Aggressive Staphylococcus lugdunensis Endocarditis in a Young Healthy Patient: A Case Report.
Staphylococcus lugdunensis (S. lugdunensis) is a β-hemolytic coagulase-negative staphylococcus causing skin and soft tissue infections with an increasing incidence. Commonly found as normal flora in the perineal region, S. lugdunensis has been found in rare cases of infective endocarditis causing increased morbidity and mortality. We present a case of a previously healthy young male diagnosed with S. lugdunensis-caused infective endocarditis. A 31-year-old male with no significant past medical history, who presented to the emergency department with acute onset crushing substernal chest pressure and dyspnea with profuse sweating following 1-week-long febrile illness and malaise. The initial electrocardiogram (ECG) showed diffuse ST depressions in all precordial leads, consistent with an acute coronary syndrome. Emergent transthoracic echocardiogram revealed an ejection fraction (EF) of 45% with severe aortic insufficiency with emanating from a torn right coronary cusp. The patient had a cardiac arrest, and recovery of spontaneous circulation (ROSC) was obtained after 13 min. He subsequently underwent mechanical aortic valve replacement surgery. The native valve specimen cultures grew S. lugdunensis. Postoperatively and after a long course of antibiotics, the patient fully recovered without complications. S. lugdunensis is a common organism with increasing incidence that can lead to significant morbidity and mortality if not properly detected and treated. We hope this case presentation would support emergency valve replacement surgery in patients with S. lugdunensis-suspected infective endocarditis.


Recursive protein modeling: a divide and conquer strategy for Protein Structure Prediction and its case study in CASP9.
After decades of research, protein structure prediction remains a very challenging problem. In order to address the different levels of complexity of structural modeling, two types of modeling techniques--template-based modeling and template-free modeling--have been developed. Template-based modeling can often generate a moderate- to high-resolution model when a similar, homologous template structure is found for a query protein but fails if no template or only incorrect templates are found. Template-free modeling, such as fragment-based assembly, may generate models of moderate resolution for small proteins of low topological complexity. Seldom have the two techniques been integrated together to improve protein modeling. Here we develop a recursive protein modeling approach to selectively and collaboratively apply template-based and template-free modeling methods to model template-covered (i.e. certain) and template-free (i.e. uncertain) regions of a protein. A preliminary implementation of the approach was tested on a number of hard modeling cases during the 9th Critical Assessment of Techniques for Protein Structure Prediction (CASP9) and successfully improved the quality of modeling in most of these cases. Recursive modeling can significantly reduce the complexity of protein structure modeling and integrate template-based and template-free modeling to improve the quality and efficiency of protein structure prediction.


Pronurturance Plus at birth: A risk reduction strategy for preventing postpartum haemorrhage.
Postpartum haemorrhage (PPH) rates continue to rise in the developed world. A recent study found that any skin-to-skin contact and breastfeeding within 30min of birth was associated with an almost 50% reduction in PPH rates. Improved oxytocin release is the biological reason proposed to explain this. The combination of skin-to-skin contact and breastfeeding within 30min of birth is termed 'Pronurturance'. Midwifery theory and research claims that optimal third stage care is more holistic than simple Pronurturnace which suggests that further reductions in PPH rates may be possible. What can midwives and women do to minimise blood loss in the third and fourth stages of labour? We present a new theory that describes and explains how to optimise the woman's reproductive psychophysiology in the third and fourth stages of labour to ensure a well contracted uterus which inhibits excessive bleeding regardless of risk status or whether active management was used. In developing the Pronurturance Plus theory we expand upon what is already known about oxytocin in relation to simple pronurturance to integrate concepts from birth territory theory, cognitive neuroscience, mindfulness psychology and the autonomic nervous system to develop an holistic understanding of how to optimise care and minimise PPH. Pronurturance Plus is a psycho-biologically grounded theory which is consistent with existing evidence. It is free, natural and socially desirable.


Hacking Acute Care: A Qualitative Study on the Health Care Impacts of Ransomware Attacks Against Hospitals.
Cyberattacks are an increasing threat to health care institutions which potentially impair patient outcomes. Current research is limited and focuses mainly on the technical consequences, whereas little is known about health care staff experiences and the effect on emergency care. This study aimed to explore the acute care effect of several large ransomware attacks against hospitals that occurred in Europe and the United States between 2017 and 2022. This interview-based qualitative study assessed the experiences of emergency health care professionals and information technology (IT) staff and investigated the challenges during the acute and recovery phase of hospital ransomware attacks. The semistructured interview guideline was based on relevant literature and cybersecurity expert consultation. Transcripts were anonymized, and traceable information regarding participants and/or their organizations was removed for privacy purposes. Nine participants were interviewed, including emergency health care providers and IT-focused staff. Five themes were constructed from the data: effects and challenges regarding patient care continuity, challenges during the recovery process, personal effect on health care staff, preparedness and lessons identified, and future recommendations. According to the participants of this qualitative study, ransomware attacks have a significant effect on emergency department workflow, acute care delivery, and the personal well-being of health care providers. Preparedness for such incidents is limited, and many challenges are encountered during the acute and recovery phase of attacks. Although there was profound hesitancy among hospitals to participate in this study, the limited number of participants provided valuable information that can be used to develop response strategies for hospital ransomware attacks.


Clinical integration across multiple hospitals: the agony, the ecstasy.
The author shares one system's experience with the clinical integration of multiple facilities over several years. This inside view relates the good, the bad, and the ugly; the difficulties and the successes; and the agonies and the ecstasies. The author arrives at the conclusion that all the pain and anguish are worth the rewards of an integrated system that is well positioned in the marketplace to meet the mission and vision of a community health care system committed to thriving in the 21st century.


Neuropeptide Y: the universal soldier.
The peptidic neuropeptide Y (NPY) has received great attention because it has been implicated in the regulation of several organ systems. In particular, NPY is involved in the regulatory loops that control food intake in the hypothalamus and appears also to be important for regulating the activity of neuroendocrine axes under poor metabolic conditions. Furthermore, NPY exerts vasoconstrictive action on the vasculature and potentiates the actions of many other vasoconstrictors. In addition, it was demonstrated to have trophic properties and could therefore contribute to cardiovascular remodeling. These various effects plus a number of others make NPY an attractive target for the potential treatment of human diseases, such as obesity, metabolic disorders, hypertension and heart failure.


Utility, Appropriateness, and Content of Electronic Consultations Across Medical Subspecialties.
Electronic consultations (e-consults) can facilitate patient access to specialists, minimize travel, and reduce unnecessary in-person visits. However, metrics to enable study of e-consults and their effect on processes and patient care are lacking. To assess novel metrics of e-consult appropriateness and utility. Retrospective cohort study. Primary and specialty care practices at 2 large academic and 2 community hospitals of an integrated health system. Patients with e-consult requests to 5 specialties-hematology, infectious disease, dermatology, rheumatology, and psychiatry-between October 2017 and November 2018. The appropriateness of e-consult inquiries was assessed by review of medical records and defined as meeting the following 4 criteria: not answerable by reviewing evidence-based summary sources ("point-of-care resource test"), not merely requesting logistic information, having appropriate clinical urgency, and having appropriate patient complexity. Interrater agreement in assessments of e-consult appropriateness was assessed by the κ statistic. Utility of e-consults was assessed by the rate of avoided visits (AVs), defined by the absence of an in-person visit to the same specialty within 120 days. Overall, 6512 eligible e-consults were made by 1096 referring providers to 121 specialist consultants. Inquiries were characterized as diagnostic, therapeutic, for provider education, or at the request of the patient. Most consultations were answered within 1 day, with variation across specialties (73.1% for psychiatry to 87.8% for infectious disease). Overall, 70.2% of e-consults met all 4 criteria for appropriateness; the frequency of unmet criteria varied among specialties. Raters agreed on the appropriateness of 94% of e-consults (κ = 0.57 [95% CI, 0.36 to 0.79]), indicating moderate agreement. The overall rate of AVs across the 5 specialties was 81.2%; the highest rate was in psychiatry (92.6%) and the lowest in dermatology (61.9%). Generalizability is unknown outside a single integrated health system, where requesting and consulting providers share a common electronic health record. Novel metrics to assess the appropriateness and utility of e-consults provide meaningful insight into practice, provide a rubric for comparison in future studies in additional settings, and suggest areas to improve resource use and patient care. None.


The effects of Pilates and yoga participant's on engagement in functional movement and individual health level.
This study was conducted to investigate the effect of Pilates and yoga participating in their functional movement and individual health level. Ninety volunteers were randomly divided into three groups and evenly recruited female and male participants in each group through a reliable organization. Their age group was between the 30s and 40s. They were informed the research process and assigned to the consent form. Pilates group (n=30), yoga group (n=30), and control group (n=30) were assigned to fulfill short form of Rand 36-item health survey (SF-36) survey form based on self-administration method and were scored functional movement screen (FMS) test before the intervention. Pilates and yoga group were carried out certain exercise program 1-hr duration 3 times per week for 8 weeks. And control group did not perform any exercise during experimental period. After completion of the 8-week Pilates and yoga program, they recorded SF-36 and were scored FMS score for posttest in same way. When we compared the differences between pre- and posttreatment scores, we found that there was statistically significant difference among three groups on FMS (F [2,89]=15.56, P<0.001) and there was significant change in favor of Pilates group groups (F [2,89]=52.36, P<0.001) on SF-36. To conclude, Pilates group was more effective for improving functional movement and individual health level to assess quality of life than yoga group and control group.


Effects of treprostinil on pulmonary arterial hypertension during surgery for congenital heart disease complicated with severe pulmonary arterial hypertension.
The aim of this study is to evaluate the effects of treprostinil injection on the control of pulmonary blood pressure in children with congenital heart disease (CHD) complicated by severe pulmonary arterial hypertension (PAH). Eighty children with CHD complicated by severe pulmonary arterial hypertension admitted to our hospital from January 2015 to June 2018 were selected and randomly divided into a control group (N.=40) and a treatment group (N.=40). Based on standard treatment, the treatment group was intravenously infused with 8-12 ng/kg·min treprostinil, while the control group received the same dose of normal saline. Hemodynamic parameters such as BP, AP, P and SpO<inf>2</inf>% were monitored before anesthesia induction (T0), before cardiopulmonary bypass (T1), 1 h after cardiopulmonary bypass (T2) and at the end of cardiopulmonary bypass (T3). Pulmonary arterial pressure parameters (PASP, PADP and PAMP) were measured at T1, T2 and T3 by transesophageal echocardiography. For the treatment group, the HR values at T2 and T3 were lower than that at T0 (P<0.05). For the control group, HR at T3 was lower than that at T0 (P<0.05). HR at T3 of the treatment group was lower than that of the control group (P<0.05). SpO<inf>2</inf> of the treatment group was higher than that of the control group at T3 (P<0.05). At T2 and T3, PASP, PADP and PAMP of both groups were lower than those before surgery (P<0.05), and the values of the treatment group were lower than those of the control group (P<0.05). Treprostinil can improve cardiac function and reduce pulmonary circulation resistance in PAH children.


Quantifying histopathological alterations in the hepatopancreas of the woodlouse Porcellio laevis (Isopoda) as a biomarker of cadmium exposure.
The aims of this study were to determine and quantify the effects of cadmium sulfate on the histological structure of the hepatopancreas of Porcellio laevis, to determine the extent of the changes due to cadmium exposure, and to assess whether these effects could serve as biomarkers of cadmium exposure. For this purpose, different batches of P. laevis were exposed for 6 weeks to shredded leaves contaminated with a range of different concentrations of cadmium sulfate. Histological sections of different parts of the hepatopancreases revealed that the exposure changed the structure of the hepatopancreas. Quantification of this change in hepatopancreas structure (expressed as the percentage cellular area or PCA) showed that there was a dose-related change in certain areas of the hepatopancreas of woodlice exposed to cadmium sulfate in comparison to those areas of unexposed controls. This change was evident despite the fact that PCA also varied over the length of the hepatopancreas in the control specimens. This study showed that PCA can be a useful measure of change in the hepatopancreas resulting from toxic stress. Although it may not be practical for regular monitoring, it could serve as a useful research tool and general biomarker in studies of toxic stress in woodlice.


A new rat model of otitis media caused by Streptococcus pneumoniae: conditions and application in immunization protocols.
Streptococcus pneumoniae (pneumococcus [Pn]) can be cultured from up to 50% of acute otitis media (AOM) effusions, and these bacteria are the most common cause of AOM-related complications. With the recent advent of antibiotic-resistant Pn strains, treatment of Pn infections may meet with serious difficulties. Prevention through vaccination, notably for the four most common occurring Pn serotypes in humans (i.e., Pn 6B, Pn 14, Pn 19F, and Pn 23F), is a helpful alternative. Testing of vaccine efficacy should occur in an appropriate animal AOM model, which is presented here. The four involved Pn serotypes are not pathogenic to the rat, which was chosen as the experimental animal for practical reasons. To induce a natural infection (i.e., ascending through the eustachian tube), the mucociliary clearance of the eustachian tube was impaired by infusing histamine into the tympanic cavity on 2 consecutive days before intranasal inoculation of the bacteria. With this simple protocol, high and reproducible infection rates, as determined with bacterial cultures, of Pn-induced AOM (approximately 70%) with the two major Pn serotypes 14 and 19F (Pn 14 and Pn 19F) were obtained, whereas lower infection rates (25 to 50%) with Pn 6B and Pn 23F were obtained. In this model, intranasal priming with pneumococci, as well as subcutaneous vaccination with Pn 14 tetanus toxoid-conjugated polysaccharide, induced a protective effect against the induction of otitis media with these bacteria. This shows that immunity to Pn 14 AOM can be induced by both mucosal and systemic presentations of antigen. In conclusion, we have developed an animal model for Pn-induced AOM, which is suitable for the evaluation of the protecting effect of immunization.


Detection of muscle fatigue caused by repeated posterior tongue lift movement from neck surface EMG: a pilot study.
Fatigue is an important factor for muscle strengthening in rehabilitation medicine. Frequency analysis has been regarded as the gold standard for muscle fatigue assessment in surface electromyography (EMG). However, there are no experiments quantifying fatigue with grouped discharge (GD), which is one of the historical phenomena observed in patients having fatigue, by using high sampling rate recording of EMG. To investigate the effect of fatigue, which is induced by repeated posterior tongue lift movement (TLM), on the occurrence of GD peaks, thus, to provide possible basis as a parameter for future fatigue evaluation. Nineteen healthy adults (9 men and 10 women) participated in this study. The muscle fatigue protocol consisted of repetitive posterior TLM and maximum voluntary contractions (MVC). Bilateral N-EMG (Neck surface EMG for measuring the muscle activity of the posterior tongue) was recorded. Subjective tongue fatigue at the end of the protocol was significantly higher than at beginning throughout the muscle fatigue protocol (p < .01). The frequency of occurrence of GD peaks was 0.9 ± 1.2 (per second) at the baseline in 33 of 38 subject sides, and significantly increased depending on fatigue progression (p < .01). It was shown that fatigue due to repetitive posterior tongue lifting resulted in significant increase in the frequency of occurrence of GD peaks. Especially, the nature of GD, showing very few occurrences at non-fatigue condition, might work as an advantageous property for its use in future absolute evaluation of fatigue phenomena.


A multidimensional approach to the relationship between individualism-collectivism and guilt and shame.
Guilt and shame proneness are commonly thought to be associated with culture, yet research on this relationship is fragmented and often inconsistent. In a review of the existing social scientific literature, we demonstrate that no consistent relationship between guilt and shame, on the one hand, and individualism and collectivism, on the other, has yet been established. To move this research area forward, we apply a new 2-dimensional, quaternary perspective to both guilt/shame and cultural orientation. Specifically, both evaluative and behavioral dimensions of guilt and shame are considered using the Guilt and Shame Proneness Scale (GASP; Cohen, Wolf, Panter, & Insko, 2011), as well as the degree of hierarchy (i.e., horizontality-verticality) in individuals' cultural orientation (Triandis & Gelfand, 1998). A study of individuals from 5 countries (United States, India, China, Iran, and Spain; total N = 1,466) confirmed our hypotheses that individuals culturally socialized to be more interpersonally oriented (i.e., horizontal collectivism) are more motivated to engage in reparative action following transgressions, whereas those culturally socialized to be more attuned to power, status, and competition (i.e., vertical individualism) are more likely to withdraw from threatening interpersonal situations, and that these relationships are stronger than corresponding relationships with guilt- and shame-related evaluations. In addition to supporting these hypotheses, our data also provide the first cross-cultural evidence regarding the invariance of the GASP. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Ketamine suppresses intestinal NF-kappa B activation and proinflammatory cytokine in endotoxic rats.
To investigate the protective effect of ketamine on the endotoxin-induced proinflammatory cytokines and NF-kappa B activation in the intestine. Adult male Wistar rats were randomly divided into 6 groups: (a) normal saline control, (b) challenged with endotoxin (5 mg/kg) and treated by saline, (c) challenged with endotoxin (5 mg/kg) and treated by ketamine (0.5 mg/kg), (d) challenged with endotoxin (5 mg/kg) and treated by ketamine (5 mg/kg ), (e) challenged with endotoxin (5 mg/kg) and treated by ketamine (50 mg/kg), and (f) saline injected and treated by ketamine (50 mg/kg). After 1, 4 or 6 h, TNF-alpha and IL-6 mRNA were investigated in the tissues of the intestine (jejunum) by RT-PCR. TNF-alpha and IL-6 were measured by ELISA. We used electrophoretic mobility shift assay (EMSA) to investigate NF-kappa B activity in the intestine. NF-kappa B activity, the expression of TNF-alpha and IL-6 were enhanced in the intestine by endotoxin. Ketamine at a dose of 0.5 mg/kg could suppress endotoxin-induced TNF-alpha mRNA and protein elevation and inhibit NF-kappa B activation in the intestine. However the least dosage of ketamine to inhibit IL-6 was 5 mg/kg in our experiment. Ketamine can suppress endotoxin-induced production of proinflammatory cytokines such as TNF-alpha and IL-6 production in the intestine. This suppressive effect may act through inhibiting NF-kappa B.


REHAL®, a telemedicine platform for home cardiac rehabilitation.
The new REHAL® platform manages home-based cardiac rehabilitation programs without most of the drawbacks of an earlier E-Remedy EC proposal. The proposal is based on the awareness that safe home rehabilitation is only possible in the post-hospital phase when the patient no longer needs direct control by medical staff and has become accustomed to the technological set-up. The platform is composed of a web-based database and client software (Ergomonitor), which allows health staff to manage the sessions without a real-time connection and legal liability. Ergomonitor permits the complete management of a bike (training session settings, web transmission and data recording) by a serial connection to a PC. Patients own their data and may approve the access of health personnel to evaluate the results and introduce longitudinal ambulatory information together with updated physical activity protocols. The health service does not bear the cost of the technological set-up. Ergomonitor acquires and records heart rate, loads, pedalling speed and other parameters of interest (i.e., arterial pressure) and forwards data to a remote database. Health personnel can modify time by time the scheduled exercise settings, analyse the results of each session and compare session by session. The platform is actually used in hospital, gymnasium and home context. More than 1000 subjects have been enrolled in the protocol, with a very good appreciation. The first experience of REHAL® (six months, more than 1000 enrolled patients) highlights the positive aspects of the solution: the patients are very satisfied with the continuity of the rehabilitation programme and the clinicians are very satisfied they can follow their patient population longitudinally and with a personalized protocol.


[Results of the intraocular lens SI-30 implantation].
clinical evaluation of the flexible silicone intraocular lens SI-30 (Allergan). retrospective study over 3 years of 2000 implantations of the SI-30 IOL. The lenses were inserted through a 3.2 mm scleral tunnel and placed in the capsular bag after continuous circular capsulorhexis and phacoemulsification. visual outcome was excellent. Without other causes of impaired vision, 99% of patients regained a visual acuity of 20/30 or better after 1 month. Induced astigmatism was unsignificant: 0.4 D; preop., 0.9 D. at day 7, 0.4 at 1 month, 0.5 D. at 1 year. A disinsertion of the inferior haptic occurred in 2 cases during the insertion manoeuver. More specific postoperative complications consisted of pigmented deposits (less than 1%), pupillary capture (4 cases), and capsule contraction associated with small size capsulorhexis. Aspecific complications were: cystoid macular oedema (3% at 1 month, less than 1% afterwards), chronic uveitis (0.6%), acute uveitis (1 patient). implantation of the SI-30 silicone lens is safe and gives the patient the benefits of a small, non enlarged, and sutureless cataract incision. The postoperative follow-up must take in account the properties of the lens.


Fair is fair: We must re-allocate livers for transplant.
The 11 original regions for organ allocation in the United States were determined by proximity between hospitals that provided deceased donors and transplant programs. As liver transplants became more successful and demand rose, livers became a scarce resource. A national system has been implemented to prioritize liver allocation according to disease severity, but the system still operates within the original procurement regions, some of which have significantly more deceased donor livers. Although each region prioritizes its sickest patients to be liver transplant recipients, the sickest in less liver-scarce regions get transplants much sooner and are at far lower risk of death than the sickest in more liver-scarce regions. This has resulted in drastic and inequitable regional variation in preventable liver disease related death rate.A new region districting proposal - an eight district model - has been carefully designed to reduce geographic inequities, but is being fought by many transplant centers that face less scarcity under the current model. The arguments put forth against the new proposal, couched in terms of fairness and safety, will be examined to show that the new system is technologically feasible, will save more lives, and will not worsen socioeconomic disparity. While the new model is likely not perfect, it is a necessary step toward fair allocation.


Infections in the malnourished: with special reference to malaria and malnutrition in the tropics.
The inter-relationship of malnutrition and infections is generally accepted as being synergistic, one promoting the other. Nevertheless, numerous published reports are available which highlight the contrary, that is, antagonism of poor nutrition to infections. This presentation is a review of such publications with emphasis on malaria and malnutrition in the tropics. The data presented suggest that the effect of poor diets on human malaria is related to the level of protein and energy intake, which in turn have important bearings not only on clinical nutrition but also on nutrition policy and planning, particularly in famine and famine relief. The data highlight the necessity for the integration of nutritional programmes and anti-malarial activities in areas where famine and malaria co-exist.


Differential effect of knee extension isometric training on the different muscles of the quadriceps femoris in humans.
This study determined the effects of a short period of knee isometric training on the quadriceps muscles accessible to surface electromyography (EMG). For this purpose, a training (n = 9) and a control (n = 7) group were tested on five identical occasions at 1 week intervals during 4 weeks. The training group exercised three times a week by making isometric knee extensions at 80% of the maximal voluntary contraction (MVC). During the test sessions, maximal and submaximal torque and associated activations of the rectus femoris (RF), vastus lateralis (VL) and vastus medialis (VM) muscles were analysed. As a result of training, differences between MVC values of the two groups were highly significant (P<0.001), whereas only RF-EMG showed significant differences (P<0.05). The VL and VM did not present any significant changes in maximal activation. The EMG torque relationships were analysed individually before and after the training period. For the control subjects, EMG-torque relationships did not present significant changes while for the training group, these relationships showed a significant increase in RF, VL, and VM maximal activation in 6, 6 and 4 subjects, respectively, and a significant decrease in 1, 2 and 5 subjects, respectively. In almost all cases, a significant downward shift of the relationship was observed. This study confirmed that the parts of the quadriceps muscle tested present different adaptation capacities and demonstrate inter-individual variability in the strategies used to enhance muscle strength. In conclusion, to analyse the neural effects resulting from training in a large and compartmentalized muscle like the quadriceps femoris, it is desirable to take into account each muscle independently. Moreover, we suggest that overall results obtained from the experiment population should be completed by an analysis on individuals.


The association of USMLE Step 1 and Step 2 CK scores with residency match specialty and location.
For future physicians, residency programs offer necessary extended training in specific medical specialties. Medical schools benefit from an understanding of factors that lead their students to match into certain residency specialties. One such factor, often used during the residency application process, is scores on the USA Medical Licensing Exam (USMLE). To determine the relationship between USMLE Step 1 and Step 2 Clinical Knowledge (CK) scores and students' residency specialty match, and the association between both USMLE scores and state of legal residency (Minnesota) at the time of admission with students staying in-state or leaving the state for residency program. USMLE scores and residency match data were analyzed from five graduating classes of students at the University of Minnesota Medical School (N = 1054). A MANOVA found significant differences (p < 0.001) between residency specialties and both USMLE Step 1 and Step 2 CK scores, as well as the combination of the two. Students who matched in Dermatology had the highest mean USMLE scores overall, while students who matched in Family Medicine had the lowest mean scores. Students who went out of state for residency had significantly higher Step 1 scores (p = 0.027) than students who stayed in-state for residency, while there was no significant difference between the groups for Step 2 scores. A significant positive association was found between a student who applied as a legal resident of Minnesota and whether the student stayed in Minnesota for their residency program. Residency specialty match was significantly associated with USMLE Step 1 and USMLE Step 2 CK scores, as was staying in-state or leaving the state for residency. Students who were legal residents of the state at the time of application were more likely to stay in-state for residency, regardless of USMLE score. CK: Clinical knowledge; COMLEX: Comprehensive Osteopathic Medical Licensing Examination; GME: Graduate medical education; NRMP: National Resident Matching Program; UME: Undergraduate medical education; USMLE: United States Medical Licensing Examination.


Trends in Treatment for Patients Hospitalized with Heart Failure with Preserved Ejection Fraction Before and After Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT).
The TOPCAT trial investigated spironolactone vs placebo in patients with heart failure with preserved ejection fraction (HFpEF). Although the primary endpoint was not statistically significant, treatment with spironolactone did reduce heart failure hospitalizations compared with placebo. TOPCAT's impact on prescribing patterns in the United States is not well-characterized. We performed a retrospective analysis of discharge prescribing data in the Get With The Guidelines-Heart Failure Registry among patients with left ventricular ejection fraction ≥50% discharged between January 2009 and December 2016 to assess prescribing trends upon dissemination of TOPCAT results. Of 142,201 patients included in the study, 18,581 (13.1%) were prescribed mineralocorticoid receptor antagonists (MRAs) at discharge. Compared with those not prescribed MRAs, patients discharged on MRAs were generally younger (75 vs 78 years), and report white race (76.7% vs 72.0%), more likely to have had prior heart failure hospitalizations (75.5% vs 65.7%), lower brain natriuretic peptide levels (492 vs 545 pg/mL), but similar serum creatinine levels (1.2 vs 1.2 mg/dL) upon admission. MRA prescribing modestly increased over time (p <0.0001), without significant change in the overall trend of prescribing rate for MRAs after TOPCAT results were presented (p =0.17). In conclusion, our findings suggest that for patients with HFpEF, the use of MRAs at hospital discharge is low, with only modest increases over time and no discernible change in the rate of MRA use after the TOPCAT results were released. There remains an important need for more clinical trials to better establish the efficacy and safety of MRAs for the treatment of HFpEF.


tRNA-like Transcripts from the NEAT1-MALAT1 Genomic Region Critically Influence Human Innate Immunity and Macrophage Functions.
The evolutionary conserved NEAT1-MALAT1 gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. Whereas functions have been assigned to the nuclear transcripts, data on biological functions of the small cytosolic transcripts are sparse. We previously found NEAT1-/- and MALAT1-/- mice to display massive atherosclerosis and vascular inflammation. Here, employing selective targeted disruption of menRNA or mascRNA, we investigate the tRNA-like molecules as critical components of innate immunity. CRISPR-generated human ΔmascRNA and ΔmenRNA monocytes/macrophages display defective innate immune sensing, loss of cytokine control, imbalance of growth/angiogenic factor expression impacting upon angiogenesis, and altered cell-cell interaction systems. Antiviral response, foam cell formation/oxLDL uptake, and M1/M2 polarization are defective in ΔmascRNA/ΔmenRNA macrophages, defining first biological functions of menRNA and describing new functions of mascRNA. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. Their NEAT1-MALAT1 region of origin appears as archetype of a functionally highly integrated RNA processing system.


Magnetisation Processes in Geometrically Frustrated Spin Networks with Self-Assembled Cliques.
Functional designs of nanostructured materials seek to exploit the potential of complex morphologies and disorder. In this context, the spin dynamics in disordered antiferromagnetic materials present a significant challenge due to induced geometric frustration. Here we analyse the processes of magnetisation reversal driven by an external field in generalised spin networks with higher-order connectivity and antiferromagnetic defects. Using the model in (Tadić et al. Arxiv:1912.02433), we grow nanonetworks with geometrically constrained self-assemblies of simplexes (cliques) of a given size n, and with probability p each simplex possesses a defect edge affecting its binding, leading to a tree-like pattern of defects. The Ising spins are attached to vertices and have ferromagnetic interactions, while antiferromagnetic couplings apply between pairs of spins along each defect edge. Thus, a defect edge induces n - 2 frustrated triangles per n-clique participating in a larger-scale complex. We determine several topological, entropic, and graph-theoretic measures to characterise the structures of these assemblies. Further, we show how the sizes of simplexes building the aggregates with a given pattern of defects affects the magnetisation curves, the length of the domain walls and the shape of the hysteresis loop. The hysteresis shows a sequence of plateaus of fractional magnetisation and multiscale fluctuations in the passage between them. For fully antiferromagnetic interactions, the loop splits into two parts only in mono-disperse assemblies of cliques consisting of an odd number of vertices n. At the same time, remnant magnetisation occurs when n is even, and in poly-disperse assemblies of cliques in the range n ∈ [ 2 , 10 ] . These results shed light on spin dynamics in complex nanomagnetic assemblies in which geometric frustration arises in the interplay of higher-order connectivity and antiferromagnetic interactions.


Cost-effectiveness of routine imaging of suspected appendicitis.
Introduction The misdiagnosis of appendicitis and consequent removal of a normal appendix occurs in one in five patients in the UK. On the contrary, in healthcare systems with routine cross-sectional imaging of suspected appendicitis, the negative appendicectomy rate is around 5%. If we could reduce the rate in the UK to similar numbers, would this be cost effective? This study aimed to calculate the financial impact of negative appendicectomy at the Queen Alexandra Hospital and to explore whether a policy of routine imaging of such patients could reduce hospital costs. Materials and methods We performed a retrospective analysis of all appendicectomies over a 1-year period at our institution. Data were extracted on outcomes including appendix histology, operative time and length of stay to calculate the negative appendicectomy rate and to analyse costs. Results A total of 531 patients over 5 years of age had an appendicectomy. The negative appendicectomy rate was 22% (115/531). The additional financial costs of negative appendicectomy to the hospital during this period were £270,861. Universal imaging of all patients with right iliac fossa pain that could result in a 5% negative appendicectomy rate would cost between £67,200 and £165,600 per year but could save £33,896 (magnetic resonance imaging), £105,896 (computed tomography) or £132,296 (ultrasound) depending on imaging modality used. Conclusions Negative appendicectomy is still too frequent and results in additional financial burden to the health service. Routine imaging of patients with suspected appendicitis would not only reduce the negative appendicectomy rate but could lead to cost savings and a better service for our patients.


Resource aromaticity affects bacterial community successions in response to different sources of dissolved organic matter.
Microbe-mediated transformation of dissolved organic matter (DOM) contributes substantially to the carbon dynamics and energy flow of aquatic ecosystems; yet, the temporal dynamics of bacterial communities in response to diverse DOM sources are scarcely known. Here, we supplied four distinct sources of DOM (algae-derived, macrophyte-derived, sewage-derived, and soil-derived) to the same bacterial community to track the effects of these DOM sources on the carbon processing and successional dynamics of bacterial communities. Although by the end of the incubation the proportion of bio-degraded DOM was significantly lower in the soil-derived DOM treatment than for the other sources, rapid initial metabolism of protein-like and aliphatic compounds and increasing aromaticity and humification degree of DOM during the incubation period were observed for all sources. The role of stochastic processes in governing the community assembly decreased substantially from 61.4% on the first day to 16.7% at the end of the incubation. Moreover, stronger deterministic selection and lower temporal turnover rate were observed for the soil-derived than the other DOM sources, indicating stronger environmental filtering by the more aromatic DOM. Significant correlations were also observed between the humification index (HIX) of DOM and bacterial community diversities, co-occurrence patterns, habitat niche breadths, and the contribution of deterministic ecological processes. In addition, we demonstrated that taxa with different abundance patterns all play crucial but different roles in the response to DOM variation. Our results indicate the importance of DOM aromaticity as a predictor of the outcome of different DOM sources on bacterial community dynamics.


Activity response to climate seasonality in species with fossorial habits: a niche modeling approach using the lowland burrowing treefrog (Smilisca fodiens).
The importance of climatic conditions in shaping the geographic distribution of amphibian species is mainly associated to their high sensitivity to environmental conditions. How they cope with climate gradients through behavioral adaptations throughout their distribution is an important issue due to the ecological and evolutionary implications for population viability. Given their low dispersal abilities, the response to seasonal climate changes may not be migration, but behavioral and physiological adaptations. Here we tested whether shifts in climatic seasonality can predict the temporal variation of surface activity of the fossorial Lowland Burrowing Treefrog (Smilisca fodiens) across its geographical distribution. We employed Ecological Niche Modeling (ENM) to perform a monthly analysis of spatial variation of suitable climatic conditions (defined by the July conditions, the month of greatest activity), and then evaluated the geographical correspondence of monthly projections with the occurrence data per month. We found that the species activity, based on the species' occurrence data, corresponds with the latitudinal variation of suitable climatic conditions. Due to the behavioral response of this fossorial frog to seasonal climate variation, we suggest that precipitation and temperature have played a major role in the definition of geographical and temporal distribution patterns, as well as in shaping behavioral adaptations to local climatic conditions. This highlights the influence of macroclimate on shaping activity patterns and the important role of fossorials habits to meet the environmental requirements necessary for survival.


Prospective follow-up study of artificial urinary sphincter placement preserving the bulbospongiosus muscle.
Artificial urinary sphincter (AUS) AMS-800® is an effective treatment for male stress urinary incontinence. The aim of the study was to assess the long-term effectiveness and complications of artificial urinary sphincter placement preserving the bulbospongiosus muscle. From April 2004 to March 2014, all consecutive male patients with urinary incontinence who underwent an AUS prosthesis insertion were prospectively evaluated. Surgical technique consisted of a perineal incision for cuff placement around the bulbous urethra preserving the bulbospongiosus muscle. Cure rate was defined as no pad use. A total of 82 consecutive patients (median age 68 years, range: 54-78) were prospectively evaluated (median follow-up 46 months, range: 12-135). Bulbospongiosus muscles were preserved intact in all cases with no intraoperative complications. Postoperative complications were reported in 14 patients (1 urethral erosion). The overall cure rate (dry rate) was 76.8% and the median ICIQ-UI score improved from 18 (range: 8-21) to 4 (range: 0-17) (P < 0.001). Artificial urinary sphincter survival rate was 95.5% (95%CI 89.4-100%) at 24 months and 62.6% (95%CI 45.5-79.6%) at 60 months. The mechanical failure rate was 6.3% (median 46.1 months, range: 22.2-100.9) and urethral atrophy and/or inadequate compression rate was 9.5% (median 58.6 months, range: 39-101.4 months). Our study suggests that placement of AUS preserving the bulbospongiosus muscle is technically easy and efficient, reports excellent continence rates and lower urethral erosion rates, and could delay the onset of urethral atrophy compared to other surgical procedures used for sphincter placement.


Urban woodland on intensive green roof improved outdoor thermal comfort in subtropical summer.
Global climate change and urban heat island effect have jointly threatened human thermal comfort in cities. Intensive green roof (IGR) could supplement urban green space to alleviate thermal comfort. Aiming at examining the impact of IGR on the thermal comfort of its users, Universal Thermal Climate Index (UTCI) and physiological equivalent temperature (PET) were applied to assess effectiveness of IGR in improving outdoor thermal comfort by IGR. Comprehensive microclimatic monitoring was conducted on urban woodland IGR and an adjacent control bare roof in humid-subtropical Hong Kong. Sunny days (n = 21) and cloudy days (n = 18) were selected from summer in 2016. Insolation, air, and surface temperatures were compared between the two roofs. UTCI and PET were computed for the daytime and nighttime period of each sampled day. On IGR, significantly higher environmental cooling was achieved during daytime in sunny weather, with mean surface and air cooling reaching 4.9 °C and 1.6 °C respectively. Woodland IGR successfully improved thermal sensation by cooling mean UTCI and PET by 5.5 °C and 10.9 °C respectively during daytime in sunny scenario. Woodland IGR reduced the occurrence of extreme and very strong heat stress which struck the control bare roof. Recommendations on about thermal sensation were provided for building owners, town planners, and landscape architects.


Protein kinase A regulates inflammatory pain sensitization by modulating HCN2 channel activity in nociceptive sensory neurons.
Several studies implicated cyclic adenosine monophosphate (cAMP) as an important second messenger for regulating nociceptor sensitization, but downstream targets of this signaling pathway which contribute to neuronal plasticity are not well understood. We used a Cre/loxP-based strategy to disable the function of either HCN2 or PKA selectively in a subset of peripheral nociceptive neurons and analyzed the nociceptive responses in both transgenic lines. A near-complete lack of sensitization was observed in both mutant strains when peripheral inflammation was induced by an intradermal injection of 8br-cAMP. The lack of HCN2 as well as the inhibition of PKA eliminated the cAMP-mediated increase of calcium transients in dorsal root ganglion neurons. Facilitation of Ih via cAMP, a hallmark of the Ih current, was abolished in neurons without PKA activity. Collectively, these results show a significant contribution of both genes to inflammatory pain and suggest that PKA-dependent activation of HCN2 underlies cAMP-triggered neuronal sensitization.


Clinicopathologic parameters and immunohistochemical study of endometrial stromal sarcomas.
We aimed to investigate the clinicopathologic features, immunohistochemical studies, and prognosis in patients with endometrial stromal sarcoma (ESS). Clinical information was reviewed retrospectively for cases of ESS (1985-2009). A histologic review and immunohistochemical staining for the estrogen receptor, progesterone receptor, c-Kit, CD-10, Ki-67, and m-TOR were performed. Sixty-one patients (median age, 44 y; range, 22-71) were eligible for analysis (1988 International Federation of Gynecology and Obstetrics Stage I, 43; Stage II, 2; Stage III, 11; Sage IV, 4; unstaged, 1). The median follow-up period for survivors was 73 mo. Of those, the patients who underwent an adnexectomy and a pelvic lymphadenectomy, 15% and 13%, respectively, revealed metastasis. There were 20 relapses/persistence, including 13 (65%) in the pelvis and abdomen and 7 (35%) in distant sites. Eight patients died from ESS at a median duration of 14.5 mo (range, 2-50 mo) after relapse. Five- and 10-yr cancer-specific survival (CSS) rates were 88% and 85%, respectively; and 5- and 10-yr progression-free survival rates were 69% and 57%, respectively. Stage, residual disease, and high proliferative index of Ki-67 were significant prognostic factors for both progression-free survival and CSS in a univariate analysis, in addition to mitotic index for CSS. Multivariate analysis selected only residual disease as an independent variable for progression-free survival and stage and residual disease for CSS. Our results support using clinical Stage I, no residual disease, low proliferative index of Ki-67, and estrogen receptor/progesterone receptor overexpression as potential biomarkers to select patients with ESS for fertility-preservation surgery (5 such patients were alive and free).


LocSigDB: a database of protein localization signals.
LocSigDB (http://genome.unmc.edu/LocSigDB/) is a manually curated database of experimental protein localization signals for eight distinct subcellular locations; primarily in a eukaryotic cell with brief coverage of bacterial proteins. Proteins must be localized at their appropriate subcellular compartment to perform their desired function. Mislocalization of proteins to unintended locations is a causative factor for many human diseases; therefore, collection of known sorting signals will help support many important areas of biomedical research. By performing an extensive literature study, we compiled a collection of 533 experimentally determined localization signals, along with the proteins that harbor such signals. Each signal in the LocSigDB is annotated with its localization, source, PubMed references and is linked to the proteins in UniProt database along with the organism information that contain the same amino acid pattern as the given signal. From LocSigDB webserver, users can download the whole database or browse/search for data using an intuitive query interface. To date, LocSigDB is the most comprehensive compendium of protein localization signals for eight distinct subcellular locations. Database URL: http://genome.unmc.edu/LocSigDB/


Dual role of cellular prion protein in normal host and Alzheimer's disease.
Using PrPC-knockout cell lines, it has been shown that the inhibition of apoptosis through STI1 is mediated by PrPC-dependent SOD activation. Antioxidant PrPC may contribute to suppression of inflammasome activation. PrPC is functionally involved in copper metabolism, signal transduction, neuroprotection, and cell maturation. Recently several reports have shown that PrPC participates in trans-membrane signaling processes associated with hematopoietic stem cell replication and neuronal differentiation. In another role, PrPC also tends to function as a neurotoxic protein. Aβ oligomer, which is associated with neurodegeneration in Alzheimer's disease (AD), has also been reported to act as a ligand of PrPC. However, the physiological role of PrPC as an Aβ42-binding protein is not clear. Actually, PrPC is critical in Aβ42-mediated autophagy in neurons. PrPC shows a beneficial role in lipid rafts to promote autophagy. Further search for PrPC-interaction molecules using Prnp-/- mice and various types of Prnp-/- cell lines under various conditions may elucidate other important PrPC important functions.


Differential requirement for P2X7R function in IL-17 dependent vs. IL-17 independent cellular immune responses.
IL17-dependent autoimmunity to collagen type V (Col V) has been associated with lung transplant obliterative bronchiolitis. Unlike the T helper 1 (Th1)-dependent immune responses to Tetanus Toxoid (TT), the Th17 response to Col V in lung transplant patients and its Th1/17 variant observed in coronary artery disease patients requires IL-1β, tumor necrosis factor α and CD14(+) cells. Given the involvement of the P2X7 receptor (P2X7R) in monocyte IL-1β responses, we investigated its role in Th17-, Th1/17- and Th1-mediated proinflammatory responses. Transfer of antigen-pulsed peripheral blood mononucleated cells (PBMCs) from Col V-reactive patients into SCID mouse footpads along with P2X7R antagonists revealed a selective inhibition of Col V-, but not TT-specific swelling responses. P2X7R inhibitors blocked IL-1β induction from monocytes, including both Col V-α1 peptide-induced (T-dependent), as well as native Col V-induced (T-independent) responses. Significantly higher P2X7R expression was found on CXCR3(neg) CCR4(+)/6(+) CD4(+) [Th17] versus CXCR3(+)CCR4/6(neg) CD4(+) [Th1] subsets in PBMCs, suggesting that the paradigm of selective dependence on P2X7R might extend beyond Col V autoimmunity. Indeed, P2X7R inhibitors suppressed not only anti-Col V, but also Th1/17-mediated alloimmunity, in a heart transplant patient without affecting anti-viral Epstein-Barr virus responses. These results suggest that agents targeting the P2X7R might effectively treat Th17-related transplant pathologies, while maintaining Th1-immunity to infection.


Antibiotic therapy for community-acquired pneumonia.
This article takes a broad perspective of community-acquired pneumonia (CAP). The arguments and data that support or refute the current approaches to initial antimicrobial treatment of CAP as outlined in the American Thoracic Society and Infectious Disease Society of America documents are provided. The complex issues involved in the decision of how to properly treat CAP are addressed.


Importance of snake venom metalloproteinases in cell biology: effects on platelets, inflammatory and endothelial cells.
Snake venom metalloproteinases (SVMPs) are widely distributed in snake venoms and play important roles in hemostatic disorders and local tissue damage that follows snakebite. The impact of SVMPs on hemostasis has been extensively studied showing diverse effects both on soluble factors and cellular components. The action of SVMPs involves catalytic and anti-adhesive properties, as well as direct cellular activation and/or the release of endogenous bioactive components. The purpose of this review is to overview the action of SVMPs on the inhibition of platelet functions; angiogenesis, particularly inducing apoptosis of endothelial cells; and regarding the pro-inflammatory reaction that follows snakebite. We discuss the structural features of the molecules that may be involved in such activities. The versatility and availability of SVMPs make them important tools for cell biology research into the mechanisms of action of endogenous metalloproteinases, for insights into cellular-matrix interactions and for clinical investigations into the treatment of snakebites.


GCP II (NAALADase) inhibition suppresses mossy fiber-CA3 synaptic neurotransmission by a presynaptic mechanism.
We tested the hypothesis that endogenous N-acetylaspartylglutamate (NAAG) presynaptically inhibits glutamate release at mossy fiber-CA3 synapses. For this purpose, we made use of 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), an inhibitor of glutamate carboxypeptidase II [GCP II; also known as N-acetylated alpha-linked acidic dipeptidase (NAALADase)], the enzyme that hydrolyzes NAAG into N-acetylaspartate and glutamate. Application of 2-MPPA (1-20 microM) had no effect on intrinsic membrane properties of CA3 pyramidal neurons recorded in vitro in whole cell current- or voltage-clamp mode. Bath application of 10 microM 2-MPPA suppressed evoked excitatory postsynaptic current (EPSC) amplitudes. Attenuation of EPSC amplitudes was accompanied by a significant increase in paired-pulse facilitation (50-ms interpulse intervals), suggesting that a presynaptic mechanism is involved. The group II metabotropic glutamate receptor (mGluR) antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-y l) propanoic acid (LY341495) prevented the 2-MPPA-dependent suppression of EPSC amplitudes. 2-MPPA reduced the frequencies of TTX-insensitive miniature EPSCs (mEPSC), without affecting their amplitudes, further supporting a presynaptic action for GCP II inhibition. 2-MPPA-induced reduction of mEPSC frequencies was prevented by LY341495, reinforcing the role of presynaptic group II mGluR. Because GCP II inhibition is thought to increase NAAG levels, these results suggest that NAAG suppresses synaptic transmission at mossy fiber-CA3 synapses through presynaptic activation of group II mGluRs.


The conversion to metered-dose inhaler with valved holding chamber to administer inhaled albuterol: a pediatric hospital experience.
Metered-dose inhalers with valved holding chambers (MDI-VHCs) have been shown to be equivalent to small-volume nebulizers (SVNs) for the delivery of bronchodilators in children. At Seattle Children's Hospital and Regional Medical Center we sought to implement the conversion from SVN to MDI-delivered albuterol in nonintubated patients receiving intermittent treatments. There were 4 distinct interventions used to plan and implement this conversion program: (1) literature review, (2) product selection, (3) policy and operational changes, and (4) staff training. Bronchodilator administration guidelines and clinical pathways for asthma and bronchiolitis were revised to recommend MDI-VHC use in lieu of SVNs. Computerized physician order sets were amended to indicate MDI-VHC as the preferred method of delivering inhaled albuterol in children with asthma and bronchiolitis. Data from administrative case mix files and computerized medication delivery systems were used to assess the impact of our program. MDI-VHC utilization increased from 25% to 77% among all non-intensive-care patients receiving albuterol, and from 10% to 79% among patients with asthma (p < 0.001). Duration of stay among patients with asthma was unchanged after conversion to MDI-VHC (p = 0.53). Our program was very successful at promoting the use of MDI-VHC for the administration of albuterol in our pediatric hospital. Duration of stay among patients with asthma did not change during or since the implementation of this program.


Targeting oligomers in neurodegenerative disorders: lessons from α-synuclein, tau, and amyloid-β peptide.
Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Prion disease, Huntington's disease, and amyotrophic lateral sclerosis are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation in selected brain regions. The aggregates usually consist of insoluble fibrillar aggregates containing misfolded protein with β-sheet conformation. The most probable explanation is that inclusions and the aggregates symbolize an end stage of a molecular cascade of several events, and that earlier event in the cascade may be more directly tied up to pathogenesis than the inclusions themselves. Small intermediates termed as 'soluble oligomers' in the aggregation process might influence synaptic dysfunction, whereas large, insoluble deposits might function as reservoir of the bioactive oligomers. Compelling evidence suggests the role of misfolded proteins in the form of oligomers might lead to synaptic dysfunction, neuronal apoptosis and brain damage. However, the mechanism by which oligomers trigger neurodegeneration still remains mysterious. The aim of this article is to review the literature around the molecular mechanism and role of oligomers in neurodegeneration and leading approaches toward rational therapeutics.


Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion.
It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target.


Transcriptional regulation of glutamic acid decarboxylase in the male mouse amygdala by dietary phyto-oestrogens.
Phyto-oestrogens are biologically active components of many human and laboratory animal diets. In the present study, we investigated, in adult male mice with C57BL/6 genetic background, the effects of a reduced phyto-oestrogens intake on anxiety-related behaviour and associated gene expression in the amygdala. After 6 weeks on a low-phyto-oestrogen diet (< 20 μg/g cumulative phyto-oestrogen content), animals showed reduced centre exploration in an open-field task compared to their littermates on a soybean-based standard diet (300 μg/g). Freezing behaviour in an auditory fear memory task, in contrast, was not affected. We hypothesised that this mildly increased anxiety may involve changes in the function of GABAergic local circuit neurones in the amygdala. Using GAD67(+/GFP) mice, we could demonstrate reduced transcription of the GAD67 gene in the lateral and basolateral amygdala under the low-phyto-oestrogen diet. Analysis of mRNA levels in microdissected samples confirmed this regulation and demonstrated concomitant changes in expression of the second glutamic acid decarboxylase (GAD) isoform, GAD65, as well as the anxiolytic neuropeptide Y. These molecular and behavioural alterations occurred without apparent changes in circulating oestrogens or testosterone levels. Our data suggest that expression regulation of interneurone-specific gene products in the amygdala may provide a mechanism for the control of anxiety-related behaviour through dietary phyto-oestrogens.


Is there any association between cognitive status and functional capacity during exacerbation of chronic obstructive pulmonary disease?
The aim of this study is to screen the cognitive function during exacerbation of chronic obstructive pulmonary disease (COPD) and investigate whether there is any association between cognitive function and functional impairment, disease severity, or other clinical parameters. Age and sex-matched 133 subjects with COPD exacerbation, 34 stable COPD subjects, and 34 non-COPD subjects were enrolled in this study. For the purpose of this study, mini-mental state examination (MMSE) and Hospital Anxiety and Depression scale were performed. Six-minute walk distance (6MWD) was recorded, and BODE index was calculated. COPD subjects with exacerbation had the lowest MMSE scores (p = 0.022). Frequency of subjects with MMSE score lower than 24 is 22.6, 8.8, and 8.8% in the COPD subjects with exacerbation, stable COPD, and non-COPD control subjects, respectively. The COPD subjects with exacerbation who had MMSE scores lower than 24 were older and less educated. Subjects with COPD exacerbation had shorter 6MWD than that of stable COPD and non-COPD subjects. After controlling for the impact of age and educational level on MMSE, there was no association between 6MWD and MMSE scores in subjects with COPD exacerbation. Cognitive impairment is an important comorbidity during COPD exacerbation. Functional capacity is also lower in exacerbation. However, no association was found between cognitive impairment and functional capacity during exacerbation.


Antibiotic treatment of acute bronchitis in smokers: a systematic review.
Community physicians in the United States prescribe antibiotics to 80% to 90% of smokers with acute bronchitis. We performed a systematic review of the literature to determine the efficacy of antibiotics for smokers with acute bronchitis. A medline search was done using the keywords bronchitis, cough, and antibiotics to identify English language articles published from January 1966 to September 2001. Randomized, placebo-controlled trials of antibiotics in previously healthy smokers and nonsmokers with acute bronchitis were included. For each study, we abstracted information on design, size, inclusion criteria, patient characteristics, and outcomes. Of 2,029 articles in the original search, 109 relevant articles were retrieved and reviewed. There have been no studies specifically addressing antibiotic use in smokers with acute bronchitis. Nine randomized, placebo-controlled trials of antibiotics have included 774 patients and over 276 smokers. Lack of subgroup reporting for smokers precluded meta-analysis. In 7 trials, smoking status did not predict or alter patients' response to antibiotics. In one trial, trimethoprim/sulfamethoxazole resulted in less-frequent cough overall, but not among smokers. In another trial, erythromycin reduced symptom scores only among nonsmokers while antibiotic-treated smokers had a trend toward higher symptom scores. Although no trials have specifically addressed antibiotic use in smokers with acute bronchitis, existing data suggest that any benefit of antibiotics is the same or less for smokers than for nonsmokers.


Gal power: the diverse roles of galectins in regulating viral infections.
Viruses, as a class of pathogenic microbe, remain a significant health burden globally. Viral infections result in significant morbidity and mortality annually and many remain in need of novel vaccine and anti-viral strategies. The development of effective novel anti-viral therapeutics, in particular, requires detailed understanding of the mechanism of viral infection, and the host response, including the innate and adaptive arms of the immune system. In recent years, the role of glycans and lectins in pathogen-host interactions has become an increasingly relevant issue. This review focuses on the interactions between a specific lectin family, galectins, and the broad range of viral infections in which they play a role. Discussed are the diverse activities that galectins play in interacting directly with virions or the cells they infect, to promote or inhibit viral infection. In addition we describe how galectin expression is regulated both transcriptionally and post-transcriptionally by viral infections. We also compare the contribution of known galectin-mediated immune modulation, across a range of innate and adaptive immune anti-viral responses, to the outcome of viral infections.


Technologies for Advanced Gait and Balance Assessments in People with Multiple Sclerosis.
Subtle gait and balance dysfunction is a precursor to loss of mobility in multiple sclerosis (MS). Biomechanical assessments using advanced gait and balance analysis technologies can identify these subtle changes and could be used to predict mobility loss early in the disease. This update critically evaluates advanced gait and balance analysis technologies and their applicability to identifying early lower limb dysfunction in people with MS. Non-wearable (motion capture systems, force platforms, and sensor-embedded walkways) and wearable (pressure and inertial sensors) biomechanical analysis systems have been developed to provide quantitative gait and balance assessments. Non-wearable systems are highly accurate, reliable and provide detailed outcomes, but require cumbersome and expensive equipment. Wearable systems provide less detail but can be used in community settings and can provide real-time feedback to patients and clinicians. Biomechanical analysis using advanced gait and balance analysis technologies can identify changes in gait and balance in early MS and consequently have the potential to significantly improve monitoring of mobility changes in MS.


Lack of beneficial effects of growth hormone treatment in conscious dogs during development of heart failure.
The effects of chronic treatment with growth hormone (porcine GH, 0.56 mg.kg-1.day-1 s.c.) were examined in dogs with heart failure induced by rapid ventricular pacing (240 beats/min) for 4 wk. Fourteen conscious dogs were studied 2-3 wk after surgical instrumentation with catheters in the descending aorta and left atrium, a pressure gauge in the left ventricle (LV), a flow probe around the ascending aorta, pacing leads on the ventricular free wall and left atrium, and ultrasonic crystals on the opposing anterior and posterior endomyocardium of the LV. GH treatment for 4 wk significantly increased both body weight and plasma insulin-like growth factor 1 (IGF-1) compared with vehicle-treated dogs (P < 0.01, +2.0 +/- 0.5 vs. +0.3 +/- 1.1 kg; 1,043 +/- 218 vs. 241 +/- 64 ng/ml, respectively). However, the changes in resting LV systolic (i.e., both isovolumic and ejection phases) and diastolic function (i.e., isovolumic relaxation time constant tau) and the systemic vascular resistance were similar for the GH- and vehicle-treated groups during the development of heart failure. LV contractile reserve, assessed with step infusion of isoproterenol or dobutamine challenge, was markedly attenuated after heart failure, but there were no differences between the GH- and vehicle-treated groups. During the progression of heart failure, the increases in plasma atrial natriuretic peptide correlated (P < 0.01) directly with left atrial pressure and inversely with LV circumferential fiber shortening. However, GH treatment did not substantially modify these relationships. In addition, renal function and myocardial ultrastructure at the advanced stage of heart failure also showed similar changes for the GH- and vehicle-treated groups. We conclude that in conscious dogs during the development of congestive heart failure produced by rapid ventricular pacing, GH at a dose that increases body weight and plasma IGF-1 levels does not affect LV performance or systemic vascular dynamics.


EASTERN EUROPE: Science Survives in Breakaway States.
Slovenia, which escaped unscathed from its 1-week war of independence in 1991, has emerged from the chaos of the Yugoslav breakup with the biggest head start in science. Croatia also has a proud scientific tradition, but it paid a much higher price than Slovenia paid for its freedom: a bloody war for independence that took nearly 4 years to settle. The problems of Croatian researchers pale in comparison to those in neighboring Bosnia-Herzegovina, however.


High-throughput Methods Redefine the Rumen Microbiome and Its Relationship with Nutrition and Metabolism.
Diversity in the forestomach microbiome is one of the key features of ruminant animals. The diverse microbial community adapts to a wide array of dietary feedstuffs and management strategies. Understanding rumen microbiome composition, adaptation, and function has global implications ranging from climatology to applied animal production. Classical knowledge of rumen microbiology was based on anaerobic, culture-dependent methods. Next-generation sequencing and other molecular techniques have uncovered novel features of the rumen microbiome. For instance, pyrosequencing of the 16S ribosomal RNA gene has revealed the taxonomic identity of bacteria and archaea to the genus level, and when complemented with barcoding adds multiple samples to a single run. Whole genome shotgun sequencing generates true metagenomic sequences to predict the functional capability of a microbiome, and can also be used to construct genomes of isolated organisms. Integration of high-throughput data describing the rumen microbiome with classic fermentation and animal performance parameters has produced meaningful advances and opened additional areas for study. In this review, we highlight recent studies of the rumen microbiome in the context of cattle production focusing on nutrition, rumen development, animal efficiency, and microbial function.


The supervisor's toolkit: A framework for doctoral supervision in health professions education: AMEE Guide No. 104.
Doctoral studies represent a complex undertaking for students and supervisors. Some research describes the experience of students while there are volumes of advice for students considering a doctorate. Yet the terrain for supervisors is less well-trodden and the concept of a pedagogy of supervision is only really starting to emerge. Texts on the doctoral journey from the supervisor's perspective are uncommon and less yet has been written in the context of health professions education. The aim of this Guide, therefore, is to provide guidance for the supervisor's journey, drawing on our collective experience and such literature as there is. We explore the doctoral journey of students and their supervisors, highlighting what the implications are for supervisory practice. Recognising the doctorate as much more than merely conducting a research project, and seeing it as a shared educational endeavour is fundamental to understanding the doctoral journey - a journey that is complex and mutable, constantly shifting as the candidate moves from novice to expert, from dependence to growing autonomy. Our intention is to present this Guide as a toolkit for both the novice and the experienced supervisor as it, on the one hand, seeks to make the practice of supervision more transparent while on the other, challenges the reader to critically reflect on the supervisory space in which they currently reside. Our hope is that the Guide opens up opportunities for generative conversations about the practice of doctoral supervision in health professions education.


miR-24 reduces serum lipid levels and inhibits brain tissue cells apoptosis of rats with cerebral infarction.
To study miR-24 effects on cerebral infarction in rats. A rat middle cerebral artery occlusion model (MCAO) was constructed. Intracerebroventricular stereotactic injection of miR-24 agomir/antagomir was performed in the rat MCAO model. According to different experiences, rats were divided into normal, sham, MCAO, miR-24 agomir and miR-24 antagomir groups. Serum TCH, HDL and TG levels were detected. Comparing the normal and sham groups, we observed decreased relative miR-24 expression (P 0.05) and increased cerebral infarction area percentage, apoptotic cells and relative caspase-3 protein expression (P 0.05) in the MCAO, miR-24 agomir and miR-24 antagomir groups. TC, TG and HDL-C levels of the MCAO and miR-24 antagomir groups were higher than those of normal and sham groups (P 0.05). Compared with the MCAO group, increased relative miR-24 expression (P 0.05) and decreased TC, TG and HDL-C levels, cerebral infarction area percentage, number of apoptotic cells and caspase-3 expression (P 0.05) were found in the miR-24 agomir group, contrasting with the observations from the miR-24 antagomir group. miR-24 reduced serum TCH, HDL and TG levels and inhibited brain tissue cell apoptosis in rats with cerebral infarction.


Youth with spina bifida and transitions: health and social participation in a nationally represented sample.
To describe outcomes and identify factors that affect social participation in youth and young adults with spina bifida. Prospective data from a nationally representative survey of youth and young adults with disabilities were analyzed. The WHO ICF framework was used with participation as the dependent category and (a) body function/structure; (b) activities; (c) personal factors; and (d) environment as independent categories. A nationally representative sample of 130 youth with spina bifida (mean age 15 years) representing 5171 individuals with spina bifida was followed up for 4 years. The general health of the sample declined over the 4-year study period. Although each outcome using the WHO ICF model had its own pattern of factors that related to it, being Latino or not speaking English at home was negatively associated with each of the outcomes. The general health of individuals with spina bifida declines during adolescence and early adulthood. Social participation is affected by many factors, and each outcome appears to have its own set of factors that affect it. Future interventions to improve health, well-being, and social participation in adults with spina bifida will need to address factors in all domains.


Synthesis of a CdS-decorated Eu-MOF nanocomposite for the construction of a self-powered photoelectrochemical aptasensor.
A composite of CdS nanoparticles and a europium metal organic framework (Eu-MOF) (CdS/Eu-MOF) was synthesized. The unique properties of MOFs help to improve the photoelectrochemical (PEC) properties of CdS by reducing charge carrier recombination and utilizing a broader spectrum for light harvesting. Under visible light illumination, the photocurrent of the CdS/Eu-MOF composite modified electrode was about 2.5-fold higher than that of the CdS modified electrode. When an ampicillin (AMP)-binding aptamer was immobilized on the CdS/Eu-MOF modified electrode as a recognition element, a self-powered PEC aptasensor exhibiting a specific photocurrent response to AMP was constructed. Several experimental conditions such as the ratio of CdS to MOF, the coating amount of the CdS/Eu-MOF suspension and the concentration of the aptamer were studied. Under optimum conditions, the photocurrent of the developed sensor was linearly related to the logarithm AMP concentration in the range of 1 × 10-10 to 2 × 10-7 M, with a detection limit (3S/N) of 9.3 × 10-11 M. Moreover, this sensor exhibited excellent selectivity, good repeatability and desirable stability. It was successfully applied to the detection of AMP in lake water and milk samples.


Leptotrichia buccalis bacteremia in neutropenic children.
Two new cases of Leptotrichia buccalis bacteremia in seriously ill patients were described. The anaerobic, gram-negative microorganism L. buccalis was isolated from blood cultures of two children with severe leukopenia. Anaerobic organisms should be taken into account when a standard protective antibiotic chemotherapy is considered in the immunosuppressed host.


Publication outcomes among intensive care trainees.
There is a paucity of literature describing the research productivity among trainees in intensive care medicine. We sought to examine the occurrence and determinants of successful publication outcomes associated with intensive care training. The study cohort consisted of all individuals admitted to fellowship of the College of Intensive Care Medicine of Australia and New Zealand (CICM) from 2012 to 2019. The primary outcome measure of this study was manuscripts indexed on PubMed within one year after and four years prior to admittance to CICM fellowship. Four hundred and eighty-five fellows were identified of whom 216 (45%) had at least one publication; 129 (27%) had one, 34 (7%) had two, 21 (4%) had three and 32 (7%) had four or more publications. Overall 138 (28%) fellows had at least one publication that was likely associated with their mandatory CICM training project for which they were first (n = 110; 80%) and/or corresponding (n = 72; 52%) author in the majority of cases. Overall 107 different senior/mentor authors were identified, with 13 individuals supporting more than one publication. Although gender and location at the time of fellowship award were not associated, location of receipt of medical degree, shorter time period between medical school graduation and fellowship award, more recent year of award, and completion of medical degree/fellowship in the same geographical region were associated with project publication. A minority of CICM fellows have PubMed-indexed publications related to their training. Further efforts are warranted to better define the determinants of successful project publication to optimise future opportunities.


A completely noninvasive method of dissolved oxygen monitoring in disposable small-scale cell culture vessels based on diffusion through permeable vessel walls.
Disposable cell culture vessels are extensively used at small scales for process optimization and validation, but they lack monitoring capabilities. Optical sensors that can be easily adapted for use in small-scale vessels are commercially available for pH, dissolved oxygen (DO), and dissolved carbon dioxide (DCO2 ). However, their use has been limited due to the contamination and compatibility issues. We have developed a novel solution to these problems for DO monitoring. Oxygen diffusion through permeable vessel wall can be exploited for noninvasive monitoring. An optical oxygen sensor can be placed outside the oxygen permeable vessel wall thereby allowing oxygen diffusing through the vessel wall to be detected by the sensor. This way the sensor stays separate from the cell culture and there are no concerns about contaminants or leachants. Here we implement this method for two cell culture devices: polystyrene-made T-75 tissue culture flask and fluorinated ethylene propylene (FEP)-made Vuelife(®) cell culture bag. Additionally, mammalian and microbial cell cultures were performed in Vuelife(®) cell culture bags, proving that a sensor placed outside can be used to track changes in cell cultures. This approach toward noninvasive monitoring will help in integrating cell culture vessels with sensors in a seamless manner.


Plasma vitamins A and E and red blood cell fatty acid profile in newborns and their mothers.
In this work, we have measured the plasma vitamins A and E and red blood cell fatty acid profile in newborns and their mothers and have determined whether there are any relationships between maternal blood and cord blood for the nutrients measured. The study was performed at the Chung Shan Memorial Hospital, Taichung, Taiwan. Twenty-nine pairs of mothers and their term infants. Maternal venous blood was collected in the first trimester and at delivery, and cord blood was collected at delivery. Plasma vitamin A and E levels were determined by high performance liquid chromatography and red blood cell fatty acid profile was estimated by gas chromatography. Mothers had significantly greater plasma vitamin A and E levels and vitamin E/total lipid than their term neonates did (P < 0.05). Maternal plasma vitamin E and vitamin E/total lipid were significantly greater in the first trimester than at delivery (P < 0.05). Red blood cell phospholipid oleate and linoleate were significantly greater in maternal red blood cell than in cord blood (P < 0.05), however, stearate and arachidonate were significantly greater in the cord blood than in the maternal blood (P < 0.05). Maternal vitamin E, vitamin E/total lipid, palmitate, linoleate, arachidonate and docosahexaenoate were found positively correlated to those in their neonates (P < 0.05). The results suggest that there is a relationship between maternal blood and cord blood for some nutrients. Therefore, the nutritional status of mothers may affect the nutritional outcome of their neonates.


Organo-Chlorinated Thin Films Deposited by Atmospheric Pressure Plasma-Enhanced Chemical Vapor Deposition for Adhesion Enhancement between Rubber and Zinc-Plated Steel Monofilaments.
A continuous-flow plasma process working at atmospheric pressure is developed to enhance the adhesion between a rubber compound and a zinc-plated steel monofilament, with the long-term objective to find a potential alternative to the electrolytic brass plating process, which is currently used in tire industry. For this purpose, a highly efficient tubular dielectric barrier discharge reactor is built to allow the continuous treatment of "endless" cylindrical substrates. The best treatment conditions found regarding adhesion are Ar/O2 plasma pretreatment, followed by the deposition from dichloromethane of a 75 nm-thick organo-chlorinated plasma polymerized thin film. Ar/O2 pretreatment allows the removal of organic residues, coming from drawing lubricants, and induces external growth of zinc oxide. The plasma layer has to be preferably deposited at low power to conserve sufficient hydrocarbon moieties. Surface analyses reveal the complex chemical mechanism behind the establishment of strong adhesion levels, more than five times higher after the plasma treatment. During the vulcanization step, superficial ZnO reacts with the chlorinated species of the thin film and is converted into porous and granular bump-shaped ZnwOxHyClz nanostructures. Together, rubber additives diffuse through the plasma layer and lead to the formation of zinc sulfide on the substrate surface. Hence, two distinct interfaces, rubber/thin film and thin film/substrate, are established. On the basis of these observations, hypotheses explaining the high bonding strength results are formulated.


Asthma-Like Symptoms in Homeless Children in the Greater Paris Area in 2013: Prevalence, Associated Factors and Utilization of Healthcare Services in the ENFAMS Survey.
Asthma remains poorly studied in homeless children. We sought to estimate the prevalence of asthma-like symptoms (ALS) and to identify the factors associated with ALS and healthcare service utilisation. A cross-sectional survey of a random sample of sheltered homeless families was conducted by interviewing 801 parents of children (0-12 years) in 17 languages. ALS were defined as wheezing or night cough without fever during the previous year. Poisson regression models with robust error variance were used to compute prevalence ratios (PR) for factors associated with ALS and healthcare service utilisation for ALS. The prevalence of ALS among the children was 19.9%. Poor housing sanitation was significantly associated with ALS, as being born in the European Union. Most of the children with ALS had used healthcare services (85.4%). The main barriers to accessing such services were having lived in France for less than 49 months, having difficulties in French and living in poor housing conditions. ALS prevalence seemed lower than in the general child population, possibly because of the children's origins. Environmental factors associated with ALS point to the need to improve the indoor environment of family shelters. The relatively high rate of healthcare service utilisation should not overshadow existing barriers.


Severity and characteristics of developmental delay can be assessed using variability measures of sitting posture.
We sought to identify measures of variability from sitting postural sway that are significantly different among infants who were developing typically, those who were developmentally delayed or hypotonic, and those who later on had a diagnosis of spastic or athetoid cerebral palsy. Sixty-five infants were evaluated when they were just developing the ability to sit upright by assessing center of pressure (COP) data, using measures of both amount and temporal organization of COP variability. The results indicated that measures of variability of COP could discriminate between infants with developmental delay and infants with cerebral palsy and add to the description of sitting postural behavior. Our method of evaluating sitting postural control could be an objective tool to help describe distinctive features of motor delay in an individual infant and could lead in the design of selective therapeutic interventions for improving postural control of infants with motor delays.


Role of adenosine deaminase, ecto-(5'-nucleotidase) and ecto-(non-specific phosphatase) in cyanide-induced adenosine monophosphate catabolism in rat polymorphonuclear leucocytes.
1. The role of adenosine deaminase (EC 126.96.36.199), ecto-(5'-nucleotidase) (EC 126.96.36.199) and ecto-(non-specific phosphatase) in the CN-induced catabolism of adenine nucleotides in intact rat polymorphonuclear leucocytes was investigated by inhibiting the enzymes in situ. 2. KCN (10mM for 90 min) induced a 20-30% fall in ATP concentration accompanied by an approximately equimolar increase in hypoxanthine, ADP, AMP and adenosine concentrations were unchanged, and IMP and inosine remained undetectable ( less than 0.05 nmol/10(7) cells). 3. Cells remained 98% intact, as judged by loss of the cytoplasmic enzyme lactate dehydrogenase (EC 22.214.171.124). 4. Pentostatin (30 microM), a specific inhibitor of adenosine deaminase, completely inhibited hypoxanthine production from exogenous adenosine (55 microM), but did not black CN-induced hypoxanthine production or cause adenosine accumulation in intact cells. This implied that IMP rather than adenosine was an intermediate in AMP breakdown in response to cyanide. 5. Antibodies raised against purified plasma-membrane 5'-nucleotidase inhibited the ecto-(5'-nucleotidase) by 95-98%. Non-specific phosphatases were blocked by 10 mM-sodium beta-glycerophosphate. 6. These two agents together blocked hypoxanthine production from exogenous AMP and IMP (200 microM) by more than 90%, but had no effect on production from endogenous substrates. 7. These data suggest that ectophosphatases do not participate in CN-induced catabolism of intracellular AMP in rat polymorphonuclear leucocytes. 8. A minor IMPase, not inhibited by antiserum, was detected in the soluble fraction of disrupted cells.


Metformin use and associated risk of total joint replacement in patients with type 2 diabetes: a population-based matched cohort study.
It is uncertain whether metformin use is associated with reduced risk of joint replacement in patients with type 2 diabetes mellitus. We aimed to establish whether metformin use was associated with a reduced risk of total knee replacement (TKR) or total hip replacement (THR) among these patients. We selected patients with type 2 diabetes mellitus that was diagnosed between 2000 and 2012 from the Taiwan National Health Insurance Research Database. We used prescription time-distribution matching and propensity-score matching to balance potential confounders between metformin users and nonusers. We assessed the risks of TKR or THR using Cox proportional hazards regression. We included 20 347 participants who were not treated with metformin and 20 347 who were treated with metformin, for a total of 40 694 participants (mean age 63 yr, standard deviation 11 yr; 49.8% were women) after prescription time-distribution matching. Compared with participants who did not use metformin, those who used metformin had lower risks of TKR or THR (adjusted hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.60-0.81 for TKR or THR; adjusted HR 0.71, 95% CI 0.61-0.84 for TKR; adjusted HR 0.61, 95% CI 0.41-0.92 for THR) after adjustment for covariates. Propensity-score matching analyses (10 163 participants not treated with metformin v. 10 163 treated with metformin) and sensitivity analyses using inverse probability of treatment weighting and competing risk regression showed similar results. Metformin use in patients with type 2 diabetes mellitus was associated with a significantly reduced risk of total joint replacement. Randomized controlled clinical trials in patients with osteoarthritis are warranted to determine whether metformin is effective in decreasing the need for joint replacement.


A prospective analysis of trauma exposure: the mediating role of PTSD symptomatology.
Trauma exposure has been associated with increased risk of exposure to additional traumatic events. Reactions to trauma exposure, specifically PTSD symptomatology, may mediate the link between trauma exposure and later traumatic events. Data from a longitudinal sample of Gulf War veterans (N = 2,949) were analyzed using a series of regression models. Higher levels of combat exposure were related to increased reports of PTSD symptomatology immediately upon return as well as increased reports of traumatic events in the 2 years following the Gulf War. PTSD symptomatology partially mediated the link between combat exposure and later trauma. Symptom clusters were also analyzed separately as potential mediators. Implications for the treatment of PTSD and prevention of exposure to multiple traumas are discussed.


Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.
Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of < 70 was seen in 27%; learning disability in 44%, intellectual disability in 19%; attention-deficit/hyperactivity disorder in 32%; autism spectrum disorders in 15%; and anxiety in 27%. Mutations affecting Dp260 isoform and 5'untranslated region of Dp140 were observed in 60% with learning disability, 50% intellectual disability, 77% with autism spectrum disorders, and 94% with anxiety. No statistically significant correlation was noted between comorbidities and dystrophin isoforms; however, there is a trend of cumulative loss of dystrophin isoforms with declining full-scale IQ. Enhanced psychology testing to include both cognitive and neurobehavioral disorders is recommended for all individuals with Duchenne muscular dystrophy.


Genetic tools to manipulate MRI contrast.
Advances in molecular biology in the early 1970s revolutionized research strategies for the study of complex biological processes, which, in turn, created a high demand for new means to visualize these dynamic biological changes noninvasively and in real time. In this respect, MRI was a perfect fit, because of the versatile possibility to alter the different contrast mechanisms. Genetic manipulations are now being translated to MRI through the development of reporters and sensors, as well as the imaging of transgenic and knockout mice. In the past few years, a new molecular biology toolset, namely optogenetics, has emerged, which allows for the manipulation of cellular behavior using light. This technology provides a few particularly attractive features for combination with newly developed MRI techniques for the probing of in vivo cellular and, in particular, neural processes, specifically the ability to control focal, genetically defined cellular populations with high temporal resolution using equipment that is magnetically inert and does not interact with radiofrequency pulses. Recent studies have demonstrated that the combination of optogenetics and functional MRI (fMRI) can provide an appropriate platform to investigate in vivo, at the cellular and molecular levels, the neuronal basis of fMRI signals. In addition, this novel combination of optogenetics with fMRI has the potential to resolve pre-synaptic versus post-synaptic changes in neuronal activity and changes in the activity of large neuronal networks in the context of plasticity associated with development, learning and pathophysiology.


Opioids in the hypothalamic paraventricular nucleus stimulate ethanol intake.
Specialized hypothalamic systems that increase food intake might also increase ethanol intake. To test this possibility, morphine and receptor-specific opioid agonists were microinjected in the paraventricular nucleus (PVN) of rats that had learned to drink ethanol. To cross-validate the results, naloxone methiodide (m-naloxone), an opioid antagonist, was microinjected with the expectation that it would have the opposite effect of morphine and the specific opioid agonists. Sprague-Dawley rats were trained, without sugar, to drink 4 or 7% ethanol and were then implanted with chronic brain cannulas aimed at the PVN. After recovery, those drinking 7% ethanol, with food and water available, were injected with 2 doses each of morphine or m-naloxone. To test for receptor specificity, 2 doses each of the mu-receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-Enkephalin (DAMGO), delta-receptor agonist D-Ala-Gly-Phe-Met-NH2 (DALA), or kappa-receptor agonist U-50,488H were injected. DAMGO was also tested in rats drinking 4% ethanol without food or water available. As an anatomical control for drug reflux, injections were made 2 mm dorsal to the PVN. A main result was a significant increase in ethanol intake induced by PVN injection of morphine. The opposite effect was produced by m-naloxone. The effects of morphine and m-naloxone were exclusively on intake of ethanol, even though food and water were freely available. In the analysis with specific receptor agonists, PVN injection of the delta-agonist DALA significantly increased 7% ethanol intake without affecting food or water intake. This is in contrast to the kappa-agonist U-50,488H, which decreased ethanol intake, and the mu-agonist DAMGO, which had no effect on ethanol intake in the presence or absence of food and water. In the anatomical control location 2 mm dorsal to the PVN, no drug caused any significant changes in ethanol, food, or water intake, providing evidence that the active site was close to the cannula tip. The delta-opioid receptor agonist in the PVN increased ethanol intake in strong preference over food and water, while the kappa-opioid agonist suppressed ethanol intake. Prior studies show that learning to drink ethanol stimulates PVN expression and production of the peptides enkephalin and dynorphin, which are endogenous agonists for the delta- and kappa-receptors, respectively. These results suggest that enkephalin via the delta-opioid system can function locally within a positive feedback circuit to cause ethanol intake to escalate and ultimately contribute to the abuse of ethanol. This is in contrast to dynorphin via the kappa-opioid system, which may act to counter this escalation. Naltrexone therapy for alcoholism may act, in part, by blocking the enkephalin-triggered positive feedback cycle.