Prevalence of common mental health problems and associated factors among university students visiting Supara mental health service: A cross-sectional study.
Background: Early studies found that the mental health problems rate was relatively high in university students. We aimed to investigate the prevalence of mental problems and associated factors in university students. Methods: We conducted a cross-sectional descriptive study at Supara mental health service in the Faculty of Medicine Vajira Hospital between February 2020 to June 2021. The primary outcome was the prevalence of psychiatric diagnosis according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). The secondary assessments included the Patient Health Questionnaire-9 (PHQ-9), 8 items from the Mini International Neuropsychiatric Interview (MINI) to assess suicidal risk (8Q), and the Thai Mental Health Indicator (TMHI-15). The prevalence of mental health problems was presented by frequency and percentage. In addition, multivariable regression analysis was used to identify potential predictors of mental health problems. Results: A total of 184 participants (62% female; mean age = 22.49 years (SD 3.93) were recruited. The depressive disorders, adjustment disorders, and anxiety disorders rates were 57.1%, 15.2% and 13.6%, respectively. Grade point averages (GPAs) below 3.0 (OR=3.09, 95%CI: 1.17-8.14) and a family history of mental disorder (OR=3.40, 95%CI: 1.10-10.48) were significant associated factors of moderate to severe mental health problems. Detecting and screening these factors may help the university to provide early detection and treatment for students. Conclusions: Depressive disorders were the most common mental health disorders. Females, low GPAs and a family history of mental disorder were predictors of moderate to severe mental health problems.


Specific expression and function of the Six3 optix in Drosophila serially homologous organs.
Organ size and pattern results from the integration of two positional information systems. One global information system, encoded by the Hox genes, links organ type with position along the main body axis. Within specific organs, local information is conveyed by signaling molecules that regulate organ growth and pattern. The mesothoracic (T2) wing and the metathoracic (T3) haltere of Drosophila represent a paradigmatic example of this coordination. The Hox gene Ultrabithorax (Ubx), expressed in the developing T3, selects haltere identity by, among other processes, modulating the production and signaling efficiency of Dpp, a BMP2-like molecule that acts as a major regulator of size and pattern. However, the mechanisms of the Hox-signal integration in this well-studied system are incomplete. Here, we have investigated this issue by studying the expression and function of the Six3 transcription factor optix during Drosophila wing and haltere development. We find that in both organs, Dpp defines the expression domain of optix through repression, and that the specific position of this domain in wing and haltere seems to reflect the differential signaling profile among these organs. We show that optix expression in wing and haltere primordia is conserved beyond Drosophila in other higher diptera. In Drosophila, optix is necessary for the growth of wing and haltere. In the wing, optix is required for the growth of the most anterior/proximal region (the 'marginal cell') and for the correct formation of sensory structures along the proximal anterior wing margin; the halteres of optix mutants are also significantly reduced. In addition, in the haltere, optix is necessary for the suppression of sensory bristles.


The structure and function of the alpha C domains of fibrinogen.
The alpha C domains have been localized on fibrinogen and fibrin. Several model systems have been developed to study their functions. Analysis of the amino acid sequence of the alpha C domains suggested that each is made up of a globular and an extended portion. Microcalorimetry confirmed this result and showed that the two alpha C domains interact intramolecularly. Electron microscopy of fibrinogen with a monoclonal antibody to the alpha C domains demonstrated that these regions normally interact with the central portion of the molecule. In the conversion from fibrinogen to fibrin there is a large scale conformational change, such that the alpha C domains dissociate from the central region and are available for intermolecular interaction. Experiments with highly purified and well characterized fragment X monomer, missing either one or both of the alpha C domains, indicate that intermolecular interactions between alpha C domains are important for the enhancement of lateral aggregation during fibrin polymerization. Isolated alpha C fragments polymerized at neutral pH and interacted with the alpha C domains of fibrin monomer to influence clot formation. Several dysfibrinogenemias in which there are amino acid substitutions in, or truncations of, the alpha C domains revealed that these changes can have dramatic effects on polymerization and clot structure. The polymerization of A alpha 251 recombinant fibrinogen, that contains A alpha chains truncated at residue 251, was altered, as were the mechanical properties and the rate of fibrinolysis of the clots. Altogether, these results help to define the role of the alpha C domains in determining the structure and properties of clots.


The Role of Oxidative Stress and Membrane Transport Systems during Endometriosis: A Fresh Look at a Busy Corner.
Endometriosis is a condition characterized by the presence of endometrial tissue outside the uterine cavity, leading to a chronic inflammatory reaction. It is one of the most widespread gynecological diseases with a 10-15% prevalence in the general female population, rising up to 30-45% in patients with infertility. Although it was first described in 1860, its etiology and pathogenesis are still unclear. It is now accepted that inflammation plays a central role in the development and progression of endometriosis. In particular, it is marked by an inflammatory process associated with the overproduction of an array of inflammatory mediators such as prostaglandins, metalloproteinases, cytokines, and chemokines. In addition, the growth and adhesion of endometrial cells in the peritoneal cavity due to reactive oxygen species (ROS) and free radicals lead to disease onset, its ensuing symptoms-among which pain and infertility. The aim of our review is to evaluate the role of oxidative stress and ROS in the pathogenesis of endometriosis and the efficacy of antioxidant therapy in the treatment and mitigation of its symptoms.


Scaling strength and power for body mass differences in rugby union players.
This study on professional rugby union players was undertaken to: 1) confirm a relationship between body mass (BM) and peak force (PF) and peak power (PP); 2) evaluate the effect of ratio and allometric scaling on these relationships; and 3) compare the PF and PP abilities of different positional groups with each approach. Seventy-nine rugby players were assessed for PF during an isometric mid-thigh pull and/or countermovement jump PP. Athlete performance was normalized for BM using standard ratio and allometric scaling methods. The performance data from inside backs (IB), outside backs (OB), tight forwards (TF) and loose forwards (LF) were compared before and after scaling for BM. Significant relationships were identified between BM and the absolute expression of PF (r=0.25) and PP (r=0.44). These relationships improved with the application of ratio scaling (r=-0.53 to -0.57), but were eliminated after allometric scaling with the derived exponents (r=0.00-0.02). No positional group differences in absolute and allometrically scaled PF and PP were seen, but ratio scaled performance favoured the lighter IB and OB over the heavier TF and/or LF (P<0.05). The PF and PP abilities of professional rugby union players were related to individual BM and these relationships were differentially affected by ratio (enhanced) and allometric (removed) scaling. Ratio scaled performance favoured the lighter backs over the heavier forwards, which could be explained by their specific movement patterns within a game. Comparing positional data in such a manner may help practitioners to better quantify, assess and monitor the position-specific needs of athletes in team sport.


How do you circumcise a nation? The Rwandan case study.
Voluntary medical male circumcision has been conclusively demonstrated to reduce the lifetime risk of male acquisition of HIV. The strategy has been adopted as a component of a comprehensive strategy towards achieving an AIDS-free generation. A number of countries in which prevalence of HIV is high and circumcision is low have been identified as a priority, where innovative approaches to scale-up are currently being explored. Rwanda, as one of the priority countries, has faced a number of challenges to successful scale-up. We discuss here how simplifications in the procedure, addressing a lack of healthcare infrastructure and mobilizing resources, and engaging communities of both men and women have permitted Rwanda to move forward with more optimism in its scale-up tactics. Examples from Rwanda are used to highlight how these barriers can and should be addressed.


[Therapy of obesity-associated hypertension].
There is a 50 % prevalence of obesity with arterial hypertension. This ratio can increase up to 80 %, depending on body mass index. Important pathogenetic origins are quantity of visceral body fat along with the activation of neuroendocrineum (sympathicus, renin-angiotensin system), an induction of insulin resistance with hyperinsulinemia, and a direct compression of the medulla by fat deposits in the kidneys, which results in hemodynamic changes and an increase in blood pressure. The primary aim is a reduction in weight by means of a balanced diet and life style modification, which can be augmented by weight reducing medication. Orlistat lowers blood pressure and body weight simultaneously, whereas sibutramine accomplishes this only under certain circumstances. Interestingly, blood pressure increases again over the course of 10 years following weight reducing surgical procedures, despite ongoing weight loss. Antihypertensive differential therapy should be focused on pathophysiology and concomitant and target organ disease. Thus ACE inhibitors (alternatively angiotensin receptor blockers), in combination with low dose diuretics, should be preferentially administered, followed by calcium antagonists. Beta blockers should be used if definite cardiac indications are present.


Exploring the potential relationships among obstructive sleep apnea, erectile dysfunction, and gut microbiota: a narrative review.
Poor sleep quality is closely associated with comorbidities affecting a multitude of organ systems. Among the sleep disorders in the population, there has recently been an increase in the prevalence of obstructive sleep apnea (OSA), which has particularly affected men. The intermittent hypoxia and sleep fragmentation associated with OSA can result in the manifestation or aggravation of a number of pathophysiologic conditions, including the impairment of reproductive function in men and women. In this context, erectile dysfunction (ED) is of particular concern. Other consequences of OSA are changes in the gastrointestinal microbiota, with the resultant dysbiosis having potentially harmful consequences that promote downstream exacerbation of various comorbidities. This narrative review aims to explore the potential relationships among ED, gut microbiota, and OSA. A search of the relevant literature was performed in the PubMed, Embase, Medline, and Web of Science databases. Sleep is important for regulating the body's functions, and sleep deprivation can negatively affect health. OSA can damage organic functions, including reproductive function, and can lead to ED. Restoring the microbiota and improving sleep can help to improve sexual function or reverse ED and enhance other associated conditions mediated through the gut-brain axis relationship. Probiotics and prebiotics can be used as supportive strategies in the prevention and treatment of OSA, as they help to reduce systemic inflammation and improve intestinal barrier function. A good diet, a healthy lifestyle, and proper bowel function are essential in controlling depression and several other pathologies. Modulating the gut microbiota through probiotics and prebiotics can provide a viable strategy for developing new therapeutic options in treating many conditions. A better understanding of these a priori unrelated phenomena would foster our understanding of the effects of OSA on human fertility and how changes in gut microbiota may play a role.


Robust Wald-type tests under random censoring.
Randomly censored survival data are frequently encountered in biomedical or reliability applications and clinical trial analyses. Testing the significance of statistical hypotheses is crucial in such analyses to get conclusive inference but the existing likelihood-based tests, under a fully parametric model, are extremely nonrobust against outliers in the data. Although there exists a few robust estimators given randomly censored data, there is hardly any robust testing procedure available in the literature in this context. One of the major difficulties here is the construction of a suitable consistent estimator of the asymptotic variance of robust estimators, since the latter is a function of the unknown censoring distribution. In this article, we take the first step in this direction by proposing a consistent estimator of asymptotic variance of the M-estimators based on randomly censored data without any assumption on the censoring scheme. We then describe and study a class of robust Wald-type tests for parametric statistical hypothesis, both simple as well as composite, under such a set-up. Robust tests for comparing two independent randomly censored samples and robust tests against one sided alternatives are also discussed. Their advantages and usefulness are demonstrated for the tests based on the minimum density power divergence estimators and illustrated with clinical trials and other medical data.


Repairing an achilles tendon rupture using the partial lindholm technique augmented by the plantaris tendon: a case report.
Many techniques have been described for the treatment of an acute achilles tendon rupture, but there is unfortunately no agreement between orthopedic surgeons regarding the best repair technique and post-treatment rehabilitation protocol. Overall, the surgical methods can be classified as either an open procedure or as a percutaneous procedure. While numerous techniques have been described for open surgical procedures, the strength of the repaired tendon, the healing time, the rerupture rates, and the changes in the range of motion due to adhesions may be the ultimate determining factors of the success of the procedure. In this case study, we report the results of treating a 35-year-old patient who suffered an achilles tendon rupture by combining two recently described surgical methods into a novel repair technique.


Lessons Learned Preparing Volunteer Midwives for Service in Haiti: After the Earthquake.
Midwives for Haiti is an organization that focuses on the education and training of skilled birth attendants in Haiti, a country with a high rate of maternal and infant mortality and where only 26% of births are attended by skilled health workers. Following the 2010 earthquake, Midwives for Haiti received requests to expand services and numerous professional midwives answered the call to volunteer. This author was one of those volunteers. The purpose of the study was: 1) to develop a description of the program's strengths and its deficits in order to determine if there was a need to improve the preparation of volunteers prior to service and 2) to make recommendations aimed at strengthening the volunteers' contributions to the education of Haiti and auxiliary midwives. Three distinct but closely related questionnaires were developed to survey Haitian students, staff midwives, and volunteers who served with Midwives for Haiti. Questions were designed to elicit information about how well the volunteers were prepared for their experience, the effectiveness of translation services, and suggestions for improving the preparation of volunteers and strengthening the education program. Analysis of the surveys of volunteers, staff, midwives, and the Haitian students generated several common themes. The 3 groups agreed that the volunteers made an effective contribution to the program of education and that the volunteer midwives need more preparation prior to serving in Haiti. The 3 groups also agreed on the need for better translators and recommended more structure to the education program. The results of this study are significant to international health care organizations that use volunteer health care professionals to provide services. The results support a growing body of knowledge that international health aid organizations may use to strengthen the preparation, support, and effectiveness of volunteer health providers.


Oral mucosal color changes as a clinical biomarker for cancer detection.
Screening is a key tool for early cancer detection/prevention and potentially saves lives. Oral mucosal vascular aberrations and color changes have been reported in hereditary nonpolyposis colorectal cancer patients, possibly reflecting a subclinical extracellular matrix abnormality implicated in the general process of cancer development. Reasoning that physicochemical changes of a tissue should affect its optical properties, we investigated the diagnostic ability of oral mucosal color to identify patients with several types of cancer. A total of 67 patients with several histologically proven malignancies at different stages were enrolled along with a group of 60 healthy controls of comparable age and sex ratio. Oral mucosal color was measured in selected areas, and then univariate, cluster, and principal component analyses were carried out. Lower red and green and higher blue values were significantly associated with evidence of cancer (all P<0.0001), and efficiently discriminated patients from controls. The blue color coordinate showed significantly higher sensitivity and specificity (96.66±2.77 and 97.16±3.46%, respectively) compared with the red and green coordinates. Likewise, the second principal component coordinate of the red-green clusters discriminated patients from controls with 98.2% sensitivity and 95% specificity (cut-off criterion≤0.4547; P=0.0001). The scatterplots of the chrominances revealed the formation of two well separated clusters, separating cancer patients from controls with a 99.4% probability of correct classification. These findings highlight the ability of oral color to encode clinically relevant biophysical information. In the near future, this low-cost and noninvasive method may become a useful tool for early cancer detection.


A family of estimators to diagnostic accuracy when candidate tests are subject to detection limits-Application to diagnosing early stage Alzheimer disease.
In disease diagnosis, individuals are usually assumed to be one of the two basic types, healthy or diseased, as typically based on an established gold standard. Candidate markers for diagnosing a disease often are much cheaper and less invasive than the gold standard but must be evaluated against the gold standard for their sensitivity and specificity to accurately diagnose the disease. When candidate diagnostic markers are fully measured, receiver operating characteristic curves have been the standard approaches for assessing diagnostic accuracy. However, full measurements of diagnostic markers may not be available above or below certain limits due to various practical and technical limitations. For example, in the diagnosis of Alzheimer disease using cerebrospinal fluid biomarkers, the Roche Elecsys® immunoassays have a measuring range for multiple cerebrospinal fluid molecular concentrations. Many cognitive tests used in diagnosing dementia due to Alzheimer disease are also subject to detection limits, often referred to as the floor and ceiling effects in the neuropsychological literature. We propose a new statistical methodology for estimating the diagnostic accuracy when a diagnostic marker is subject to detection limits by dividing the entire study sample into two sub-samples by a threshold of the diagnostic marker. We then propose a family of estimators to the area under the receiver operating characteristic curve by combining a conditional nonparametric estimator and another conditional semi-parametric estimator derived from Cox's proportional hazards model. We derive the variance to the proposed estimators, and further, assess the performance of the proposed estimators as a function of possible thresholds through an extensive simulation study, and recommend the optimum thresholds. Finally, we apply the proposed methodology to assess the ability of several cerebrospinal fluid biomarkers and cognitive tests in diagnosing early stage Alzheimer disease dementia.


Increasing Prevalence and High Risk of Associated Anomalies in Congenital Vertebral Defects: A Population-based Study.
Congenital vertebral anomalies are a heterogeneous group of diagnoses, and studies on their epidemiology are sparse. Our aim was to investigate the national prevalence and mortality of these anomalies, and to identify associated anomalies. We conducted a population-based nationwide register study and identified all cases with congenital vertebral anomalies in the Finnish Register of Congenital Malformations from 1997 to 2016 including live births, stillbirths, and elective terminations of pregnancy because of major fetal anomalies. Cases were categorized based on the recorded diagnoses, associated major anomalies were analyzed, and prevalence and infant mortality were calculated. We identified 255 cases of congenital vertebral anomalies. Of these, 92 (36%) were diagnosed with formation defects, 18 (7.1%) with segmentation defects, and 145 (57%) had mixed vertebral anomalies. Live birth prevalence was 1.89 per 10,000, and total prevalence was 2.20/10,000, with a significantly increasing trend over time (P<0.001). Overall infant mortality was 8.2% (18/219); 3.5% (3/86) in patients with formation defects, 5.6% (1/18) in segmentation defects, and 12.2% (14/115) in mixed vertebral anomalies (P=0.06). Co-occurring anomalies and syndromes were associated with increased mortality, P=0.006. Majority of the cases (82%) were associated with other major anomalies affecting most often the heart, limbs, and digestive system. In conclusion, the prevalence of congenital vertebral anomalies is increasing significantly in Finnish registers. Detailed and systematic examination is warranted in this patient population to identify underlying comorbidities as the majority of cases are associated with congenital major anomalies. Level III.


Effect of Surgery on Postoperative Levels of the Gut Homeostasis-Regulating Enzyme Intestinal Alkaline Phosphatase.
Intestinal homeostasis is a crucial factor for complication-free short- and long-term postoperative recovery. The brush border enzyme intestinal alkaline phosphatase (IAP) is an important regulator of gut barrier function and intestinal homeostasis and prevents endotoxemia by detoxifying lipopolysaccharides (LPSs). As IAP is predominantly secreted by enterocytes in the duodenum, we hypothesized that pancreaticoduodenectomy (PD) leads to a significantly stronger decrease in IAP than other major abdominal surgery. Pre- and postoperative blood, stool, and intestinal samples were collected from patients undergoing PD, as well as other major surgical procedures without duodenectomy. The samples were analyzed using enzyme histochemistry, the para -nitrophenyl phosphate method for IAP, and the limulus amebocyte lysate assay for LPS. Overall, 88 patients were prospectively enrolled in the study. Fecal IAP activity negatively correlated with serum LPS (r = -0.3603, p = 0.0006). PD led to a significant decline in IAP compared to preoperative baseline levels (p < 0.0001). The decline in IAP correlated with the length of proximal small intestinal resection (r = 0.4271, p = 0.0034). Compared to controls, PD was associated with a much more pronounced reduction in IAP-also after adjusting for surgical trauma (operative time, blood loss; r = 0.4598, p = 0.0086). Simultaneously, PD triggered a clearly more prominent increase in serum LPS compared to controls (p = 0.0001). Increased postoperative LPS was associated with an elongated hospitalization (r = 0.7534, p = 0.0062) and more prominent in pancreatic cancer (p = 0.0009). Based upon the functional roles for IAP, supplementation with exogenous IAP might be a new treatment option to improve short- and long-term outcome after PD.


Curative and palliative MRI-guided laser ablation for drug-resistant epilepsy.
Epilepsy is a common neurological disorder occurring in 3% of the US adult population. It is characterised by seizures resulting from aberrant hypersynchronous neural activity. Approximately one-third of newly diagnosed epilepsy cases fail to become seizure-free in response to antiseizure drugs. Optimal seizure control, in cases of drug-resistant epilepsy, often requires neurosurgical intervention targeting seizure foci, such as the temporal lobe. Advances in minimally invasive ablative surgical approaches have led to the development of MRI-guided laser interstitial thermal therapy (LITT). For refractory epilepsy, this surgical intervention offers many advantages over traditional approaches, including real-time lesion monitoring, reduced morbidity, and in some reports increased preservation of cognitive and language processes. We review the use of LITT for epileptic indications in the context of its application as a curative (seizure freedom) or palliative (seizure reduction) measure for both lesional and non-lesional forms of epilepsy. Furthermore, we address the use of LITT for a variety of extratemporal lobe epilepsies. Finally, we describe clinical outcomes, limitations and future applications of LITT for epilepsy.


Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and diabetic patients.
Endoglin is involved in the regulation of endothelial function, but there are no studies concerning its relation with hypertension- and diabetes-associated pathologies. Thus, we studied the relationship between plasma levels of soluble endoglin and cardiovascular alterations associated with hypertension and diabetes. We analyzed 288 patients: 64 with type 2 diabetes, 159 with hypertension and 65 healthy patients. We assessed the relationship of soluble endoglin plasma levels measured by enzyme-linked immunosorbent assay with basal glycemia, glycosylated hemoglobin, blood pressure, endothelial dysfunction (assessed by pressure wave velocity), hypertensive retinopathy (by Keith-Wagener classification), left ventricular hypertrophy (by Cornell and Sokolow indexes), cardiovascular risk and target organ (heart, vascular, kidney) damage. There are significant correlations between endoglin and glycemia, systolic blood pressure, pulse pressure, pressure wave velocity and electrocardiographically assessed left ventricular hypertrophy. Endoglin levels were significantly higher in patients with diabetes who had nondipper and extreme dipper circadian blood pressure patterns than in dipper circadian patterns, in patients with hypertension and diabetes who had riser pattern than in the other patients, and in patients with diabetes but not hypertension who had extreme dipper pattern than in dipper, nondipper and riser groups. There was also a significant correlation between plasma-soluble endoglin and lower levels of systolic night-day ratio. Higher endoglin levels were found in patients with diabetes who had retinopathy, in patients with diabetes who had a high probability of 10-year cardiovascular risk, and in patients with diabetes and hypertension who had three or more damaged target organs (heart, vessels, kidney) than in those with no organs affected. This study shows that endoglin is an indicator of hypertension- and diabetes-associated vascular pathologies as endothelial dysfunction and cardiovascular damage.


The role of dopaminergic mechanisms on the brain in various models of anxious states.
In tests of "illuminated area" and the "threatening situation" avoidance by rats, apomorphine and phenamine, administered intraperitoneally, attenuate the state of alarm. A similar effect is observed when sulpiride, a selective blocker of D2-receptors of dopamine, and of picrotoxin, a GABA antagonist, are administered. Sulpiride effectively counteracts the anxiolytic effects of all of the dopaminomimetics investigated and of picrotoxin. Haloperidol, a nonselective blocker of the D1- and D2-receptors of dopamine removes the anxiolytic effect of apomorphine, phenamine, and picrotoxin. The microinjection into the ventral region of the midbrain tegmentum of dopamine, or of sulpiride into the nucleus accumbens of the septum, attenuates the state of alarm formed by aversive influences of various biological modalities. By contrast, sulpiride, introduced locally into the tegmentum, or chemical stimulation of the nucleus accumbens of the septum by dopamine, intensifies the state of alarm in the "illuminated area" avoidance test. The participation of dopaminergic mechanisms of the mesolimbic system of the brain in anxiety of various aversive causations is discussed.


Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials.
Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal phase 3 trials. Two randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in nonelderly (18-64 years) and elderly (≥65 years) patients with insomnia. Suvorexant doses of 40/30 mg (nonelderly/elderly) and 20/15 mg (nonelderly/elderly) were evaluated. The primary focus was 40/30 mg, with fewer patients randomized to 20/15 mg. There was an optional 3-month double-blind extension in trial 1. Each trial included a 1-week, randomized, double-blind run-out after double-blind treatment to assess withdrawal/rebound. Efficacy was assessed at week 1, month 1, and month 3 by patient-reported subjective total sleep time and time to sleep onset and in a subset of patients at night 1, month 1, and month 3 by polysomnography end points of wakefulness after persistent sleep onset and latency to onset of persistent sleep (LPS). One thousand twenty-one patients were randomized in trial 1 and 1019 patients in trial 2. Suvorexant 40/30 mg was superior to placebo on all subjective and polysomnography end points at night 1/week 1, month 1, and month 3 in both trials, except for LPS at month 3 in trial 2. Suvorexant 20/15 mg was superior to placebo on subjective total sleep time and wakefulness after persistent sleep onset at night 1/week 1, month 1, and month 3 in both trials and at most individual time points for subjective time to sleep onset and LPS in each trial. Both doses of suvorexant were generally well tolerated, with <5% of patients discontinuing due to adverse events over 3 months. The results did not suggest the emergence of marked rebound or withdrawal signs or symptoms when suvorexant was discontinued. Suvorexant improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.


Corticosteroids decrease glomerular angiotensin receptors.
Angiotensin II (ANG II) receptors of glomerular mesangial cells are regulated in vivo by changes in Na balance, effects that are presumed to be secondary to changes in circulating ANG II. However, since changes in ANG II were accompanied by parallel changes in plasma aldosterone in all models tested, it is possible that aldosterone may have also participated in the modulation of glomerular ANG II receptors. To test this hypothesis, short-term aldosterone infusions within the physiological range were employed to favor actions that would be mediated through a high-affinity mineralocorticoid receptor. The glucocorticoid, dexamethasone, was also tested to determine the mineralocorticoid specificity of the response. Two infusion rates were associated with a decrease in glomerular ANG II receptor density of 33 and 45%, respectively. There were no changes in the affinity of ANG II in either tissue or in adrenal receptor density. Serum potassium and urinary Na/K ratio were lower in the aldosterone group. Spironolactone abolished the effect of aldosterone consistent with an action mediated through a specific mineralocorticoid receptor. Dexamethasone administration produced similar downregulation of glomerular ANG II receptor and was unaccompanied by a change in electrolyte balance or blood volume. These studies support the hypothesis that corticosteroids modulate glomerular ANG II receptors and validate the complexity of glomerular receptor modulation. The downregulation observed would be expected to diminish the ability of ANG II to influence glomerular hemodynamics in models such as mineralocorticoid and glucocorticoid-induced hypertension.


Major Bleeding and Case Fatality Rate with the Direct Oral Anticoagulants in Orthopedic Surgery: A Systematic Review and Meta-Analysis.
The novel direct oral anticoagulants (DOACs) have been proposed as alternatives to low-molecular-weight heparins (LMWHs) for the prevention of venous thromboembolism in orthopedic surgery. However, the clinical impact of postsurgical bleeding with the DOACs has not been extensively evaluated. MEDLINE and EMBASE databases, supplemented with conference abstract books and www.clinicaltrial.gov, were searched up to the first week of March 2015. We included phase II and phase III randomized controlled trials comparing the DOACs with LMWHs in patients undergoing major orthopedic surgery. Data regarding major, fatal, and intracranial bleeding were collected, to calculate the pooled relative risk (RR) and the case-fatality rate (CFR), with 95% confidence interval (CI). We retrieved 25 studies (5 evaluating dabigatran, 4 apixaban, 6 edoxaban, and 10 rivaroxaban), enrolling 42,170 patients. There was no significant difference between the DOACs and LMWHs in the risk of major (1.23 vs. 1.16%; RR: 1.07, 95% CI: 0.89-1.29), fatal (0.02 vs. 0.01%; RR: 1.63, 95% CI: 0.39-6.77), and intracranial bleeding (0 vs. 0.01%; RR: 0.33, 95% CI: 0.03-3.18). The weighted mean CFR of major bleeding was 3.3% (95% CI, 1.5-5.7) and 2.3% (95% CI, 0.7-4.6), respectively. Bleeding complications and the associated CFR during prophylactic anticoagulation in orthopedic surgery were very low and not significantly different between the DOACs and LMWHs.


Pantothenate kinase-associated neurodegeneration is not a synucleinopathy.
Mutations in the pantothenate kinase 2 gene (PANK2) are responsible for the most common type of neurodegeneration with brain iron accumulation (NBIA), known as pantothenate kinase-associated neurodegeneration (PKAN). Historically, NBIA is considered a synucleinopathy with numerous reports of NBIA cases with Lewy bodies and Lewy neurites and some cases reporting additional abnormal tau accumulation. However, clinicopathological correlations in genetically proven PKAN cases are rare. We describe the clinical, genetic and neuropathological features of three unrelated PKAN cases. All three cases were genetically screened for the PANK2 gene mutations using standard Sanger polymerase chain reaction sequencing. A detailed neuropathological assessment of the three cases was performed using histochemical and immunohistochemical preparations. All cases had classical axonal swellings and Perls' positive iron deposition in the basal ganglia. In contrast to neuroaxonal dystrophies due to mutation of the phospholipase A2, group VI (PLA2G6) gene, in which Lewy body pathology is widespread, no α-synuclein accumulation was detected in any of our PKAN cases. In one case (20-year-old male) there was significant tau pathology comprising neurofibrillary tangles and neuropil threads, with very subtle tau pathology in another case. These findings indicate that PKAN is not a synucleinopathy and, hence the cellular pathways implicated in this disease are unlikely to be relevant for the pathomechanism of Lewy body disorders.


Unraveling toxicological mechanisms and predicting toxicity classes with gene dysregulation networks.
The use of genes for distinguishing classes of toxicity has become well established. In this paper we combine the reconstruction of a gene dysregulation network (GDN) with a classifier to assign unseen compounds to their appropriate class. Gene pairs in the GDN are dysregulated in the sense that they are linked by a common expression pattern in one class and differ in this pattern in another class. The classifier gives a quantitative measure on this difference by its prediction accuracy. As an in-depth example, gene pairs were selected that were dysregulated between skin cells treated with either sensitizers or irritants. Pairs with known and novel markers were found such as HMOX1 and ZFAND2A, ATF3 and PPP1R15A, OXSR1 and HSPA1B, ZFP36 and MAFF. The resulting GDN proved biologically valid as it was well-connected and enriched in known interactions, processes and common regulatory motifs for pairs. Classification accuracy was improved when compared with conventional classifiers. As the dysregulated patterns for heat shock responding genes proved to be distinct from those of other stress genes, we were able to formulate the hypothesis that heat shock genes play a specific role in sensitization, apart from other stress genes. In conclusion, our combined approach creates added value for classification-based toxicogenomics by obtaining novel, well-distinguishing and biologically interesting measures, suitable for the formulation of hypotheses on functional relationships between genes and their relevance for toxicity class differences.


Should prostate cancer be considered as a differential diagnosis in patients with osteolytic bone lesions?
Prostate cancer is the most frequently diagnosed cancer in men, as well as the second leading cause of death among cancers after lung cancer. In the United States, it is more prevalent in African-American men than in Caucasian men. Prostate cancer frequently metastasizes to the bone, with most of the reported lesions appearing to be osteoblastic on radiographs. Here, we describe an unusual presentation of metastatic prostate cancer with diffuse osteolytic bone lesions. An 80-year-old previously healthy Hispanic man presented with worsening back pain, difficulty with ambulation, and bladder outlet obstruction. Physical examination was significant for spinal tenderness in the thoracic and lumbar region. Digital rectal examination was remarkable for asymmetric enlargement of the prostate with nodularity and firmness. Imaging studies revealed diffuse osteolytic lesions. His prostate-specific antigen was 562.8 ng/mL (normal 0-4). Prostate biopsy and imaging studies confirmed a diagnosis of metastatic prostate cancer. This case demonstrates that bone metastases of prostate cancer are not purely osteoblastic although most of the reported bone metastases in prostate cancer have been osteoblastic in nature. Therefore, clinicians are to consider metastatic prostate cancer as a differential diagnosis for patients with osteolytic bone lesions.


Multivariate risks among extremely premature infants.
This study was designed to identify risk factors for mortality and morbidity of extremely premature infants born in the surfactant era. The study cohort included 194 infants born at < 29 weeks' gestation at one regional tertiary center between 1983 and 1986. Forty-one infants died. Blinded neurodevelopmental assessments were performed on 149 of 153 (97%) survivors at a mean age of 52 months. Thirty-one (21%) survivors had major impairments: 15 had mental retardation, 8 had multiple impairments, 7 had cerebral palsy, and 1 was blind. Logistic regression analysis identifies five significant risk factors for mortality: grade III or IV intraventricular hemorrhage, birth weight < 800 gm, 5-minute Apgar score < or = 3, male sex, and absence of surfactant therapy. Significant risk factors for any major impairment included sepsis (relative risks [RR] = 6.4), male sex (RR = 3.1), and nonwhite race (RR = 2.8). Hydrocephalus requiring shunting was a significant risk factor for cerebral palsy (RR = 16.4) and neonatal retardation (RR = 16.0). Nonwhite race (RR = 7.3), sepsis (RR = 6.8), and male sex (RR = 3.7) also were significant risk factors for mental retardation. Confirmation of these risk factors should facilitate development of targeted interventions for optimizing long-term outcome.


A new species of the planthopper genus Conosimus associated with an endemic shrub in southern Spain.
The poorly-known genus Conosimus Mulsant et Rey, 1855 (Hemiptera: Fulgoroidea: Issidae) includes six species and is briefly reviewed. Adults and fifth instars of a new species, Conosimus baenai n sp., are described and compared with other species in the genus. The new species is associated with an endemic shrub, Echinospartum boissieri, in Jaen, Spain, in the south of the Iberian Peninsula, one of the richest botanical areas of the Mediterranean Basin.


The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma.
Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) may contribute to tumorigenesis in a subset of tumors via inhibition of tumor suppressors such as retinoblastoma (RB1) by mutated viral T antigens, but the molecular pathogenesis of MCPyV-negative MCC is largely unexplored. Through our MI-ONCOSEQ precision oncology study, we performed integrative sequencing on two cases of MCPyV-negative MCC, as well as a validation cohort of 14 additional MCC cases (n = 16). In addition to previously identified mutations in TP53, RB1, and PIK3CA, we discovered activating mutations of oncogenes, including HRAS and loss-of-function mutations in PRUNE2 and NOTCH family genes in MCPyV-negative MCC. MCPyV-negative tumors also displayed high overall mutation burden (10.09 ± 2.32 mutations/Mb) and were characterized by a prominent UV-signature pattern with C > T transitions comprising 85% of mutations. In contrast, mutation burden was low in MCPyV-positive tumors (0.40 ± 0.09 mutations/Mb) and lacked a UV signature. These findings suggest a potential ontologic dichotomy in MCC, characterized by either viral-dependent or UV-dependent tumorigenic pathways.


Dietary effect of a symmetrical triacylglycerol, 1,3-biseicosapentaenoyl-2-gamma-linolenoyl glycerol, on fatty acid composition of guinea pigs.
The dietary effect of 1,3-biseicosapentaenoyl-2-gamma-linolenoyl glycerol (STG) on the fatty acid composition of guinea pigs was examined and compared with that of an eicosapentaenoic acid ethyl ester (EPA-E) and of a soybean oil (SBO) diet. In terms of content of plasma lipid, EPA-E had a greater hypolipidemic effect than STG. On the other hand, in terms of EPA incorporation, contents of EPA in liver lipid were almost the same in the STG and EPA-E groups. Considering that the amount of EPA administered in the EPA-E group was almost 1.5 times that of the STG group, EPA may be absorbed more effectively as the glycerol ester than as the ethyl ester in guinea pigs. In all the tissue lipids, the STG group had a higher unsaturation index (UI) than the EPA-E group even though there is a lower UI in the STG diet than the EPA-E diet. These results suggest that greater amounts of desaturase products as a whole were synthesized in the STG group than in the other two groups. The dihomo-gamma-linolenic acid/arachidonic acid (DGLA/AA) ratio in plasma total lipids in the STG group was 3.5 times that of SBO group, and the DGLA/AA ratio in the EPA-E group was half that of the SBO group. In liver lipid, the ratios of DGLA/AA and EPA/AA in the STG group were 0.687 and 0.488 (phosphatidylcholine fraction) and 0.237 and 0.752 (phosphatidylethanolamine fraction), respectively. The ratio of DGLA/AA as well as the high EPA/AA ratio obtained in the present study with the STG diet may lead to physiological alterations, including enhanced synthesis of 1- and 3-series eicosanoids.


Pulmonary Embolism in Acute Asthma Exacerbation: Clinical Characteristics, Prediction Model and Hospital Outcomes.
Little is known about the characteristics and impact of acute pulmonary embolism (PE) during episodes of asthma exacerbation. We aimed to characterize patients diagnosed with acute PE in the setting of asthma exacerbation, develop a prediction model to help identify future patients and assess the impact of acute PE on hospital outcomes. We included 758 patients who were treated for asthma exacerbation and underwent a computed tomographic pulmonary angiography (CTA) during the same encounter at a university-based hospital between June 2011 and October 2018. We compared clinical characteristics of patients with and without acute PE and developed a machine learning prediction model to classify the PE status based on the clinical variables. We used multivariable regression analysis to evaluate the impact of acute PE on hospital outcomes. Twenty percent of the asthma exacerbation patients who underwent CTA had an acute PE. Factors associated with acute PE included previous history of PE, high CHA2DS2-VASc score, hyperlipidemia, history of deep vein thrombosis, malignancy, chronic systemic corticosteroids use, high body mass index and atrial fibrillation. Using these factors, we developed a random forest machine learning prediction model which had an 88% accuracy in classifying the acute PE status of the patients (area under the receiver operating characteristic curve = 0.899; 95% confidence interval: 0.885-0.913). Acute PE in asthma exacerbation was associated with longer hospital stay and intensive care unit stay. It is important to consider acute PE, a potentially life-threatening event, in the setting of asthma exacerbation especially when other risk factors are present.


Replacement of SARS-CoV-2 strains with variants carrying N501Y and L452R mutations in Japan: an epidemiological surveillance assessment.
Monitoring the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is important due to concerns regarding infectivity, transmissibility, immune evasion and disease severity. We evaluated the temporal and regional replacement of previous SARS-CoV-2 variants by the emergent strains, Alpha and Delta. We obtained the results of polymerase chain reaction screening tests for variants conducted in multiple commercial laboratories. Assuming that all previous strains would be replaced by one variant, the new variant detection rate was estimated by fitting a logistic growth model. We estimated the transmission advantage of each new variant over the pre-existing virus strains. The variant with the N501Y mutation was first identified in the Kinki region in early February 2021, and by early May, it had replaced more than 90% of the previous strains. The variant with the L452R mutation was first detected in the Kanto-Koshin region in mid-May, and by early August, it comprised more than 90% of the circulating strains. Compared with pre-existing strains, the variant with the N501Y mutation showed transmission advantages of 48.2% and 40.3% in the Kanto-Koshin and Kinki regions, respectively, while the variant with the L452R mutation showed transmission advantages of 60.1% and 71.9%, respectively. In Japan, Alpha and Delta variants displayed regional differences in the replacement timing and their relative transmission advantages. Our method is efficient in monitoring and estimating changes in the proportion of variant strains in a timely manner in each region.


Ischiofemoral Impingement Syndrome: Clinical and Imaging/Guidance Issues with Special Focus on Ultrasonography.
Ischiofemoral impingement syndrome is a neglected cause of posterior hip pain which is derived from narrowing of the space between the lateral aspect of the ischium and the medial aspect of the lesser trochanter. Its diagnosis is challenging and requires the combination of physical tests and imaging studies. In the present narrative review, we found that femoral anteversion predisposes patients to the narrowing of the ischiofemoral space and subsequent quadratus femoris muscle injury. Magnetic resonance imaging serves as the gold-standard diagnostic tool, which facilities the quantification of the ischiofemoral distance and the recognition of edema/fat infiltration/tearing of the quadratus femoris muscle. Ultrasound is useful for scrutinizing the integrity of deep gluteal muscles, and its capability to measure the ischiofemoral space is comparable to that of magnetic resonance. Various injection regimens can be applied to treat ischiofemoral impingement syndrome under ultrasound guidance and they appear to be safe and effective. Finally, more randomized controlled trials are needed to build solid bases of evidence on ultrasound-guided interventions in the management of ischiofemoral impingement syndrome.


Multimorbidity and Mortality Models to Predict Complications Following Percutaneous Coronary Interventions.
Previous percutaneous coronary intervention risk models were focused on single outcome, such as mortality or bleeding, etc, limiting their applicability. Our objective was to develop contemporary percutaneous coronary intervention risk models that not only determine in-hospital mortality but also predict postprocedure bleeding, acute kidney injury, and stroke from a common set of variables. We built risk models using logistic regression from first percutaneous coronary intervention for any indication per patient (n=19 322, 70.6% with acute coronary syndrome) using the Mayo Clinic registry from January 1, 2000 to December 31, 2016. Approval for the current study was obtained from the Mayo Foundation Institutional Review Board. Patients with missing outcomes (n=4183) and those under 18 (n=10) were removed resulting in a sample of 15 129. We built both models that included procedural and angiographic variables (Models A) and precatheterization model (Models B). Death, bleeding, acute kidney injury, and stroke occurred in 247 (1.6%), 650 (4.3%), 1184 (7.8%), and 67 (0.4%), respectively. The C statistics from the test dataset for models A were 0.92, 0.70, 0.77, and 0.71 and for models B were 0.90, 0.67, 0.76, and 0.71 for in-hospital death, bleeding, acute kidney injury, and stroke, respectively. Bootstrap analysis indicated that the models were not overfit to the available dataset. The probabilities estimated from the models matched the observed data well, as indicated by the calibration curves. The models were robust across many subgroups, including women, elderly, acute coronary syndrome, cardiogenic shock, and diabetes. The new risk scoring models based on precatheterization variables and models including procedural and angiographic variables accurately predict in-hospital mortality, bleeding, acute kidney injury, and stroke. The ease of its application will provide useful prognostic and therapeutic information to both patients and physicians.


Role of interferon in the pathogenesis of virus diseases in mice as demonstrated by the use of anti-interferon serum. I. Rapid evolution of encephalomyocarditis virus infection.
The role of interferon in the pathogenesis of encephalomyocarditis (EMC) virus infection was determined by treating mice with potent, partially purified sheep anti-mouse interferon globulin. In control mice, EMC virus was present in low titers in various visceral organs but attained high titers in the brain towards the 4th to 5th day, at which time mice died with signs of central nervous system disease. In mice treated with anti-mouse interferon globulin, virus was present in high titer in visceral organs 24--36 h after viral inoculation and virtually all mice were dead by 45 h. This rapid evolution of EMC virus infection was not observed in mice treated with the globulin fraction prepared from a normal sheep, from a sheep exhibiting a low anti-mouse interferon-neutralizing titer, nor from a sheep having a high titer of antibody to human leukocyte interferon. The experimental results indicated that anti-interferon globulin neutralized the interferon liberated by virus-infected cells, thus permitting extensive virus multiplication in several visceral organs. We conclude that interferon is an important early component of host resistance to this virus infection.


In vitro cormlet production of saffron (Crocus sativus L. Kashmirianus) and their flowering response under greenhouse.
A complete protocol for the saffron cormlet production under in vitro conditions and subsequent flowering under greenhouse conditions is described. Highest number of cormlets (70.0 ± 0.30) per corm slice (explant) could be regenerated on Murashige and Skoog (MS) half strength medium supplemented with thidiazuron (TDZ) (20 µM), Indole acetic acid (IAA) (10 µM), and sucrose (40 g/l). Maximum germination (90%) of these cormlets could be achieved on MS medium containing 6-benzyl amino purine (BAP) (20 µM) and α-naphthalene acetic acid (NAA) (15 µM). In order to increase the size of the in vitro raised cormlets, these were cultured on MS medium containing TDZ (15 µM) and IAA in the range of 1.5-30 µM. Maximum increase in cormlet size could be attained on TDZ (15 µM) + IAA (12.5 µM) + sucrose (30 g/l), and the average size of cormlets was 2.5g. In another experiment, apical vegetative buds of actively growing corms were cultured for cormlet development, and corms of size 2.5g could be developed on MS medium with NAA (15 µM), BAP (20 µM), and sucrose (30 g/l). The in vitro developed cormlets were dried under shade at 25 ± 2°C for 7 d. These were then planted in small cups containing clay loam soil and kept in green house at 20 ± 2°C. In vitro developed cormlets with mean weight 2.5 g showed maximum flowering (25%) as well as vegetative growth (55%), while only 19% cormlets of 2.0 g flowered. To our knowledge this is the first report on successful flowering from in vitro raised cormlets under greenhouse.


Abnormal regulation of insulin secretion in the genetically obese (ob/ob) mouse.
To determine whether the abnormal insulin-secretory activity encountered in obese mice is due to an anomaly in the production of cyclic AMP, islets of lean and obese mice were incubated with forskolin under various conditions. Our data show that, in addition to the well-known quantitative differences in insulin-secretory activity between islets of lean and obese mice, there are important qualitative differences. The islets of obese mice accumulated less cyclic AMP than did those of lean mice in response to given doses of forskolin, yet their insulin secretion was enhanced to much higher values. In the islets of obese mice, but not in those of lean mice, the stimulatory effect of forskolin on insulin secretion was evident even at non-stimulatory concentrations of glucose or in Ca2+-deprived incubation media, showing that the islet of the obese mouse is less dependent on a primary stimulus (glucose) and on the provision of normal concentrations of Ca2+ in the bathing medium than is the islet of the lean mouse.


Assessment of Actin FS and Actin FSL sensitivity to specific clotting factor deficiencies.
We present a two centre study designed to assess the sensitivity of Actin FS and Actin FSL to deficiencies of factor VIII, IX, XI or XII. The study was undertaken at two centres to avoid bias due to the investigations being undertaken on one analyser. Samples from patients with a factor VIII (n = 36, F VIII = < 1.0-50 iu/dl), factor IX (n = 22, F IX = 2-48 iu/dl), factor XI (n = 23, F XI = 5-50 u/dl) or a factor XII (n = 18, F XII = 1-50 u/dl) deficient state were studied. Activated partial thromboplastin times (APTT) were determined using two batches of Actin FS and of Actin FSL; comparison of APTT results between centres was facilitated by the conversion of clotting times to ratios (test divided by geometric mean normal clotting time). APTT ratios were considered to be elevated if greater than two standard deviations above the mean normal. The factor deficient status of each sample was verified by assaying all samples for factors VIII, IX, XI and XII. Clotting factor assays were performed on a Sysmex CA-1000 fitted with research software, which permitted the auto-dilution and testing of three serial dilution of both a reference preparation and each patient's sample. Assay results were calculated using parallel-line Bioassay principles. This procedure allowed for variation in clotting times due to the effect of temporal drift of any of the reagents within the assay system. Actin FS and Actin FSL demonstrate acceptable sensitivity to factor VIII deficiency, however, both reagents failed to detect a large proportion of factor XI (17.4% and 30.4% of samples, respectively) and factor XII (66.7% and 72.2%, respectively) deficiencies. The detection rate with Actin FSL for factor IX deficiency was also poor (36.4% not detected). As factor IX and XI deficiencies are both associated with haemorrhagic disorders, the inability of these reagents to detect such abnormalities gave cause for concern.


Characterisation of the Mechanical Loads and Metabolic Intensity of the CAPO Kids Exercise Intervention for Healthy Primary School Children.
Sedentarism is associated with obesity and other chronic diseases at all ages. Increasing physical activity with in-school interventions, focusing on energy expenditure and bone loading reduces risk of a number of costly chronic diseases. The aim of the current study was to characterise the metabolic and musculoskeletal load intensity of the recent successful CAPO Kids exercise intervention. Pre and early pubertal children (10.4 ± 0.5 years old) from the CAPO Kids trial wore an armband sensor to estimate energy expenditure during a 10-minute CAPO Kids session. Eleven participants performed manoeuvres from the session on a force platform to determine vertical ground reaction forces. In total, 28 boys and 20 girls had armband measures and 11 boys and girls undertook GRF testing. The energy expenditure associated with the 10-minute session was 39.7 ± 9.3 kcal, with an average of 4 kcal·min-1. The intensity of physical activity was 'vigorous' to 'very vigorous' for 34% of the session. Vertical ground reaction forces of the CAPO Kids manoeuvres ranged from 1.3 ± 0.2 BW (cartwheels) to 5.4 ± 2.3 BW (360° jump). CAPO Kids generates adequate load intensity to stimulate positive health adaptations in both metabolic and musculoskeletal systems of pre and early pubertal children. Key pointsEnergy expenditure of a single bout of CAPO Kids yields 39.7±9.3 kcal and includes activities performed at a vigorous and very vigorous intensity.Mechanical loads associated with CAPO Kids surpass five times bodyweight and more than 140 bodyweights per second.CAPO Kids intervention represents a viable approach to stimulate musculoskeletal and metabolic adaptation in children.


The outbreak of monkeypox: A clinical overview.
The development of new zoonotic diseases such as coronavirus disease 2019 (COVID-19) and monkeypox that can cause epidemics and high mortality rates have significantly threatened global health security. However, the increasing number of people with no immunity to poxvirus because of the end of the smallpox vaccination programme has created a vulnerable population for the monkeypox outbreak. On 23 July 2022, it was announced that the World Health Organization's director-general has determined that the multicountry outbreak of monkeypox constitutes a Public Health Emergency of International Concern. The monkeypox virus is an orthopoxvirus that causes a disease with symptoms similar to smallpox but less severe. Many unanswered questions remain regarding monkeypox's pathogenesis, transmission and host reservoir. There is currently no evidence that transmission by individuals can sustain zoonotic infections during human-to-human transmissions; the continued emergence of these pathogens highlights the interconnectedness of animals and humans. The increasing number of monkeypox cases outside the endemic region has highlighted the need for effective global capacity building to prevent the spread of the disease and its impact on global health security. The priority now is to stop the spread of the disease and protect frontline healthcare workers and the most vulnerable individuals. This article aims to comprehensively analyse the various aspects of the transmission and epidemiology of monkeypox. It also explores possible diagnostic techniques, therapeutics and prevention strategies. A key recommendation is that primary care and public health professionals are expected to increase their efforts to be vigilant and contain any potential outbreaks.


Theoretical evaluation of the surface electrochemistry of perovskites with promising photon absorption properties for solar water splitting.
In this work, we present first-principles calculations describing the catalytic activity for of a set of photoelectrocatalysts identified as candidates for total water splitting in a previous screening study for bulk stability and bandgap. Our Density Functional Theory (DFT) calculations of the intermediate energetics for hydrogen evolution and oxygen evolution suggest that none of the proposed materials has the ideal combination of bandgap and surface chemical properties that should allow for total water splitting in a single material. This result suggests that co-catalysts are necessary to overcome the kinetic limitations of the both reactions, although some materials may catalyze one half-reaction, as has been observed in experiment.


Restricted Diffusion in the Bilateral Subcortical Motor Areas Associated with Status Epilepticus in an Infant with Kawasaki Disease.
Status epilepticus (SE) often causes neuronal death in the cerebrum and consequent long-term sequelae. Acute encephalopathy with biphasic seizures and late reduced diffusion is clinically characterized by SE associated with fever and seizure clusters that occur 3-9 days after symptom onset. MRI reveals reduced diffusion in the frontal or frontoparietal subcortical white matter, with sparing of the perirolandic region following seizure clusters. Kawasaki disease (KD) is an acute self-limited vasculitis secondary to activation of the immune system; KD is rarely complicated by acute encephalopathy. We report the case of a male infant who developed SE associated with KD and showed late reduced diffusion in the subcortical white matter beneath the bilateral motor cortices (primary motor, premotor and supplementary motor areas) and the right frontal cortex. The patient had characteristic neurological sequelae in the chronic phase, including clumsiness of fingers and forearms, impaired discrimination of tactile sensation and position sense on digits in his hands and feet, corresponding to the lesions with reduced diffusion at the acute phase.


Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials.
We performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups. Our pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed as well as one-stage regression models with single treatment covariate interactions for subgroup analyses. Four trials were included with a total of 1453 patients. For the primary outcomes, there was no effect of vasopressin on 28-day mortality [relative risk (RR) 0.98, 95% CI 0.86-1.12] or serious adverse events (RR 1.02, 95% CI 0.82-1.26). Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%-3.2%] but fewer arrhythmias (ARD - 2.8%, 95% CI - 0.2% to - 5.3%). Mesenteric ischaemia and acute coronary syndrome events were similar between groups. Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74-0.99), but this finding was not robust to sensitivity analyses. There were no statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion). Vasopressin therapy in septic shock had no effect on 28-day mortality although the confidence intervals are wide. It appears safe but with a different side effect profile from norepinephrine. The finding on reduced RRT should be interpreted cautiously. Future trials should focus on long-term outcomes in select patient groups as well as incorporating cost effectiveness analyses regarding possible reduced RRT use.


Initial and residual activity of VectoBac 12 AS, VectoBac WDG, and VectoLex WDG for control of mosquitoes in Ararat Valley, Turkey.
Two formulations, VectoBac 12 AS and VectoBac WDG, of Bacillus thuringiensis israelensis (Bti) and one formulation, VectoLex WDG, of Bacillus sphaericus were tested against Anopheles maculipennis, Culex pipiens, Culex theileri, Aedes caspius, and Aedes dorsalis larvae in drainage canals, a flooded plain, and a drainage well in the Igdir Plain of Arafat Valley, Turkey. VectoBac 12 AS applied at 0.5 and 1 liter/ha to a drainage canal provided complete control of Cx. theileri and 80% to 98% control of An. maculipennis. VectoLex WDG at 400 g/ha provided 100% larval control of Cx. pipiens and Cx. theileri in polluted drainage canals. High larval density of Ae. caspius decreased the efficacy of VectoBac 12 AS and VectoBac WDG in the flooded plain. Residual effects of Bti formulations lasted only a few days in the breeding areas. Residual activity of VectoLex WDG was negatively influenced by water depth, organic pollution, and sunlight and positively influenced by low water velocity and emergent vegetation.


The amino terminus of the vaccinia virus E3 protein is necessary to inhibit the interferon response.
Vaccinia virus (VACV) encodes a multifunctional protein, E3L, that is necessary for interferon (IFN) resistance in cells in culture. Interferon resistance has been mapped to the well-characterized carboxy terminus of E3L, which contains a conserved double-stranded RNA binding domain. The amino terminus of E3L has a Z-form nucleic acid binding domain, which has been shown to be dispensable for replication and IFN resistance in HeLa and RK13 cells; however, a virus expressing E3L deleted of the amino terminus has reduced pathogenicity in an animal model. In this study, we demonstrate that the pathogenicity of a virus expressing E3L deleted of the amino terminus was fully rescued in type I IFN receptor knockout (IFN-α/βR(-/-)) mice. Furthermore, this virus was IFN sensitive in primary mouse embryo fibroblasts (MEFs). This virus induced the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α) in MEFs in an IFN-dependent manner. The depletion of double-stranded RNA-dependent protein kinase (PKR) from these MEFs restored the IFN resistance of this virus. Furthermore, the virus expressing E3L deleted of the amino terminus was also IFN resistant in PKR(-/-) MEFs. Thus, our data demonstrate that the amino terminus of E3L is necessary to inhibit the type I IFN response both in mice and in MEFs and that in MEFs, the amino terminus of E3L functions to inhibit the PKR pathway.


A Prognostic Molecular Signature of N⁶-Methyladenosine Methylation Regulators for Soft-Tissue Sarcoma from The Cancer Genome Atlas Database.
BACKGROUND Soft-tissue sarcomas are a group of heterogeneous and rare mesenchymal tumors with aggressive behavior. We aimed to identify the molecular signatures of N⁶-methyladenosine (m6A) methylation regulators associated with patient prognosis using The Cancer Genome Atlas (TCGA) database. MATERIAL AND METHODS To evaluate the role of m⁶A in soft-tissue sarcomas, genomic and clinical data were downloaded from TCGA. The copy number variations (CNVs) and mutations of m6A regulators were analyzed. RESULTS Alterations of m⁶A regulators were common, and ALKBH5 showed the highest frequency of copy number gain, while ZC3H13 had the highest frequency of loss. CNVs and mutations were closely correlated with histology (P<0.001) and tumor size (P=0.040), and CNVs were correlated with mRNA expression. Furthermore, patients with gains of METTL16, RMB15, RMB15B, YTHDC, and YTHDF3 displayed poorer overall survival (OS), and patients with gains of RBM15 and YTHDC2 and loss of IGF2BP1 had poorer disease-free survival (DFS). Further analysis indicated that CNVs and mutations of KIAA1429, YTHDF3, and IGF2BP1 were independent risk factors predicting OS and DFS. Gain of "writers" with loss of "erasers" led to worse OS than gain of "writers". Genes involved in JAK2 oncogenic signature were enriched in cases of higher expressions of METTL16, YTHDC2, and YTHDF3. Similarly, the core serum response signature was enriched in patients with higher expressions of IGF2BP1, METTL16, RBM15, and YTHDC2. CONCLUSIONS Our study provides a useful molecular tool to predict the outcome of soft-tissue sarcomas and deepens our understanding of the molecular mechanisms of the development of the disease.


Exploring the feasibility of cryopreserving larvae of the common cockle (Cerastoderma edule) for hatchery production.
The decline of natural populations of the common cockle (Cerastoderma edule) through the European coast is posing a threat to local small-scale fisheries. These declines are primarily attributed to the prevalence of several pathogens and the disseminated neoplasia in cockle populations. The institution of a biobank of cryopreserved larvae could enhance hatchery production and help the restocking. The present work aimed at the development of a cryopreservation protocol for larvae of the common cockle using the mollusk cryopreservation protocols designed in our laboratory. Toxicity bioassays and short-term cryopreservation experiments were performed for protocol optimization according with cellular tolerance. Once settled, the viability of cryopreserved larvae was studied long term. Toxicity tests evidenced high tolerance of larvae against detrimental effects of Cryoprotecting Agents (CPAs). Cryopreservation of 48 h-old D-larva showed a 100% survival when increasing the equilibrium time from 15 to 60 min and using Propylene-Glycol (PG) + 0.4 M Trehalose (TRE) in Filtered Sea Water (FSW) and 60 min of exposure to CPA solution before slow-cooling. However, when cryopreserving the older larvae, the variation in equilibrium times hardly showed any effect but 10% Ethylene-Glycol (EG) + 0.4 M TRE and 60 min of exposure yielded the best relative survivorship (100%). Cryopreservation caused a significant delay on the growth rate of the latest larval stage. However, cryopreserved larvae survived to day 4-6, while 30 ± 12.17% of control larvae developed into pediveliger stage, of which 50% settled and transformed into juvenile cockles. These results demonstrated the role of the cell-type specificity in cryopreservation and highlight the importance of studying potential long-term effects of this tool to ensure the viability of the protocols.


Vascular Anomalies of the Pediatric Liver.
The liver is a unique organ as it receives afferent blood supply from the umbilical vein, portal vein, and hepatic artery in the developing embryo but has only one efferent drainage method, through the hepatic veins. In the postnatal period, about 70% of the afferent blood flow into the liver is from the portal venous system, unique vessels that begin and end in a capillary system. Vascular anomalies of the hepatic artery, hepatic veins, portal vein, and/or umbilical vein can be congenital or acquired secondary to inflammation and/or infection, trauma, systemic disorders, or iatrogenic causes. The vascular anomalies can be incidental findings at imaging, or the infant or child can present with symptoms such as abdominal pain and ascites, be diagnosed with gastrointestinal bleeding, and have abnormal liver function test results. Imaging can demonstrate vascular findings such as shunts, thrombosis, or collaterals; secondary parenchymal findings such as diffuse or focal abnormal enhancement patterns; and parenchymal lesions such as regenerative nodules. This article discusses and illustrates vascular disorders of the liver that may be encountered in the pediatric population. These include (a) normal vascular variants; (b) congenital anomalies (preduodenal portal vein and infradiaphragmatic total anomalous pulmonary venous return); (c) acquired thromboses (extrahepatic portal venous thrombosis); (d) inflammatory vascular conditions, which can result in hepatic artery aneurysms or pseudoaneurysms; (e) hepatic venous outflow disorders (veno-occlusive disease); and shunt lesions. Liver transplantation and associated vascular complications are a large topic and will not be reviewed in this article. Knowledge of the vascular and parenchymal changes seen with these entities can aid imaging diagnosis and guide appropriate management. ©RSNA, 2019.


Toll-like receptor 7 stimulates the expression of Epstein-Barr virus latent membrane protein 1.
Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus. Toll-like receptor 7 (TLR7) is involved in host innate immunity against pathogens, and its aberrant activation is linked to the development of systemic lupus erythematosus (SLE, also called "lupus"). Type I interferons (IFN) are apparently driving forces for lupus pathogenesis. Previously, we found that EBV latent membrane protein 1 (LMP1) primes cells for IFN production. In this report, the relationship among EBV LMP1, TLRs, and IFN production are examined. We find that TLR7 activation increases the expression of EBV LMP1, and IFN regulatory factor 7 (IRF7) is involved in the stimulation process. TLR7 activation did not induce IFNs from EBV-infected cells, but potentiates those cells for IFN production by TLR3 or TLR9 activation. In addition, we find that LMP1 and IFNs are co-expressed in the same cells in some lupus patients. Therefore, the aberrant activation of TLR7 might induce LMP1 expression and LMP1-expression cells may be producing IFNs in lupus patients. These results suggest EBV might be an exacerbating factor in some lupus patients via promoting IFN production.


Hats Off to the CIM Reviewers of 2021.
For over 40 years the journal of Clinical and Investigative Medicine (CIM) has published articles of interest to clinician investigators in Canada and elsewhere. We strive for the highest standards and to remain relevant to our readers, but we cannot achieve this goal without the help of our reviewers, all of whom play a vital role in maintaining the integrity of the scientific process. Without their efforts, academic excellence would falter.


Abiotic ammonium formation in the presence of Ni-Fe metals and alloys and its implications for the Hadean nitrogen cycle.
Experiments with dinitrogen-, nitrite-, nitrate-containing solutions were conducted without headspace in Ti reactors (200 degrees C), borosilicate septum bottles (70 degrees C) and HDPE tubes (22 degrees C) in the presence of Fe and Ni metal, awaruite (Ni80Fe20) and tetrataenite (Ni50Fe50). In general, metals used in this investigation were more reactive than alloys toward all investigated nitrogen species. Nitrite and nitrate were converted to ammonium more rapidly than dinitrogen, and the reduction process had a strong temperature dependence. We concluded from our experimental observations that Hadean submarine hydrothermal systems could have supplied significant quantities of ammonium for reactions that are generally associated with prebiotic synthesis, especially in localized environments. Several natural meteorites (octahedrites) were found to contain up to 22 ppm Ntot. While the oxidation state of N in the octahedrites was not determined, XPS analysis of metals and alloys used in the study shows that N is likely present as nitride (N3-). This observation may have implications toward the Hadean environment, since, terrestrial (e.g., oceanic) ammonium production may have been supplemented by reduced nitrogen delivered by metal-rich meteorites. This notion is based on the fact that nitrogen dissolves into metallic melts.


Divergent phenological and leaf gas exchange strategies of two competing tree species drive contrasting responses to drought at their altitudinal boundary.
In Mediterranean mountains, Pinus sylvestris L. is expected to be displaced under a warming climate by more drought-tolerant species such as the sub-Mediterranean Quercus pyrenaica Willd. Understanding how environmental factors drive tree physiology and phenology is, therefore, essential to assess the effect of changing climatic conditions on the performance of these species and, ultimately, their distribution. We compared the cambial and leaf phenology and leaf gas exchange of Q. pyrenaica and P. sylvestris at their altitudinal boundary in Central Spain and assessed the environmental variables involved. Results indicate that P. sylvestris cambial phenology was more sensitive to weather conditions (temperature at the onset and water deficit at the end of the growing season) than Q. pyrenaica. On the other hand, Q. pyrenaica cambial and leaf phenology were synchronized and driven by photoperiod and temperatures. Pinus sylvestris showed lower photosynthetic nitrogen-use efficiency and higher intrinsic water-use efficiency than Q. pyrenaica as a result of a tighter stomatal control in response to summer dry conditions, despite its less negative midday leaf water potentials. These phenological and leaf gas exchange responses evidence a stronger sensitivity to drought of P. sylvestris than that of Q. pyrenaica, which may therefore hold a competitive advantage over P. sylvestris under the predicted increase in recurrence and intensity of drought events. On the other hand, both species could benefit from warmer springs through an advanced phenology, although this effect could be limited in Q. pyrenaica if it maintains a photoperiod control over the onset of xylogenesis.


The Relationship Between Hospital Construction and High-Risk Infant Auditory Function at NICU Discharge: A Retrospective Descriptive Cohort Study.
To describe the difference in auditory function at neonatal intensive care unit (NICU) discharge between high-risk infant cases exposed to hospital construction during NICU stay and those not exposed. Noise produced by routine NICU caregiving exceeds recommended intensity. As California hospitals undergo construction to meet seismic safety regulations, vulnerable neonates are potentially exposed to even higher levels of noise. Ramifications are unknown. Retrospective data-based descriptive cohort design was used to compare high-risk infant auditory function at NICU discharge between hospital construction exposed and unexposed groups. N = 540 infant cases (243 construction exposed and 297 unexposed controls). Infant cases born and discharged from the study site NICU in the year 2010 (unexposed) and year 2015 (exposed) and received a newborn hearing screening by automated auditory brainstem evoked response (ABER) prior to discharge with results reported. Infant cases excluded: hearing screen results by ABER unavailable, potentially confounding characteristics (congenital infection, major anomalies including cleft lip and/or palate), and transferred into or out of the study site. ABER. descriptive statistics (SPSS Version 24.0), hypothesis testing, correlation, and logistic regression. The difference in auditory function at NICU discharge between high-risk infant cases exposed to hospital construction noise and those unexposed was statistically insignificant, χ2 = 1.666, df = 4, p = .1968, 95% confidence interval [-0.635, 2.570]. More research is needed to better understand whether hospital construction exposure during NICU admission negatively affects high-risk infant auditory function. Findings may catalyze theory development, future research, and child health policy.


Electrochemical immunosensor for rapid and highly sensitive detection of SARS-CoV-2 antigen in the nasal sample.
A label-free electrochemical biosensing approach as an appropriate analysis technique for SARS-CoV-2 spike protein (SARS-CoV-2 S-protein) was investigated to facilitate the diagnosis of coronavirus in real samples. It is crucial to construct diagnostic features that can rapidly identify infected individuals to limit the spread of the virus and assign treatment choices. Therefore, a novel and selective method using SiO2@UiO-66 and a label-free electrochemical immunoassay for rapidly detecting spike protein. The development of innovative approaches for direct viral detection employing simplified and ideally reagent-free assays is a pressing and difficult topic. The absence of speedy and effective ways to diagnose viral diseases especially SARS-CoV-2 on demand has worsened the issue of combating the COVID-19 pandemic. The developed electrode illustrated a wide dynamic range of 100.0 fg mL-1 to 10.0 ng mL-1 with low limit detection. Therefore, the as-fabricated electrochemical SARS-CoV-2 S-protein sensor suggests an appropriate perspective in the point-of-care system, within 5.0 min, in nasal samples with satisfactory recovery.


The surgeon's responsibility for asepsis.
Eighty percent of postoperative wound infections result from bacteria acquired elsewhere than in the operating room. Concomitant infections--such as dermatitis; periodontitis; infections of the respiratory, gastrointestinal, or urinary tracts--are not identified preoperatively, despite a threat to the patient greater than that of anesthesia and surgery combined. Isolation of overt infection is neglected. The entire hospital becomes a reservoir of bacterial debris that is reflected in the carriage of pathogens by personnel and patients. Infections are often initiated by medical devices that invade the vascular system, respiratory tract, or urinary bladder. Professional leadership at the bedside is the key to detecting and correcting breaches in technique and setting an example of a philosophy of total patient care.


Osteoprotegerin Expression in Liver is Induced by IL13 through TGFβ.
Osteoprotegerin (OPG) is a profibrotic mediator produced by myofibro-blasts under influence of transforming growth factor β (TGFβ). Its expression in experimental models of liver fibrosis correlates well with disease severity and treatment responses. The regulation of OPG in liver tissue is largely unknown and we therefore set out to elucidate which growth factors/interleukins associated with fibrosis induce OPG and through which pathways. Precision-cut liver slices of wild type and STAT6-deficient mice and 3T3 fibroblasts were used to investigate the effects of TGFβ, interleukin (IL) 13 (IL13), IL1β, and platelet-derived growth factor BB (PDGF-BB) on expression of OPG. OPG protein was measure by ELISA, whereas OPG mRNA and expression of other relevant genes was measured by qPCR. In addition to TGFβ, only IL13 and not PDGF-BB or IL1β could induce OPG expression in 3T3 fibroblasts and liver slices. This IL13-dependent induction was not shown in liver slices of STAT6-deficient mice and when wild type slices were cotreated with TGFβ receptor 1 kinase inhibitor galunisertib, STAT6 inhibitor AS1517499, or AP1 inhibitor T5224. This suggests that the OPG-inducing effect of IL13 is mediated through IL13 receptor α1-activation and subsequent STAT6-dependent upregulation of IL13 receptor α2, which in turn activates AP1 and induces production of TGFβ and subsequent production of OPG. We have shown that IL13 induces OPG release by liver tissue through a TGFβ-dependent pathway involving both the α1 and the α2 receptor of IL13 and transcription factors STAT6 and AP1. OPG may therefore be a novel target for the treatment liver fibrosis as it is mechanistically linked to two important regulators of fibrosis in liver, namely IL13 and TGFβ1.


TRPV4 participates in the establishment of trailing adhesions and directional persistence of migrating cells.
Calcium signaling participates in different cellular processes leading to cell migration. TRPV4, a non-selective cation channel that responds to mechano-osmotic stimulation and heat, is also involved in cell migration. However, the mechanistic involvement of TRPV4 in cell migration is currently unknown. We now report that expression of the mutant channel TRPV4-(121)AAWAA (lacking the phosphoinositide-binding site (121)KRWRK(125) and the response to physiological stimuli) altered HEK293 cell migration. Altered migration patterns included periods of fast and persistent motion followed by periods of stalling and turning, and the extension of multiple long cellular protrusions. TRPV4-WT overexpressing cells showed almost complete loss of directionality with frequent turns, no progression, and absence of long protrusions. Traction microscopy revealed higher tractions forces in the tail of TRPV4-(121)AAWAA than in TRPV4-WT expressing cells. These results are consistent with a defective and augmented tail retraction in TRPV4-(121)AAWAA- and TRPV4-WT-expressing cells, respectively. The activity of calpain, a protease implicated in focal adhesion (FA) disassembly, was decreased in TRPV4-(121)AAWAA compared with TRPV4-WT-expressing cells. Consistently, larger focal adhesions were seen in TRPV4-(121)AAWAA compared with TRPV4-WT-expressing HEK293 cells, a result that was also reproduced in T47D and U87 cells. Similarly, overexpression of the pore-dead mutant TRPV4-M680D resumed the TRPV4-(121)AAWAA phenotype presenting larger FA. The migratory phenotype obtained in HEK293 cells overexpressing TRPV4-(121)AAWAA was mimicked by knocking-down TRPC1, a cationic channel that participates in cell migration. Together, our results point to the participation of TRPV4 in the dynamics of trailing adhesions, a function that may require the interplay of TRPV4 with other cation channels or proteins present at the FA sites.


The CaregiverVoice Survey: A Pilot Study Surveying Bereaved Caregivers To Measure the Caregiver and Patient Experience at End of Life.
To integrate patient and caregiver feedback into end-of-life (EOL) care improvement, we tested the feasibility of a standardized, common instrument to measure care experiences across multiple settings in the last three months of life. We developed and tested a survey, called the CaregiverVoice survey, which combined two validated questionnaires, the FAMCARE-2 and VOICES-SF. A retrospective, observational design was used to survey bereaved caregivers of decedents who had received homecare services in Ontario, Canada. In total, 330 surveys were completed (overall response rate of 13%, regional rates ranged from 4% to 83%). There was less than 5% missing data. Most patients received care from multiple settings in the last three months of life, including 60% for which a hospital stay was reported. The overall mean of the 19 FAMCARE-2 items was 1.7 (SD 0.7), with 72% of ratings as 1 very satisfied to 2 satisfied. On VOICES-SF items, 6% of respondents rated "all end-of-life services" as fair or poor, 24% as good, and 70% as excellent or outstanding, with variation depending on care site rated. 13% of caregivers reported that pain management was fair or poor in the last week of life. This pilot study provides preliminary evidence that it is feasible to capture the patient and caregiver experience at EOL using a comprehensive survey, though survey distribution method greatly affected response rates. The majority of responses rated care as excellent or very good, although several specific areas for improvement were identified.


Electrical and thermal modulation of silicon photonic bandgap microcavities containing liquid crystals.
Electrical and thermal modulation of porous silicon microcavities is demonstrated based on a change in the refractive index of liquid crystals infiltrated in the porous silicon matrix. Positive and negative anisotropy liquid crystals are investigated, leading to controllable tuning to both longer and shorter wavelengths. Extinction ratios greater than 10 dB have been demonstrated. Larger attenuation can be achieved by increasing the Q-factor of the microcavities.


Travel-associated Legionnaires disease in residents from England and Wales travelling to Corfu, Greece, August to October 2011.
Fourteen cases of Legionnaires' disease were confirmed in residents from England and Wales with history of travel to Corfu, Greece, in the 14 days before symptom onset. These cases were reported to the Health Protection Agency national surveillance scheme for Legionnaires' disease in residents of England and Wales between August and October 2011. In addition, one case in a Greek national and a case of non-pneumonic legionellosis in a resident from Scotland were also reported. Few cases shared the same accommodation site in Corfu during their incubation period. Epidemiological investigations and microbiological analysis of clinical and environmental samples excluded a single source but rather implicated several accommodation sites as sources of sporadic infection. Control measures have since been implemented at these accommodation sites and no further cases have been reported. This incident highlights the value of epidemiological typing and the importance of effective international response to control and prevent legionella infection.


[Borderline personality disorder, self-mutilation and suicide: literature review].
Borderline personality disorder (BPD) is a serious public health problem. It is associated with high levels of mental health service utilization, an important degree of psychosocial impairment and a high rate of suicide (10%). BPD is a common psychiatric disorder and the most frequent personality disorders. Approximately, 15 to 50% of psychiatric inpatients and 11% of psychiatric outpatients meet current criteria for BPD. Recurrent suicidal threats, gestures or behaviour or self-mutilation are common in patients suffering from borderline personality disorder. However, despite their similarities, self-mutilation behaviour differs from suicide attempts by the lack of systematic suicidal intentions. The purpose of our study is to examine the relationships between self-mutilations, suicide and related therapeutic approach. We have reviewed the literature published from January 1980 to October 2006, using the following keywords: self-mutilation, suicide, borderline personality (44 articles) with five other additional articles. Self-mutilation refers to the deliberate, direct destruction or alteration of one's body tissue without conscious suicidal intent. This pattern of behaviour is common in BPD (50 to 80% of cases) and is frequently repetitive (more than 41% of patients make more than 50 self-mutilations). The most common form of self-mutilation behaviour is cutting, but bruising, burning, head banging or biting are not unusual. The functions of self-mutilation are variable: it provides relief from negative mood states, reduces distress, obtains care from other people as well as therapists and expresses emotions in a symbolic fashion. The rate of suicide in clinical samples of BPD is of around 5 to 10%. This rate is about 400 times that of the general population. Authors estimated that 40 to 85% of borderline patients carry out suicide attempts that are usually multiple (average=3). The relationships between self-mutilation and suicide are paradoxical. Some authors identify self-mutilation as a protective factor against suicide. Self-mutilation behaviour can be defined as an attenuated form of suicide ("focal suicide"). In this way, self-mutilation plays the role of an anti-suicide act, allowing patients to emerge from their dissociation and to feel that they are living again. The risk of suicide will not increase so long as self-mutilation produces the expected relief. Nevertheless, most of the authors exhibit self-mutilation as a risk factor of completed suicide. Thus, borderline patients with history of self-mutilation behaviour have about twice the rate of suicide than those without. Repetitive self-mutilations may increase dysphoria, which will only be relieved by suicidal gestures. Self-mutilating suicide attempters may be at greater risk for suicide for several reasons: they experience more feeling of depression and hopelessness, they are more aggressive and display more affective instability, they underestimate the lethality of their suicidal behaviour and finally, they are troubled by suicidal thoughts for longer and more frequent periods of time. Treatment of these patients requires a multidisciplinary approach. Psychoanalytic/psychodynamic therapy and dialectal behaviour therapy (DBT) have been shown to lower rates of attempted suicide among BPD patients. Pharmacotherapy focuses on key symptoms: aggression, irritability and depressed mood (selective serotonin reuptake inhibitors), behavioural dyscontrol and affective dysregulation (mood stabilizers), anxiety, psychoticism and hostility (antipsychotics). These findings highlight the possibility of self-mutilation as a risk factor of suicide in borderline personality disorder. Nevertheless, to reinforce this assertion, further studies on large sample of borderline patients, with or without self-mutilation, are needed. Moreover, prospective controlled studies on the various treatment models in suicidal BPD patients are necessary.


Cytotoxicity and metabolic stress induced by deoxynivalenol in the porcine intestinal IPEC-J2 cell line.
The digestive tract is a target for the Fusarium toxin deoxynivalenol (DON), a major cereal grain contaminant of animal and public health concern. Toxic effects of DON range from diarrhoea, vomiting and gastrointestinal inflammation to necrosis of several tissues. Following ingestion of contaminated food or feed, intestinal epithelial cells are exposed to a high concentration of ingested DON, potentially affecting intestinal functions. Pigs are considered to be the species most sensitive to DON toxicity. However, only few studies directly evaluated DON effects on porcine intestinal epithelial cells. Therefore, we used the porcine intestinal cell line (IPEC-J2) to assess short-term effects of DON on functional characteristics of the intestinal epithelial cells. The cytotoxic effect of DON on IPEC-J2 cells was evaluated by measuring the count of living cells and the activity of lactate dehydrogenase (LDH) released in the culture media at a DON concentration range from 0, 0.5, 2.5 and 10 μm. We demonstrated that DON at concentrations of 2.5 and 10 μm decreased significantly (p < 0.001) the cell count in a dose-dependent manner. At a concentration of 10 μm, DON caused cell damage, including rounding of cells, autolysis and cell loss from the monolayer. The mycotoxin, DON, increased LDH release into the culture medium compared with the control value. The alterations of LDH showed a good agreement with the decrease in cell count. Deoxynivalenol decreased the l-lactate concentration in the fluid supernatant of IPEC-J2 cells at 2.5 μm (p < 0.05) with a maximal effect at 10 μm of DON. To determine whether the altered lactate production may be linked to alterations of energy balance, we measured cellular ATP levels in IPEC-J2 cells. A significant decrease in ATP levels was seen at 48 h in a dose-dependent manner. It could be demonstrated that DON has a distinct cytotoxic effect on IPEC-J2 cells.


Case Report of COVID-19 Positive Male with Late-Onset Full Body Maculopapular Rash.
Each day, novel information is being learned about Coronavirus disease 19 (COVID-19), a disease increasingly seen in the emergency department (ED). Our case adds to reports of a maculopapular rash among the newer symptoms to be aware of in diagnosing COVID-19. A 35-year-old male presented with an 11-day history of fever, dry cough, diarrhea, and change in taste. He endorsed two known exposures to COVID-19 and had previously tested negative twice for the virus. The patient additionally complained of a whole-body, pruritic rash that presented six days after his initial symptoms. A workup was completed for the patient's fever and labs only revealed a potassium of 3.3 mEq/L. A chest X-ray showed right basilar patchy opacities consistent with pneumonia, and the patient tested positive for COVID-19 and negative for Epstein-Barr Virus, a commonly missed culprit in those with a rash, via polymerase chain reaction (PCR). The patient's vitals were stable, and he was discharged with supportive measures at home. COVID-19 was determined as a likely etiology for the rash. With new insights into COVID-19 every day, we demonstrate a case of viral exanthema as a potential presenting manifestation in a COVID-19 patient and one that medical providers should be familiar with in these patients in the ED. COVID-19, dermatology, infectious disease, viral exanthema.


Bacterial RNA mediates activation of caspase-1 and IL-1β release independently of TLRs 3, 7, 9 and TRIF but is dependent on UNC93B.
Recognition of foreign nucleic acids is important for the induction of an innate immune response against invading pathogens. Although the pathways involved in sensing bacterial DNA and viral RNA are now well established, only limited knowledge is available on mechanisms underlying recognition of bacterial RNA. It has been reported that intracellular delivery of Escherichia coli RNA activates the Nlrp3 inflammasome, but whether this is a general property of bacterial RNA remains unclear as are the pathways involved in pro-IL-1β induction and caspase-1 activation by bacterial RNA. In this study, we report that bacterial RNA from both Gram-positive and Gram-negative bacteria induces activation of caspase-1 and secretion of IL-1β by murine dendritic cells and bone-marrow derived macrophages. Stimulation was independent of the presence of 5'-triphosphate termini and occurred with whole RNA preparations from bacteria but not from eukaryotes. Induction of pro-IL-1β as well as the priming for caspase-1 activation by bacterial RNA was dependent on UNC93B, an endoplasmic reticulum protein essential for delivery of TLRs to the endosome, whereas the established nucleic acid sensing endosomal TLRs 3, 7, and 9 were dispensable. Additionally, caspase-1 activation and IL-1β production by transfected bacterial RNA were absent in MyD88-deficient cells but independent of TRIF. Thus, our data indicate the presence of a yet unidentified intracellular nucleic acid receptor involved in bacterial RNA-induced inflammasome activation and release of IL-1β.