiotic than in placebo group after the treatment period. ITF consumption selectively modulates Bifidobacterium spp. and decreases fecal SCFA concentration in obese women. ITF could lessen metabolic risk factors associated with higher fecal SCFA concentration in obese individuals.


Sugar-seeking insects as a source of diverse bread-making yeasts with enhanced attributes.
Insects represent a particularly interesting habitat in which to search for novel yeasts of value to industry. Insect-associated yeasts have the potential to have traits relevant to modern food and beverage production due to insect-yeast interactions, with such traits including diverse carbohydrate metabolisms, high sugar tolerance, and general stress tolerance. Here, we consider the potential value of insect-associated yeasts in the specific context of baking. We isolated 63 yeast strains from 13 species of hymenoptera from the United States, representing 37 yeast species from 14 genera. Screening for the ability to ferment maltose, a sugar important for bread production, resulted in the identification of 13 strains of Candida, Lachancea, and Pichia species. We assessed their ability to leaven dough. All strains produced baked loaves comparable to a commercial baking strain of Saccharomyces cerevisiae. The same 13 strains were also grown under various sugar and salt conditions relevant to osmotic challenges experienced in the manufacturing processes and the production of sweet dough. We show that many of these yeast strains, most notably strains of Lachancea species, grow at a similar or higher rate and population size as commercial baker's yeast. We additionally assessed the comparative phenotypes and genetics of insect-associated S. cerevisiae strains unable to ferment maltose and identified baking-relevant traits, including variations in the HOG1 signaling pathway and diverse carbohydrate metabolisms. Our results suggest that non-conventional yeasts have high potential for baking and, more generally, showcase the success of bioprospecting in insects for identifying yeasts relevant for industrial uses.


Tranexamic acid reduces intraoperative blood loss in orthognathic surgery.
Medline, Embase and the reference lists of identified articles were also scanned for relevant papers. Only randomised controlled trials in English were considered. Two reviewers extracted data independently and study quality was assessed using the Jadad score. Meta-analysis was conducted. Four RCTs with a total of 183 patients were included. Intraoperative blood loss in the tranexamic acid group was statistically reduced (weighted mean difference [WMD] = -93.56, 95% CI = -132.59-54.52, P < .00001). No statistical difference was seen in the postoperative levels of haemoglobin and haematocrit (WMD = 0.50, 95% CIs = -0.43-1.43, P = .29 and WMD = 0.18, 95% CIs = -1.64-1.99, P = .85, respectively). This meta-analysis confirms that tranexamic acid can effectively reduce intraoperative blood loss in orthognathic surgery, especially by intravenous administration. But tranexamic acid cannot affect postoperative levels of haemoglobin and haematocrit.


Genetic influences on mammographic density in Korean twin and family: the Healthy Twin study.
Higher mammographic density is a strong risk factor for breast cancer. This study was conducted to determine the role of genetic factors on mammographic density measurements in Korean women. Study subjects were 730 women (122 monozygotic (MZ) twin pairs, 28 dizygotic (DZ) twin pairs, and 430 first degree relatives) from the Healthy Twin study. Mammographic density was measured using a computer-assisted method. Pairwise correlations of residual variance of each component of mammographic density were calculated within each pair of twins and family members. Quantitative genetic analysis was completed using SOLAR. Age and measured covariates accounted for 50% of the variation in dense area, 70% of non-dense area, and 67% of percent dense area. Fully adjusted heritability coefficients for dense area, non-dense area, and percent dense area were 0.76 (SE = 0.04), 0.69 (SE = 0.04) and 0.68 (SE = 0.04), respectively. Pairwise correlation coefficients of the adjusted residual variance of the mammographic density measures within MZ pairs and within DZ and sibling pairs combined were, respectively, 0.70 and 0.28 for dense area, 0.52 and 0.31 for non-dense area, and 0.58 and 0.24 for percent dense area. Covariance between dense and non-dense area had a significant genetic basis (correlation coefficient = -0.25, SE = 0.06). The same high heritability of mammographic density in Korean women as found in Western women supports a significant role of genetic determinants in breast cancer development. Genes that are responsible for familial correlation in mammographic density and have opposite effects on dense and non-dense mammographic areas need to be elucidated.


Predictors of False Negative Sentinel Lymph Node Biopsy in Clinically Localized Merkel Cell Carcinoma.
Sentinel lymph node biopsy (SLNB) is routinely recommended for clinically localized Merkel cell carcinoma (MCC); however, predictors of false negative (FN) SLNB are undefined. Patients from six centers undergoing wide excision and SLNB for stage I/II MCC (2005-2020) were identified and were classified as having either a true positive (TP), true negative (TN) or FN SLNB. Predictors of FN SLNB were identified and survival outcomes were estimated. Of 525 patients, 28 (5.4%), 329 (62.7%), and 168 (32%) were classified as FN, TN, and TP, respectively, giving an FN rate of 14.3% and negative predictive value of 92.2% for SLNB. Median follow-up for SLNB-negative patients was 27 months, and median time to nodal recurrence for FN patients was 7 months. Male sex (hazard ratio [HR] 3.15, p = 0.034) and lymphovascular invasion (LVI) (HR 2.22, p = 0.048) significantly correlated with FN, and increasing age trended toward significance (HR 1.04, p = 0.067). The 3-year regional nodal recurrence-free survival for males >75 years with LVI was 78.5% versus 97.4% for females ≤75 years without LVI (p = 0.009). Five-year disease-specific survival (90.9% TN vs. 51.3% FN, p < 0.001) and overall survival (69.9% TN vs. 48.1% FN, p = 0.035) were significantly worse for FN patients. Failure to detect regional nodal microscopic disease by SLNB is associated with worse survival in clinically localized MCC. Males, patients >75 years, and those with LVI may be at increased risk for FN SLNB. Consideration of increased nodal surveillance following negative SLNB in these high-risk patients may aid in early identification of regional nodal recurrences.


Erythropoietin Signaling Regulates Key Epigenetic and Transcription Networks in Fetal Neural Progenitor Cells.
Erythropoietin (EPO) and its receptor are highly expressed in the developing nervous system, and exogenous EPO therapy is potentially neuroprotective, however the epigenetic and transcriptional changes downstream of EPO signaling in neural cells are not well understood. To delineate epigenetic changes associated with EPO signaling, we compared histone H3 lysine 4 dimethylation (H3K4me2) in EPO treated and control fetal neural progenitor cells, identifying 1,150 differentially bound regions. These regions were highly enriched near protein coding genes and had significant overlap with H4Acetylation, a mark of active regulatory elements. Motif analyses and co-occupancy studies revealed a complex regulatory network underlying the differentially bound regions, including previously identified mediators of EPO signaling (STAT5, STAT3), and novel factors such as REST, an epigenetic modifier central to neural differentiation and plasticity, and NRF1, a key regulator of antioxidant response and mitochondrial biogenesis. Global transcriptome analyses on neural tubes isolated from E9.0 EpoR-null and littermate control embryos validated our in vitro findings, further suggesting a role for REST and NRF1 downstream of EPO signaling. These data support a role for EPO in regulating the survival, proliferation, and differentiation of neural progenitor cells, and suggest a basis for its function in neural development and neuroprotection.


Success under duress: policies and practices managers view as keys to profitability in five California hospitals with challenging payer mix.
Hospitals with a challenging payer mix (CPM)-high proportions of uninsured and Medicaid patients and a low proportion of commercially insured patients-are an important source of care for low-income, uninsured people. Achieving profitability is difficult for CPM hospitals. From 2005 through 2008, only one-third of 67 CPM hospitals in California reported positive total margins. In-depth group interviews were completed with the management leadership teams of a diverse group of five profitable CPM hospitals to identify the management strategies and practices that the hospitals' leadership teams credited for their financial success. Twelve management policy and practice topics were identified. Four of the policies and practices that managers identified involve organizational actions to increase hospital revenue or operational efficiency. These factors are consistent with those identified in previous research. However, managers also identified eight factors not previously revealed in research on hospital profitability, including management policies and practices that establish the organizational culture, workforce, relationships, monitoring systems, and governance necessary to ensure that hospital employees and affiliated physicians support and successfully implement organizational actions necessary to achieve profitability.


Vero cytotoxin-producing Escherichia coli O157 outbreaks in England and Wales, 1995: phenotypic methods and genotypic subtyping.
Vero cytotoxin-producing Escherichia coli O157 belonging to four phage types (PTs) caused 11 outbreaks of infection in England and Wales in 1995. Outbreak strains of different PTs were distinguishable by DNA-based methods. Pulsed-field gel electrophoresis best discriminated among strains belonging to the same PT, distinguishing six of the seven PT2 outbreak strains and both PT49 outbreak strains.


Parallel age-associated changes in brain and plasma neuronal pentraxin receptor levels in a transgenic APP/PS1 rat model of Alzheimer's disease.
Neuronal pentraxin receptor (NPR) is a synaptic protein implicated in AMPA receptor trafficking at excitatory synapses. Since glutamate neurotransmission is disrupted in Alzheimer's disease (AD), NPR levels measured from plasma represent a potential biomarker for synaptic dysfunction associated with AD. We sought to determine the relationship between AD pathology and brain and plasma NPR levels by examining age-associated NPR levels in these compartments in a transgenic APP/PS1 rat model of AD. NPR levels in cortical homogenate were similar in wild-type (Wt) and APP/PS1 rats at 3 months of age (prior to Aβ plaque deposition), but significantly increased in APP/PS1 rats by 9 and 18-20 months of age (after the onset of plaque deposition). These age-dependent differences were driven by proportional increases in NPR in membrane-associated cortical fractions. Genotype-related differences in NPR expression were also seen in the hippocampus, which exhibits significant Aβ pathology, but not in the cerebellum, which does not. Plasma analyses revealed increased levels of a 26 kDa NPR fragment in APP/PS1 rats relative to Wt rats by 18-20 months of age, which correlated with the levels of full-length NPR in cortex. Our findings indicate that cerebral accumulation of NPR and Aβ occurs with similar temporal and regional patterns in the APP/PS1 model, and suggest that a 26 kDa plasma NPR fragment may represent a peripheral biomarker of this process.


Cryogenic superresolution correlative light and electron microscopy on the frontier of subcellular imaging.
Electron microscopy (EM) reveals cellular ultrastructure at high definition but faces the challenges of identification of specific subcellular structures and localization of specific macromolecules, whereas fluorescence microscopy (FM) can label and localize specific molecules in cells. Correlative light and electron microscopy (CLEM) combines the advantages of both microscopic techniques. Imaging vitreous hydrated samples at cryogenic temperatures using CLEM enables observations of cellular components of interest and their cellular context in a near-native state. This cryo-CLEM approach is further strengthened by incorporation of superresolution fluorescence microscopy, which can precisely pinpoint targets on electron micrographs. Cryogenic superresolution correlative light and electron microscopy (csCLEM) is an emerging and promising imaging technique that is expected to unveil its full power in ultrastructural studies. The present review describes the logic and principles behind this technique, how the method is implemented, the prospects, and the challenges.


Absolute compartment pressure versus differential pressure for the diagnosis of compartment syndrome in tibial fractures.
We studied 39 patients with 42 diaphyseal tibial fractures in whom we suspected a high risk for the development of a compartment syndrome. We measured the anterior absolute compartment pressure (ACP) every 12 h for 72 h and also recorded the differential pressure (DeltaP=diastolic blood pressure-ACP). Fasciotomy of the extremity was only performed when the differential pressure was less than 30 mmHg for more than 30 min. The highest values of the ACP were recorded between 24 h and 36 h after admission. Three fractures had a differential pressure less than 30 mmHg and all were treated by fasciotomy. In three fractures the ACP was equal to or higher than 50 mmHg, of which two had a differential pressure less than 30 mmHg. The patients were followed up for a mean of 36 months (29-45). All fractures healed, and none of our patients showed any sequelae of compartment syndrome at their last review.


A Mediterranean and low-fat dietary intervention in non-alcoholic fatty liver disease patients: Exploring participant experience and perceptions about dietary change.
A Mediterranean diet (MD) appears to be beneficial in non-alcoholic fatty liver disease (NAFLD) patients in Mediterranean countries; however, the acceptability of a MD in non-Mediterranean populations has not been thoroughly explored. The present study aimed to explore the acceptability through understanding the barriers and enablers of the MD and low-fat diet (LFD) interventions as perceived by participating Australian adults from multicultural backgrounds with NAFLD. Semi-structured telephone interviews were performed with 23 NAFLD trial participants at the end of a 12-week dietary intervention in a multicentre, parallel, randomised clinical trial. Data were analysed using thematic analysis. Participants reported that they enjoyed taking part in the MD and LFD interventions and perceived that they had positive health benefits from their participation. Compared with the LFD, the MD group placed greater emphasis on enjoyment and intention to maintain dietary changes. Novelty, convenience and the ability to swap food/meals were key enablers for the successful implementation for both of the dietary interventions. Flavour and enjoyment of food, expressed more prominently by MD intervention participants, were fundamental components of the diets with regard to reported adherence and intention to maintain dietary change. Participants randomised to the MD reported greater acceptability of the diet than those randomised to the LFD, predominantly related to perceived novelty and palatability of the diet.


Cyclic Carbonate Formation from Epoxides and CO2 Catalyzed by Sustainable Alkali Halide-Glycol Complexes: A DFT Study to Elucidate Reaction Mechanism and Catalytic Activity.
We provide a comprehensive DFT investigation of the mechanistic details of CO2 fixation into styrene oxide to form styrene carbonate, catalyzed by potassium iodide-tetraethylene glycol complex. A detailed view on the intermediate steps of the overall reaction clarifies the role of hydroxyl substances as co-catalysts for the alkali halide-catalyzed cycloaddition. The increase of iodide nucleophilicity in presence of tetraethylene glycol is examined and rationalized by NBO and Hirshfeld charge analysis, and bond distances. We explore how different alkali metal salts and glycols affect the catalytic performance. Our results provide important hints on the synthesis of cyclic carbonates from CO2 and epoxides promoted by alkali halides and glycol complexes, allowing the development of more efficient catalysts.


Knowledge of contraceptive effectiveness.
The purpose of this study was to determine women's knowledge of contraceptive effectiveness. We performed a cross-sectional analysis of a contraceptive knowledge questionnaire that had been completed by 4144 women who were enrolled in the Contraceptive CHOICE Project before they received comprehensive contraceptive counseling and chose their method. For each contraceptive method, women were asked "what percentage would get pregnant in a year: <1%, 1-5%, 6-10%, >10%, don't know." Overall, 86% of subjects knew that the annual risk of pregnancy is >10% if no contraception is used. More than 45% of women overestimate the effectiveness of depo-medroxyprogesterone acetate, pills, the patch, the ring, and condoms. After adjustment for age, education, and contraceptive history, the data showed that women who chose the intrauterine device (adjusted relative risk, 6.9; 95% confidence interval, 5.6-8.5) or implant (adjusted relative risk, 5.9; 95% confidence interval, 4.7-7.3) were significantly more likely to identify the effectiveness of their method accurately compared with women who chose either the pill, patch, or ring. This cohort demonstrated significant knowledge gaps regarding contraceptive effectiveness and over-estimated the effectiveness of pills, the patch, the ring, depo-medroxyprogesterone acetate, and condoms.


Primary health care in China: is China's health reform reform for the whole nation?
Good primary health care can enhance national health status at relatively low cost. The barefoot doctor model in China was once considered to have been a successful health care policy. It was a model which was followed by other low-developed or developing countries. In recent decades, the Chinese government promulgated a number of new policies and health reforms to improve its health care system. This paper aimed to highlight the great significance of primary health care and appeal to the policymakers to change the priority to primary health care in order to be able to guarantee universal health care for the whole nation at least at primary care level. This study discussed Chinese primary health care by reviewing its history and development. Chinese government's efforts do not seem to be leading to a completely successful outcome for all the people of China as a result of the substantial imbalance of investments between tertiary level hospitals and grass-root level health care institutions. The government appears to have neglected the importance of primary health care in the implementation of health systems and resources.


Argon as Distending Medium in Laparoscopy Compared with Carbon Dioxide and Nitrous Oxide
The study investigated the inert gas argon as a distending medium during laparoscopic tubal sterilization under local anesthesia, and compared it with carbon dioxide (CO2) and nitrous oxide (N2O). Ninety women were assigned to three groups of 30 each, and one of three gases was randomly selected for abdominal distention. The chosen gas was blinded to surgeon, patient, and anesthetist. Induction and maintenance analgesia with midazolam and alfentanil were given by the anesthetist at a predetermined dosage as needed. Lidocaine 1% was given for paracervical block and in the subumbilical suprapubic areas for local anesthesia. A modified McGill pain assessment rating was used to record patients' pain at 1, 24, and 48 hours postoperatively. Postoperative analgesia requirement and time to return to work were also recorded. Intraoperatively, argon required similar analgesia as CO2 and N2O, but at 72 hours was associated with greater discomfort, probably relating to its lower solubility and retention in the abdomen. Time to return to work was not affected. Owing to its similar density (atomic weight 40) compared with molecular weight of 44 for CO2 and N2O, argon can be used interchangeably for distention in the standard insufflator machine. It should undergo further study for this purpose, however.


Enzymatic synthesis/hydrolysis of cholesteryl oleate in surface films. Inhibition by lecithin and its reversal by bile salts.
The synthesis/hydrolysis of cholesteryl oleate as catalyzed by porcine pancreatic cholesterol esterase has been studied in lipid films at the air-buffer interface. With only reactants and products initially present at the interface, equilibrium is rapidly attained at subphase enzyme concentrations of 4 x 10(-8) M or less. The equilibrium constant for the reaction, 1.4 x 10(-8) mol/cm2, is independent of pH, initial composition, and surface pressure. Lecithin, if present in molar excess relative to the sum of free and esterified cholesterol, is inhibitory. Inhibition is associated with division of the substrate into reactive and unreactive pools which are not exchangeable. Bile salts and other surfactants reverse the inhibition at concentrations one-tenth their critical micelle concentrations. Presumably this occurs through formation of a surfactant surface excess at the lipid-water interface which disrupts the unreactive lecithin-substrate complex. The adsorption of cholesterol esterase to oleic acid monolayers is first order with respect to enzyme and is saturable. At saturation, the enzyme forms a close packed monolayer at the lipid-water interface with a molecular area of 4510 A2. Adsorption of cholesterol esterase to lecithin monolayers is less than one-tenth that to oleic acid monolayers and is proportional to subphase enzyme concentration. With either lipid monolayer, enzyme denaturation at the interface was negligible. In the presence of substrate, differences in enzyme absorption can only partially account for the observed inhibition of catalysis by lecithin, indicating that the reactivity or availability of substrate to the adsorbed enzyme is also affected.


Characterization of human adipose-derived stem cells using flow cytometry.
One of the hallmark characteristics of human adipose-derived stem cells (hASCs) is their ability to differentiate into cells of mesenchymal lineages. It is also becoming apparent that ASCs can mediate a therapeutic benefit through cytokine, paracrine-driven mechanisms influencing apoptosis, angiogenesis, and potent anti-inflammatory responses. Although there is still no clear consensus on the antigen expression pattern that will define hASCs, a protocol is also presented for the flow cytometric analysis utilizing a series of antibody panels. The analysis of these surface epitope patterns can aide in the isolation and characterization of hASCs. Moreover, using this standardized antibody panel, direct comparisons can be made between ASCs isolated from various tissue sources, which will benefit the field by providing uniformity to the comparison process.


Hypertension prevention: from nutrients to (fortified) foods to dietary patterns. Focus on fatty acids.
Diet affects significantly the incidence and severity of cardiovascular diseases and fatty acid intake, in its qualitative as well as quantitative aspects, and influences several risk factors including cholesterol (total, LDL and HDL), triglycerides, platelet aggregation and blood pressure, as evidenced in the 2001 WHO report. This review focuses on the qualitative concern of lipid intake, the various classes of fatty acids of the lipid fraction of the diet, saturated, monounsaturated and polyunsaturated, and their effects on blood pressure. Saturated fat have a bad file and several experimental studies in the rat showed a progressive increase in blood pressure in response to a highly saturated diet. Moreover, a highly saturated diet during gestation led to offspring which, when adults, presented a gender-related hypertension. The mechanism of this effect may be related to the polyunsaturated/saturated ratio (p/s). During the past 20 years, trans fatty acids have been suspected of deleterious health effects, but the investigations have shown that these fatty acids display a biological behaviour close to that of saturated fatty acids (SFA). Moreover, epidemiological investigations did not confirm the relationship between trans fatty acids and cardiovascular pathology. Polyunsaturated fatty acids have been shown to exert a positive action on hypertension. This effect could be attributed to the alteration of the p/s, but mainly to the omega3 polyunsaturated fatty acids (PUFAs). The comparison of several animal models led to the conclusion that long-chain omega3 PUFAs (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) can prevent the increase in blood pressure and reduce established hypertension, but the efficient dose remains an object of discussion. Moreover, the two long-chain omega3 PUFAs, EPA and DHA, display specific effects, which vary with the aetiology of hypertension, because their mechanism of action is different. DHA acts on both blood pressure and heart function (heart rate and ECG) and interferes with the adrenergic function. Conversely, EPA, which is not incorporated in cardiac phospholipids, has no effect on the heart and its mechanism of action is largely unknown. Although it is accepted by the scientific community that the intake of EPA and DHA needs to be increased, we will have to discover new ways to do it, since marine products are the main source of these fatty acids, and this source is not inexhaustible.


Prednisolone induced pneumatosis coli and pneumoperitoneum.
Pneumatosis intestinalis (PI) is defined as the presence of gas within the submucosal or subserosal layer of the gastrointestinal tract. It is a radiologic sign suspicious for bowel ischemia, hence non-viable bowel must be ruled out in patients with PI. However, up to 15% of cases with PI are not associated with bowel ischemia or acute abdomen. We described an asymptomatic patient with prednisolone-induced PI and modified the Naranjo score to aid in a surgeon's decision-making for emergency laparotomy vs non-operative management with serial assessment in patients who are immunocompromised due to long-term steroid use.


Hospitalisations related to lower respiratory tract infections in Northern Queensland.
To investigate the admission characteristics and hospital outcomes for patients admitted with lower respiratory tract infections (LRTI) in Northern Queensland. We perform a retrospective analysis of the data covering an 11-year period, 2006-2016. Length of hospital stay (LOS) is modelled by negative binomial regression and heterogeneous effects are checked using interaction terms. A total of 11,726 patients were admitted due to LRTI; 2,430 (20.9%) were of Indigenous descent. We found higher hospitalisations due to LRTI for Indigenous than non-Indigenous patients, with a disproportionate increase in hospitalisations occurring during winter. The LOS for Indigenous patients was higher by 2.5 days [95%CI: -0.15; 5.05] than for non-Indigenous patients. The average marginal effect of 17.5 [95%CI: 15.3; 29.7] implies that the LOS for a patient, who was admitted to ICU, was higher by 17.5 days. We highlighted the increased burden of LRTIs experienced by Indigenous populations, with this information potentially being useful for enhancing community-level policy making. Implications for public health: Future guidelines can use these results to make recommendations for preventative measures in Indigenous communities. Improvements in engagement and partnership with Indigenous communities and consumers can help increase healthcare uptake and reduce the burden of respiratory diseases.


Whole genome sequencing data of native isolates of Bacillus and Trichoderma having potential biocontrol and plant growth promotion activities in rice.
Six native isolates of Trichoderma and Bacillus having potential for biocontrol and plant growth-promoting activities in rice were isolated from different rice growing regions of India. These isolates were screened for their efficiency in both in vitro and in vivo conditions for three years. The identity of the isolates was confirmed both by morphological and molecular characterization. Three Bacillus spp. viz., Bacillus velenzensis strain BIK2, Bacillus cabrialesii strain BIK3 and Bacillus paralicheniformis strain BIK4 and Trichoderma spp. viz., Trichoderma asperellum strain TAIK1, and T. asperellum strain TAIK5, native to the Telangana state, in Southern India except for strain TAIK4 (Rewa district in the state of Madhya Pradesh in Central India). These promising isolates were subjected for whole genome sequencing using the Illumina platform and data was presented. The data was emanated for Trichoderma asperellum (TAIK1), Trichoderma asperellum (TAIK4), Trichoderma asperellum (TAIK5), Bacillus velezensis (BIK2), Bacillus cabrialesii (BIK3) and Bacillus paralicheniformis (BIK4) isolates had an average 100X coverage of 109X, 150X and 116X; 1447X, 905X and 585X respectively. Further studies on the annotation of the data obtained in correlation with the lab and field performance of these microbes would enable them to be used in metagenomics studies to compare their performance under natural conditions with different microbiota and popular rice varieties. Bioformulation of these strains would be more appropriate with the availability of this genomic data.


Epigenetic inheritance in the mouse.
Acquired epigenetic modifications, such as DNA methylation or stable chromatin structures, are not normally thought to be inherited through the germline to future generations in mammals [1] [2]. Studies in the mouse have shown that specific manipulations of early embryos, such as nuclear transplantation, can result in altered patterns of gene expression and induce phenotypic alterations at later stages of development [3] [4] [5]. These effects are consistent with acquired epigenetic modifications that are somatically heritable, such as DNA methylation. Repression and DNA methylation of genes encoding major urinary proteins, repression of the gene encoding olfactory marker protein, and reduced body weight can be experimentally induced by nuclear transplantation in early embryos [4]. Strikingly, we now report that these acquired phenotypes are transmitted to most of the offspring of manipulated parent mice. This is the first demonstration of epigenetic inheritance of specific alterations of gene expression through the germline. These observations establish a mammalian model for transgenerational effects that are important for humal health, and also raise the question of the evolutionary importance of epigenetic inheritance.


A practical equation to predict resting metabolic rate in older females.
To develop a practical and accurate age-specific equation for predicting resting metabolic rate (RMR) in older women and, thereafter, to cross-validate existing equations for predicting RMR in older females. Cross-sectional validation study. General Clinical Research Center. A convenience sample of 75 healthy older women (age 50-81) free of significant cardiovascular or any other non-cardiac disease that may affect cardiovascular function or metabolic rate. All 75 volunteers were characterized for resting metabolic rate (RMR), body composition, anthropometrics, physical activity, and energy intake. A practical equation for predicting RMR in older women using easily measured variables was: [RMR (kcal/d) = 7.8 (weight,kg) + 4.7 (standing height, cm) -39.5 (menopausal status; 1-3) + 143.5]. These variables accounted for 59% (R2) of the variation in RMR and predicted RMR within +/- 66 kcal/d. When five previously published equations were applied to our sample of older women to predict RMR, individual predicted values deviated by -31% to 20% from the measured value. We offer a practical equation to predict RMR in healthy older women based on a measure of body weight, standing height, and menopausal status.


Tutorial: guidelines for annotating single-cell transcriptomic maps using automated and manual methods.
Single-cell transcriptomics can profile thousands of cells in a single experiment and identify novel cell types, states and dynamics in a wide variety of tissues and organisms. Standard experimental protocols and analysis workflows have been developed to create single-cell transcriptomic maps from tissues. This tutorial focuses on how to interpret these data to identify cell types, states and other biologically relevant patterns with the objective of creating an annotated map of cells. We recommend a three-step workflow including automatic cell annotation (wherever possible), manual cell annotation and verification. Frequently encountered challenges are discussed, as well as strategies to address them. Guiding principles and specific recommendations for software tools and resources that can be used for each step are covered, and an R notebook is included to help run the recommended workflow. Basic familiarity with computer software is assumed, and basic knowledge of programming (e.g., in the R language) is recommended.


Mental disorder prevalence among U.S. Department of Veterans Affairs outpatients with spinal cord injuries.
Depression and other mental disorders are more prevalent among individuals living with spinal cord injury (SCI) than in the community at large, and have a strong association with quality of life. Yet little is known about the prevalence and predictors of mental disorders among U.S. military Veterans living with SCI. The primary aim of this study was to present an estimate of mental disorder point prevalence in this population. The secondary aim was to examine the relationship of mental disorders to demographics, injury characteristics, and other clinically relevant features such as impairment from mental health problems and life satisfaction. Cross-sectional. A SCI & Disorders Center at a U.S. Veterans Affairs Medical Center. Administrative and medical records of 280 Veterans who attended annual comprehensive SCI evaluations were evaluated. Demographics, injury characteristics, self-reported mental and emotional functioning (i.e. SF-8 Health Survey), and clinician-determined mental disorder diagnoses were attained. Overall, 40% of patients received at least one mental disorder diagnosis, most commonly depressive disorders (19%), posttraumatic stress disorder (12%), and substance or alcohol use disorders (11%). Several patient characteristics predicted mental disorders, including age, racial minority identity, non-traumatic SCI etiology, and incomplete (i.e. AIS D) vs. complete injury. Mental disorders were associated with greater impairment from health and mental health-related problems and less satisfaction with life. Mental disorders are common among outpatients receiving VA specialty care for SCI. These findings highlight the importance of having adequate and effective available mental health services available for Veterans with SCI.


Confined space fatalities in Virginia.
To better understand the frequency and characteristics of occupational confined space fatalities in Virginia, we reviewed death certificates, workers' compensation files, a Virginia Occupational Safety and Health Administration listing, and medical examiner records for all 50 fatalities (41 accidents) reported during 1979 to 1986. All fatalities were identified in medical examiner records (50), more than in any other source. The majority of decedents were male craftsmen, operators, or laborers less than 50 years old (mean 38). Drug screens of the 43 decedents tested were negative, with the exception of 2 cases where blood alcohol was detected (greater than or equal to 0.06%). Approximately 5% of "at work" civilian deaths (excluding plane, train, and motor vehicle fatalities) were confined space related. Virginia resident death rates per million employees were highest for shipbuilding and repair facilities (23.2), local government (8.9), and manufacturing other than shipbuilding (5.4%). Multiple fatalities occurred in 4 (10%) of the accidents, with 3 involving 2 fatalities each, and 1 accident involving 7 fatalities. Three fatalities (6%) were rescuers. Fifty nonfatal injuries of rescuers were known to have occurred in these accidents, 15 of co-workers and 35 of community rescue personnel (firefighters and rescue squad members). Approximately half the accidents occurred during the fourth quarter of the year and on a Thursday or Friday, and about one third occurred at night. The leading accident type was atmospheric condition, most commonly oxygen deficiency (33%) or the presence of carbon monoxide (20%). In 6 (40%) of the 15 accidents involving atmospheric condition, the toxic gas or oxygen deficiency was absent in the confined space at the time of entry.(ABSTRACT TRUNCATED AT 250 WORDS)


Binding of sulfonamides to carbonic anhydrase: influence on distribution within blood and on pharmacokinetics.
Four new aromatic sulfonamides were synthesized and purified by standard techniques. Two were unsubstituted, primary sulfonamides and two possessed substituents on the sulfonamide nitrogen. The affinity of the inhibitors for the enzyme carbonic anhydrase was determined in terms of the inhibitory potency, which was found to be dependent on the presence of an unsubstituted sulfonamide group. Binding studies were performed in erythrocyte suspensions using a range of concentrations and the unbound, extracellular concentrations were determined by high-performance liquid chromatographic (HPLC) assay. The dissociation constant of binding and the total binding capacity of the erythrocytes were estimated by nonlinear regression using a two-site binding model. The affinity of the compounds for erythrocytes reflected their inhibitory potency against the enzyme. Binding to plasma proteins was more dependent on lipophilicity and pKa and was stronger for the substituted sulfonamides. Pharmacokinetic studies in rats showed that the unsubstituted sulfonamides with a high affinity for carbonic anhydrase in erythrocytes have longer half-lives and lower clearance values than the substituted sulfonamides which were more strongly bound to plasma proteins. However, comparison of unbound clearance values showed that the variations in molecular structure, which produced differences in carbonic anhydrase binding and in distribution, also produced variations in susceptibility to elimination processes.


Inhibition of IGF-1 receptor kinase blocks the differentiation into cardiomyocyte-like cells of BMSCs induced by IGF-1.
Bone marrow mesenchymal stem cells (BMSCs) have the potential to transdifferentiate into cardiomyocyte‑like cells (CLCs) if an appropriate cardiac environment is provided. Insulin‑like growth factor‑1 (IGF‑1) plays an important role in the cell migration, survival and differentiation of BMSCs. However, the effect of IGF‑1 on the cellular differentiation remains unclear. In the present study, BMSCs were isolated from rat femurs and tibias and the cells were purified at passage 6 (P6). IGF‑1 and IGF‑1 receptor (IGF‑1R) kinase inhibitor I‑OMe AG538 were added to detect if IGF‑1 could induce BMSCs to transdifferentiate into CLCs and if I‑OMe AG538 could inhibit IGF‑1‑mediated receptor activation and downstream signaling. Immunostaining demonstrated that all P6 BMSCs express CD29 and CD44 but not CD45. BMSCs induced by 15 ng/ml IGF‑1 revealed positivity for cardiac troponin‑T and cardiac troponin‑I. The optimal induction time was 14 days but the expression of these proteins were incompletely inhibited by 300 nmol/l I‑OMe AG538 and completely inhibited by 10 µmol/l I‑OMe AG538. Western blotting showed that the level of IGF‑1R autophosphorylation and the expression of cTnT and cTnI were higher when BMSCs were induced for 14 days. I‑OMe AG538 selectively inhibited IGF‑1‑mediated growth and signal transduction and the inhibitory effect of I‑OMe AG538 were not reverted in the presence of exogenous IGF‑1. In addition, when a time course analysis of the effects of I‑OMe AG538 on mitogen‑activated protein kinase kinase and phosphatidylinositol 3‑kinase signaling were done, we observed a transient inhibitory effect on Erk1/2 and Akt phosphorylation, in keeping with the inhibitory effects on cell growth. Taken together, these data indicate that I‑OMe AG538 could inhibit IGF-1-induced CLCs in BMSCs and this effect is time- and concentration-dependent.


Isolation by resistance explains genetic diversity in the Arremon brushfinches of northern Mesoamerica.
Genetic differentiation between and within natural populations is the result of the joint effects of neutral and adaptative processes. In addition, the spatial arrangement of the landscape promotes connectivity or creates barriers to gene flow, directly affecting speciation processes. In this study, we carried out a landscape genomics analysis using NextRAD data from a montane forest specialist bird complex, the Mesoamerican Chestnut-capped/Green-striped Brushfinch of the genus Arremon. Specifically, we examined population genomic structure using different assignment methods and genomic differentiation and diversity, and we tested alternative genetic isolation hypotheses at the individual level (e.g., isolation by barrier, IBB; isolation by environment, IBE; isolation by resistance, IBR). We found well-delimited genomic structuring (K = 5) across Mesoamerican montane forests in the studied group. Individual-level genetic distances among major montane ranges were mainly explained by IBR hypotheses in this sedentary Neotropical taxon. Our results uncover genetic distances/differentiation and patterns of gene flow in allopatric species that support the role of tropical mountains as spatial landscape drivers of biodiversity. IBR clearly supports a pattern of conserved niche-tracking of suitable habitat conditions and topographic complexity throughout glacial-interglacial dynamics.


A new species of Pygoluciola Wittmer with unusual abdominal configuration, from lowland dipterocarp forest in Peninsular Malaysia (Coleoptera: Lampyridae: Luciolinae).
A new species of firefly (Coleoptera: Lampyridae) Pygoluciola dunguna Nada sp. nov. is described from males and reliably associated females, collected mainly from lowland dipterocarp forests of Peninsular Malaysia at elevations below 300 m a.s.l. This species is found to be terrestrial, flying at low heights between 10-15 m above ground in between the herbaceous plants. Males are intermediate between the two types of Pygoluciola Wittmer known until now. A list of species, and a key to males and known females of Pygoluciola is given. The female bursa has paired elongate hook like bursa plates.


The 2021 Texas Power Crisis: distribution, duration, and disparities.
Precipitated by an unusual winter storm, the 2021 Texas Power Crisis lasted February 10 to 27 leaving millions of customers without power. Such large-scale outages can have severe health consequences, especially among vulnerable subpopulations such as those reliant on electricity to power medical equipment, but limited studies have evaluated sociodemographic disparities associated with outages. To characterize the 2021 Texas Power Crisis in relation to distribution, duration, preparedness, and issues of environmental justice. We used hourly Texas-wide county-level power outage data to estimate geographic clustering and association between outage exposure (distribution and duration) and six measures of racial, social, political, and/or medical vulnerability: Black and Hispanic populations, the Centers for Disease Control and Prevention (CDC) Social Vulnerability Index (SVI), Medicare electricity-dependent durable medical equipment (DME) usage, nursing homes, and hospitals. To examine individual-level experience and preparedness, we used a preexisting and non-representative internet survey. At the peak of the Texas Power Crisis, nearly 1/3 of customers statewide (N = 4,011,776 households/businesses) lost power. We identified multiple counties that faced a dual burden of racial/social/medical vulnerability and power outage exposure, after accounting for multiple comparisons. County-level spatial analyses indicated that counties where more Hispanic residents resided tended to endure more severe outages (OR = 1.16, 95% CI: 1.02, 1.40). We did not observe socioeconomic or medical disparities. With individual-level survey data among 1038 respondents, we found that Black respondents were more likely to report outages lasting 24+ hours and that younger individuals and those with lower educational attainment were less likely to be prepared for outages. Power outages can be deadly, and medically vulnerable, socioeconomically vulnerable, and marginalized groups may be disproportionately impacted or less prepared. Climate and energy policy must equitably address power outages, future grid improvements, and disaster preparedness and management.


Association Between Oregon's 12-Month Contraceptive Supply Policy and Quantity of Contraceptives Dispensed.
Eighteen states, including Oregon, have passed legislation requiring insurers to cover dispensation of a 12-month supply of short-acting, hormonal contraception. To determine whether Oregon's 2016 12-month supply law was associated with an increase in contraceptive supply received. This retrospective cohort study of hormonal contraceptive users using Oregon's All Payer All Claims database examined the quantity of contraceptive supply dispensed 3 years before and 3 years after the 2016 policy change. We also assessed changes among patients attributed to Title X clinics. Legislation requiring insurers in Oregon to cover a 12-month supply of contraception to continuing users. Receipt of a 12-month supply of hormonal contraception. This cohort study of insured users (mean [SD] age, 27.4 [2.1] years) of short-acting hormonal contraception included 639 053 contraceptive prescriptions. Results indicated that more than 80% of prescriptions for contraceptives cover 3 months or fewer. Most women in the study population used the oral contraceptive pill, lived in a metropolitan area, and were privately insured. We did not observe a significant association between the passage of the 12-month supply policy and receipt of a 12-month supply (aOR, 1.01; 95% CI, 0.74-1.38). Receipt of a 12-month supply was more common for Medicaid recipients than the privately insured (aOR, 9.40; 95% CI, 6.62-13.34). We did find a shift from 1 month to 2 to 3 months supply being dispensed. The policy change was associated with a small, overall increase in quantity dispensed (0.27 months supply; 95% CI, 0.15 to -0.38). Title X clinics prescribed 3 months more of contraceptive supply than non-Title X clinics (3.03 months supply; 95% CI, 2.64-3.41). However, the policy change was not associated with increased contraceptive supply dispensed at Title X clinics. In this cohort study of insured users of short-acting hormonal contraception, the passage of a 12-month contraceptive supply policy was not associated with an increase in contraceptive supply dispensed.


Maternal and neonatal outcome after vaginal breech delivery of nulliparous versus multiparous women of singletons at term-A prospective evaluation of the Frankfurt breech at term cohort (FRABAT).
The best way to deliver a term breech infant is still a much discussed topic among obstetricians. The question whether nulliparity should be considered an exclusion criterion for an intended vaginal breech delivery is not fully answered. We compared maternal and neonatal outcome of intended vaginal breech deliveries of nulliparous versus multiparous women at term. We conducted a prospective case-control study between January 2004 and December 2016. 1046 women expecting singletons at term with favorable pelvic measurements were enrolled in the study. Neonatal morbidity and mortality was not significantly different in deliveries of nulliparous (n = 647) versus multiparous (n = 399) women. Nulliparous women had a significantly higher rate of a cesarean section during labor than multiparous women. Maternal birth-injury rates and the use of epidural anesthesia were significantly higher comparing vaginal births of nulliparous (n = 384) versus multiparous (n = 331) women. Nulliparity seems not be an exclusion criterion for intended vaginal breech birth at term. It is still important to inform the women of an increased risk of a cesarean section during labor. A clinical management built on this evidence might reduce negative implications for future pregnancies.