Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline.
Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in Caucasian populations, accounting for 20% of all cutaneous malignancies. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cSCC diagnosis and management, based on a critical review of the literature, existing guidelines and the expert's experience. The diagnosis of cSCC is primarily based on clinical features. A biopsy or excision and histologic confirmation should be performed in all clinically suspicious lesions in order to facilitate the prognostic classification and correct management of cSCC. The first line treatment of cutaneous SCC is complete surgical excision with histopathological control of excision margins. The EDF-EADO-EORTC consensus group recommends a standardised minimal margin of 5 mm even for low-risk tumours. For tumours, with histological thickness of >6 mm or in tumours with high risk pathological features, e.g. high histological grade, subcutaneous invasion, perineural invasion, recurrent tumours and/or tumours at high risk locations an extended margin of 10 mm is recommended. As lymph node involvement by cSCC increases the risk of recurrence and mortality, a lymph node ultrasound is highly recommended, particularly in tumours with high-risk characteristics. In the case of clinical suspicion or positive findings upon imaging, a histologic confirmation should be sought either by fine needle aspiration or by open lymph node biopsy. In large infiltrating tumours with signs of involvement of underlying structures, additional imaging tests, such as CT or MRI imaging may be required to accurately assess the extent of the tumour and the presence of metastatic spread. Current staging systems for cSCC are not optimal, as they have been developed for head and neck tumours and lack extensive validation or adequate prognostic discrimination in certain stages with heterogeneous outcome measures. Sentinel lymph node biopsy has been used in patients with cSCC, but there is no conclusive evidence of its prognostic or therapeutic value. In the case of lymph node involvement by cSCC, the preferred treatment is a regional lymph node dissection. Radiation therapy represents a fair alternative to surgery in the non-surgical treatment of small cSCCs in low risk areas. It generally should be discussed either as a primary treatment for inoperable cSCC or in the adjuvant setting. Stage IV cSCC can be responsive to various chemotherapeutic agents; however, there is no standard regimen. EGFR inhibitors such as cetuximab or erlotinib, should be discussed as second line treatments after mono- or polychemotherapy failure and disease progression or within the framework of clinical trials. There is no standardised follow-up schedule for patients with cSCC. A close follow-up plan is recommended based on risk assessment of locoregional recurrences, metastatic spread or development of new lesions.


Improvement in upright and supine lung mechanics with bariatric surgery affects bronchodilator responsiveness and sleep quality.
Obesity and weight loss have complex effects on respiratory physiology, but these have been insufficiently studied, particularly at early time points following weight loss surgery and in the supine position. We evaluated 15 female participants with severe obesity before and 5 wk and 6 mo after bariatric surgery using the Pittsburgh Sleep Quality Index (PSQI), spirometry, plethysmography, and oscillometry to measure respiratory system mechanics. Oscillometry and spirometry were conducted in the upright and supine position and before and after bronchodilation with 200 µg of salbutamol. At 5 wk postsurgery, weight loss was 11.9 kg (SD 2.7) with no effect on spirometric outcomes and a slight effect on oscillometric outcomes. However, at 6 mo weight loss was 21.4 kg (SD 7.1) with a 14.1% (SD 6.1) and 17.8 (5.4)% reduction in upright and supine respiratory system resistance (Rrs),6, respectively. Respiratory system elastance also decreased by 25.7% (SD 9.4) and 20.2 (SD 7.2)% in the upright and supine positions. No changes were observed in spirometry, but sleep quality improved from PSQI of 8.4 (SD 3.5) to 4.1 (SD 2.9). Bronchodilator responsiveness was low at baseline but increased significantly after surgery, and this response was comparable to the improvement in Rrs produced by weight loss. Modeling the impedance spectra with a two-compartment model demonstrated that improvements in lung mechanics with weight loss begin in the upper or central compartment of the lungs and progress to include the peripheral compartment. Respiratory mechanics are impaired in individuals with severe obesity and is associated with poor sleep quality, but these improved substantially with weight loss. Our data provide new evidence that individuals with severe obesity may have poor sleep quality because of abnormal respiratory mechanics that weight loss improves.NEW & NOTEWORTHY This is the first study to quantify the degree of weight loss-induced improvements in respiratory system mechanics in both upright and supine positions, and its association with bronchodilator responsiveness and sleep quality at multiple time points. Weight loss induced large improvements in upright and supine respiratory system mechanics with corresponding improvements in bronchodilator responsiveness and sleep quality. Using mathematical modeling, we demonstrate that these improvements begin in the central airways and progress to include the lung periphery.


Anti-angiogenic activity of melatonin in advanced cancer patients.
The anticancer activity of the indole melatonin has been explained to be due to its immunomodulatory, anti-prolferative and anti-oxidant effects, whereas at present no data are available about its possible influence on the angiogenesis, which has been shown to be one of the main biological mechanisms responsible for tumor dissemination. Vascular endothelial growth factor (VEGF) is the most active angiogenic factor, and the evidence of abnormally high blood levels or VEGF has been proven to be associated with poor prognosis in cancer patients. To investigate the influence of melatonin on angiogenesis, in this preliminary study we have evaluated the effects of melatonin therapy on VEGF blood levels in advanced cancer patients. The study included 20 metastatic patients, who progressed on previous conventional antitumor therapies and for whom no other effective treatment was available. Melatonin was given orally at 20 mg/day in the evening for at least 2 months. Serum levels of VEGF were measured by an enzyme immunoassay on venous blood samples collected at 15-day intervals. The clinical response consisted of minor response (MR) in 2, stable disease (SD) in 6 and progressive disease (PD) in the remaining 12 patients. VEGF mean levels decreased on therapy, without, however, statistical differences with respect to the pre-treatment values. In contrast, by evaluating changes in VEGF levels in relation to the clinical response, non-progressing patients (MR + SD) showed a significant decline in VEGF mean concentrations, whereas no effect was achieved in progressing patients. This study, by showing that melatonin-induced control or the neoplastic growth is associated with a decline in VEGF secretion, would suggest that the pineal hormone may control tumor growth at least in part by acting as a natural anti-angiogenic molecule, with a following opposition or angiogenesis-dependent cancer proliferation.


Above- and belowground linkages in Sphagnum peatland: climate warming affects plant-microbial interactions.
Peatlands contain approximately one third of all soil organic carbon (SOC). Warming can alter above- and belowground linkages that regulate soil organic carbon dynamics and C-balance in peatlands. Here we examine the multiyear impact of in situ experimental warming on the microbial food web, vegetation, and their feedbacks with soil chemistry. We provide evidence of both positive and negative impacts of warming on specific microbial functional groups, leading to destabilization of the microbial food web. We observed a strong reduction (70%) in the biomass of top-predators (testate amoebae) in warmed plots. Such a loss caused a shortening of microbial food chains, which in turn stimulated microbial activity, leading to slight increases in levels of nutrients and labile C in water. We further show that warming altered the regulatory role of Sphagnum-polyphenols on microbial community structure with a potential inhibition of top predators. In addition, warming caused a decrease in Sphagnum cover and an increase in vascular plant cover. Using structural equation modelling, we show that changes in the microbial food web affected the relationships between plants, soil water chemistry, and microbial communities. These results suggest that warming will destabilize C and nutrient recycling of peatlands via changes in above- and belowground linkages, and therefore, the microbial food web associated with mosses will feedback positively to global warming by destabilizing the carbon cycle. This study confirms that microbial food webs thus constitute a key element in the functioning of peatland ecosystems. Their study can help understand how mosses, as ecosystem engineers, tightly regulate biogeochemical cycling and climate feedback in peatlands.


3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation.
Hydroxylation and fluorination of proline alters the pyrrolidine ring pucker and the trans:cis amide bond ratio in a stereochemistry-dependent fashion, affecting molecular recognition of proline-containing molecules by biological systems. While hydroxyprolines and fluoroprolines are common motifs in medicinal and biological chemistry, the synthesis and molecular properties of prolines containing both modifications, i.e., fluoro-hydroxyprolines, have not been described. Here we present a practical and facile synthesis of all four diastereoisomers of 3-fluoro-4-hydroxyprolines (F-Hyps), starting from readily available 4-oxo-l-proline derivatives. Small-molecule X-ray crystallography, NMR spectroscopy, and quantum mechanical calculations are consistent with fluorination at C3 having negligible effects on the hydrogen bond donor capacity of the C4 hydroxyl, but inverting the natural preference of Hyp from C4-exo to C4-endo pucker. In spite of this, F-Hyps still bind to the von Hippel-Lindau (VHL) E3 ligase, which naturally recognizes C4-exo Hyp in a stereoselective fashion. Co-crystal structures and electrostatic potential calculations support and rationalize the observed preferential recognition for (3 R,4 S)-F-Hyp over the corresponding (3 S,4 S) epimer by VHL. We show that (3 R,4 S)-F-Hyp provides bioisosteric Hyp substitution in both hypoxia-inducible factor 1 alpha (HIF-1α) substrate peptides and peptidomimetic ligands that form part of PROTAC (proteolysis targeting chimera) conjugates for targeted protein degradation. Despite a weakened affinity, Hyp substitution with (3 S,4 S)-F-Hyp within the PROTAC MZ1 led to Brd4-selective cellular degradation at concentrations >100-fold lower than the binary Kd for VHL. We anticipate that the disclosed chemistry of 3-fluoro-4-hydroxyprolines and their application as VHL ligands for targeted protein degradation will be of wide interest to medicinal organic chemists, chemical biologists, and drug discoverers alike.


Management of Acute Traumatic Central Cord Syndrome: A Narrative Review.
Narrative review. To provide an updated overview of the management of acute traumatic central cord syndrome (ATCCS). A comprehensive narrative review of the literature was done to identify evidence-based treatment strategies for patients diagnosed with ATCCS. ATCCS is the most commonly encountered subtype of incomplete spinal cord injury and is characterized by worse sensory and motor function in the upper extremities compared with the lower extremities. It is most commonly seen in the setting of trauma such as motor vehicles or falls in elderly patients. The operative management of this injury has been historically variable as it can be seen in the setting of mechanical instability or preexisting cervical stenosis alone. While each patient should be evaluated on an individual basis, based on the current literature, the authors' preferred treatment is to perform early decompression and stabilization in patients that have any instability or significant neurologic deficit. Surgical intervention, in the appropriate patient, is associated with an earlier improvement in neurologic status, shorter hospital stay, and shorter intensive care unit stay. While there is limited evidence regarding management of ATCCS, in the presence of mechanical instability or ongoing cord compression, surgical management is the treatment of choice. Further research needs to be conducted regarding treatment strategies and patient outcomes.


Assessment of the intensive care unit treatment of pneumonia at a veterans affairs facility.
Pneumonia is a common cause of morbidity and mortality in the critically ill. Clinicians use a range of duration for antibiotic treatment from 7 to 14 days or longer. Failure to de-escalate antimicrobial therapy in a timely manner may lead to increased antimicrobial resistance, increased risk of side effects, and increased cost. To investigate potential methods to improve treatment of pneumonia for patients in 4 intensive care units (ICUs). A retrospective descriptive chart review was conducted at the Veterans Affairs North Texas Health Care System (VANTHCS). Veterans aged 18 to 90 years admitted to the ICU with a diagnosis of pneumonia were included. Descriptive statistics were used to interpret the data. Current management was reviewed to identify markers such as length of antibiotic therapy, ICU length of stay, and inpatient mortality. Secondary objectives included appropriateness and accuracy of the empiric regimen. Of the 1,854 Veterans admitted, 107 met inclusion criteria. Antibiotic choices for positive cultures were appropriate in 45 out of 46 (98%) patients, with an average length of therapy of 8.6 ± 6.3 days. De-escalation of antibiotics based on sensitivity data occurred in 73% of positive cultures. Pneumonia in the VANTHCS ICUs is initially treated with empiric antibiotics. Empiric antibiotic therapy for pneumonia was appropriate and accurate over this time period. Opportunities exist for de-escalation in patients with or without positive cultures. The procalcitonin assay is now being utilized at VANTHCS to optimize patient care.


Origin of highly efficient photoluminescence in AgIn5S8 nanoparticles.
The photoluminescence of AgIn5S8 nanoparticles was examined to clarify the emissive relaxation processes of defect states and to explain the highly efficient photoluminescence of defect states. The large Stokes shift of the defect emission was explained by strong electron-phonon coupling in the nanoparticles. Steady-state and time-resolved photoluminescence spectroscopy indicated two emissive defect states with characteristic emission energies and lifetimes. Change of the surface-to-volume ratio in the nanoparticles affected the relative contribution of the two states, implying that defect emission in higher energy was attributable to surface-related defects. The defect emission in lower energy was attributable to intrinsic defects, which were also present in bulk. The quantum yield of the surface defects was larger than that of the intrinsic defects, which accounted for the unusually high quantum yield of AgIn5S8 nanoparticles, although the origin of emission was the defect states, not the exciton recombination found in typical semiconductor nanoparticles.


Monte Carlo modeling of the dual-mode regime in quantum-well and quantum-dot semiconductor lasers.
Monte Carlo markovian models of a dual-mode semiconductor laser with quantum well (QW) or quantum dot (QD) active regions are proposed. Accounting for carriers and photons as particles that may exchange energy in the course of time allows an ab initio description of laser dynamics such as the mode competition and intrinsic laser noise. We used these models to evaluate the stability of the dual-mode regime when laser characteristics are varied: mode gains and losses, non-radiative recombination rates, intraband relaxation time, capture time in QD, transfer of excitation between QD via the wetting layer... As a major result, a possible steady-state dual-mode regime is predicted for specially designed QD semiconductor lasers thereby acting as a CW microwave or terahertz-beating source whereas it does not occur for QW lasers.


Is preattentive bias predictive of autonomic reactivity in response to a stressor?
Biased processing of threatening information may play a casual role in the development of anxiety disorders. Even though empirical evidence points to the fact that preattentive bias can predict subjectively experienced distress in response to a stressor, it is still unknown whether it could be useful in predicting the physiological reactivity in response to a stressor. In the present study, the emotional Stroop task was used to measure preattentive bias. Whereas Stroop interference for masked threat words (i.e., preattentive bias) was found to be positively associated with emotional distress (self-reported) in response to a laboratory stressor, this association was reversed when the autonomic reactivity (electrodermal activity) was used as a measure of emotional response to the very same stressor. Also, neither of these effects were a function of pre-existing anxiety levels. The negative association between preattentive bias and autonomic reactivity corresponds to the autonomic inflexibility seen in clinical anxiety (or very high scores of trait anxiety) when exposed to stressful events. Results were discussed in terms of an inability to automatically inhibit the processing of threatening cues that seems to be a vulnerability marker for anxiety.


Temporomandibular Joint Disorders in Patients With Different Facial Morphology. A Systematic Review of the Literature.
The present article aimed to review systematically the literature on the relation between facial skeletal structures and temporomandibular joint (TMJ) disorders. A systematic search in the dental and medical literature was performed to identify all studies of humans assessing the relation between TMJ disorders and facial morphology. Articles were included based on study design, irrespective of TMJ disorder (eg, disc displacement, osteoarthrosis, or unspecified), skeletal features, diagnostic strategies (e.g., imaging techniques or clinical assessment), and population (eg, demographic features of participants) under investigation. The selected articles were assessed according to a format based on patients, problem, and population, intervention, comparison, and outcome and quality was evaluated based on the Newcastle-Ottawa Scale. Thirty-four articles were included in the review, 27 of which concerned adult samples and 7 concerned adolescent samples. Quality was generally moderate. The articles dealt with the relation between facial morphology and the following TMJ disorders, assessed clinically or by magnetic resonance (MR): disc displacement (n = 20), osteoarthritis or osteoarthrosis (n = 8), and temporomandibular disorder signs and symptoms (n = 6). The different approaches featuring the various investigations and the presence of some potential methodologic biases complicated a summary of the findings. Most studies reported that some features related to the vertical dimension of the face might help distinguish patients with potential TMJ disc displacement or MR-detected signs of osteoarthrosis from those without TMJ disorders. The quality of the available literature is not adequate to provide an evidence base on the topic. Despite the heterogeneity of design and findings of the reviewed articles, it seems reasonable to suggest that skeletal Class II profiles and hyperdivergent growth patterns are likely associated with an increased frequency of TMJ disc displacement and degenerative disorders.


Evaluation of the efficacy of excimer laser ablation of cross-linked porcine cornea.
Combination of riboflavin/UVA cross-linking (CXL) and excimer laser ablation is a promising therapy for treating corneal ectasia. The cornea is strengthened by cross-linking, while the irregular astigmatism is reduced by laser ablation. This study aims to compare the efficacy of excimer laser ablation on porcine corneas with and without cross-linking. The porcine cornea was de-epithelialized and treated with 0.1% riboflavin solution for 30 minutes. A half of the cornea was exposed to UVA-radiation for another 30 minutes while the controlled half of the cornea was protected from the UVA using a metal shield. Photo therapeutic keratectomy (PTK) was then performed on the central cornea. Corneal thickness of 5 paired locations on the horizontal line, ± 0.5, ± 1.0, ± 1.5, ± 2.0, and ± 2.5 mm from the central spot, were measured using optical coherence tomography prior to and after PTK. The ablation depth was then determined by the corneal thickness. There was a 9% difference (P<0.001) in the overall ablation depth between the CXL-half corneas (158 ± 22 µm) and the control-half corneas (174 ± 26 µm). The ablation depths of all 5 correspondent locations on the CXL-half were significantly smaller (P<0.001). The efficacy of the laser ablation seems to be lower in cross-linked cornea. Current ablation algorithms may need to be modified for cross-linked corneas.


A cross-cultural comparison of health behaviors between Saudi and British adolescents living in urban areas: gender by country analyses.
This study investigated the cross-cultural differences and similarity in health behaviors between Saudi and British adolescents. A school-based cross-sectional study was conducted at four cities in Saudi Arabia (Riyadh and Al-Khobar; N = 1,648) and Britain (Birmingham and Coventry; N = 1,158). The participants (14-18 year-olds) were randomly selected using a multistage stratified cluster sampling technique. Measurements included anthropometric, screen time, validated physical activity (PA) questionnaire and dietary habits. The overweight/obesity prevalence among Saudi adolescents (38.3%) was significantly (p < 0.001) higher than that found among British adolescents (24.1%). The British adolescents demonstrated higher total PA energy expenditure than Saudi adolescents (means ± SE = 3,804.8 ± 81.5 vs. 2,219.9 ± 65.5 METs-min/week). Inactivity prevalence was significantly (p < 0.001) higher among Saudi adolescents (64%) compared with that of British adolescents (25.5%). The proportions of adolescents exceeding 2 h of daily screen time were high (88.0% and 90.8% among Saudis and British, respectively). The majority of Saudi and British adolescents did not have daily intakes of breakfast, fruit, vegetables and milk. MANCOVA showed significant (p < 0.05) gender by country interactions in several lifestyle factors. There was a significant (p < 0.001) gender differences in the ratio of physical activity to sedentary behaviors. In conclusion, Saudi and British adolescents demonstrated some similarities and differences in their PA levels, sedentary behaviors and dietary habits. Unhealthy lifestyle behaviors among adolescents appear to be a cross-cultural phenomenon.


A yoga program for the symptoms of post-traumatic stress disorder in veterans.
The purpose of this pilot study was to evaluate the feasibility and effectiveness of a yoga program as an adjunctive therapy for improving post-traumatic stress disorder (PTSD) symptoms in Veterans with military-related PTSD. Veterans (n = 12) participated in a 6 week yoga intervention held twice a week. There was significant improvement in PTSD hyperarousal symptoms and overall sleep quality as well as daytime dysfunction related to sleep. There were no significant improvements in the total PTSD, anger, or quality of life outcome scores. These results suggest that this yoga program may be an effective adjunctive therapy for improving hyperarousal symptoms of PTSD including sleep quality. This study demonstrates that the yoga program is acceptable, feasible, and that there is good adherence in a Veteran population.


Toxic mechanisms of microcystins in mammals.
Microcystins, such as microcystin-leucine arginine (MC-LR), are some of the most toxic and prevalent cyanotoxins produced by cyanobacteria in freshwater and saltwater algal blooms worldwide. Acute and chronic exposures to microcystins are primarily known to cause hepatotoxicity; cellular damage and genotoxicity within mammalian livers. However, in vivo studies indicate that similar damage may occur in other mammalian organs and tissues, such as the kidney, heart, reproductive systems, and lungs - particularly following chronic low-dose exposures. Mechanisms of toxicity of mycrocystins are reviewed herein; including cellular uptake, interaction with protein phosphatases PP1 and PP2A, cytoskeletal effects, formation of oxidative stress and induction of apoptosis. In general, the mode of action of toxicity by MCs in mammalian organs are similar to those that have been observed in liver tissues. A comprehensive understanding of the toxic mechanisms of microcystins in mammalian tissues and organs will assist in the development of risk assessment approaches to public health protection strategies and the development of robust drinking water policies.


Vasculitis in patients with inflammatory bowel diseases: A study of 32 patients and systematic review of the literature.
Published small case series suggest that inflammatory bowel disease [IBD; Crohn's disease (CD) or ulcerative colitis (UC)] and vasculitis co-occur more frequently than would be expected by chance. To describe this association by an analysis of a large cohort of carefully studied patients and through a systematic literature review. Patients with both IBD and vasculitis enrolled in the Vasculitis Clinical Research Consortium (VCRC) Longitudinal Studies, followed in Canadian Vasculitis research network (CanVasc) centers and/or in the University of Toronto's IBD clinic were included in this case series. A systematic literature review of patients with IBD and vasculitis involved a PubMed search through February 2014. The main characteristics of patients with Takayasu arteritis (TAK) and IBD were compared to those in patients with TAK without IBD followed in the VCRC. The study identified 32 patients with IBD and vasculitis: 13 with large-vessel vasculitis [LVV; 12 with TAK, 1 with giant cell arteritis (GCA); 8 with CD, 5 with UC]; 8 with ANCA-associated vasculitis [AAV; 6 granulomatosis with polyangiitis (GPA), 2 with eosinophilic granulomatosis with polyangiitis (EGPA)]; 5 with isolated cutaneous vasculitis; and 6 with other vasculitides. Patients with LVV and AAV were mostly female (18/21). The diagnosis of IBD preceded that of vasculitis in 12/13 patients with LVV and 8/8 patients with AAV. The review of the literature identified 306 patients with IBD and vasculitis: 144 with LVV (133 TAK; 87 with IBD preceding LVV), 19 with AAV [14 GPA, 1 EGPA, 4 microscopic polyangiitis (MPA)], 66 with isolated cutaneous vasculitis, and 77 with other vasculitides. Patients with IBD and TAK were younger and had more frequent headaches, constitutional symptoms, or gastrointestinal symptoms compared to those patients in the VCRC who had TAK without IBD. These findings highlight the risk of vasculitis, especially TAK, in patients with IBD (both CD and UC).


Efficacy of oral versus long-acting antipsychotic treatment in patients with early-phase schizophrenia in Europe and Israel: a large-scale, open-label, randomised trial (EULAST).
Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication. EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete. Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94-1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ2=1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study. We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice. Lundbeck and Otsuka.


Maternal Pregravid Obesity Remodels the DNA Methylation Landscape of Cord Blood Monocytes Disrupting Their Inflammatory Program.
Prepregnancy maternal obesity is associated with adverse outcomes for the offspring, including increased incidence of neonatal bacterial sepsis and necrotizing enterocolitis. We recently reported that umbilical cord blood (UCB) monocytes from babies born to obese mothers generate a reduced IL-6/TNF-α response to TLR 1/2 and 4 ligands compared to those collected from lean mothers. These observations suggest altered development of the offspring's immune system, which in turn results in dysregulated function. We therefore investigated transcriptional and epigenetic differences within UCB monocytes stratified by prepregnancy maternal body mass index. We show that UCB monocytes from babies born to obese mothers generate a dampened response to LPS stimulation compared with those born to lean mothers, at the level of secreted immune mediators and transcription. Because gene expression profiles of resting UCB monocytes from both groups were comparable, we next investigated the role of epigenetic differences. Indeed, we detected stark differences in methylation levels within promoters and regulatory regions of genes involved in TLR signaling in resting UCB monocytes. Interestingly, the DNA methylation status of resting cells was highly predictive of transcriptional changes post-LPS stimulation, suggesting that cytosine methylation is one of the dominant mechanisms driving functional inadequacy in UCB monocytes obtained from babies born to obese mothers. These data highlight a potentially critical role of maternal pregravid obesity-associated epigenetic changes in influencing the function of an offspring's monocytes at birth. These findings further our understanding of mechanisms that explain the increased risk of infection in neonates born to mothers with high prepregnancy body mass index.


Glucoregulation has greater impact on cognitive performance than macro-vascular disease in men with type 2 diabetes: data from the Caerphilly study.
To compare vascular and glucose related mechanisms of type 2 diabetes on cognitive performance. A cross-sectional observational study of type 2 diabetes defined by non insulin dependant self-report diabetes or fasting blood glucose < or = 7.0 mmol/l of 2205 men eligible for the third phase of the Caerphilly Collaborative Heart Disease Study. Men were aged 55-69 years at time of testing. Tests of cognitive function included NART (crystallised IQ), AH4 (fluid IQ), verbal fluency (executive function) Cambridge Cognitive Examination (CAMCOG) and Mini Mental State Examination (MMSE) (global function), four choice serial reaction time (psychomotor function) and memory. Men with prior stroke were omitted from the analysis. Men with diabetes showed cognitive deficits for verbal fluency, National Adult Reacting Test (NART) and AH4. Adjusting for vascular risk factors had minimal effect. Including blood glucose removed the deficit for verbal fluency and NART but the effect on AH4 score (-2.58; 95% CI: -5.0, -0.1, p = 0.039) was retained. More detailed analyses of AH4 score on men with diabetes showed a curvilinear relationship indicating that men with both low and high glucose levels had worse performance (AH4 = -66 + 80 log(e) glucose - 18 log(e )glucose(2); 95% CI: -29, -6; p=0.002). These data identify a direct effect of glucose regulation on cognitive performance associated with diabetes in a population sample. These data suggest that an effect of glucose regulation on cognitive performance in diabetes is distinct from any effect of macro-vascular disease.


Nine-hour X-ray quasi-periodic eruptions from a low-mass black hole galactic nucleus.
In the past two decades, high-amplitude electromagnetic outbursts have been detected from dormant galaxies and often attributed to the tidal disruption of a star by the central black hole1,2. X-ray emission from the Seyfert 2 galaxy GSN 069 (2MASX J01190869-3411305) at a redshift of z = 0.018 was first detected in July 2010 and implies an X-ray brightening by a factor of more than 240 over ROSAT observations performed 16 years earlier3,4. The emission has smoothly decayed over time since 2010, possibly indicating a long-lived tidal disruption event5. The X-ray spectrum is ultra-soft and can be described by accretion disk emission with luminosity proportional to the fourth power of the disk temperature during long-term evolution. Here we report observations of quasi-periodic X-ray eruptions from the nucleus of GSN 069 over the course of 54 days, from December 2018 onwards. During these eruptions, the X-ray count rate increases by up to two orders of magnitude with an event duration of just over an hour and a recurrence time of about nine hours. These eruptions are associated with fast spectral transitions between a cold and a warm phase in the accretion flow around a low-mass black hole (of approximately 4 × 105 solar masses) with peak X-ray luminosity of about 5 × 1042 erg per second. The warm phase has kT (where T is the temperature and k is the Boltzmann constant) of about 120 electronvolts, reminiscent of the typical soft-X-ray excess, an almost universal thermal-like feature in the X-ray spectra of luminous active nuclei6-8. If the observed properties are not unique to GSN 069, and assuming standard scaling of timescales with black hole mass and accretion properties, typical active galactic nuclei with higher-mass black holes can be expected to exhibit high-amplitude optical to X-ray variability on timescales as short as months or years9.


Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii's ability to alter host behaviour.
With increasing pressure to understand transmissible agents, renewed recognition of infectious causation of both acute and chronic diseases is occurring. Epidemiological and neuropathological studies indicate that some cases of schizophrenia may be associated with environmental factors, such as exposure to the ubiquitous protozoan Toxoplasma gondii. Reasons for this include T. gondii's ability to establish persistent infection within the central nervous system, its ability to manipulate intermediate host behaviour, the occurrence of neurological and psychiatric symptoms in some infected individuals, and an association between infection with increased incidence of schizophrenia. Moreover, several of the medications used to treat schizophrenia and other psychiatric disease have recently been demonstrated in vitro to possess anti-parasitic, and in particular anti-T. gondii, properties. Our aim here was thus to test the hypothesis that the anti-psychotic and mood stabilizing activity of some medications may be achieved, or at least augmented, through their in vivo inhibition of T. gondii replication and invasion in infected individuals. In particular we predicted, using the epidemiologically and clinically applicable rat-T. gondii model system, and following a previously described and neurologically characterized 'feline attraction' protocol that haloperidol (an anti-psychotic used in the treatment of mental illnesses including schizophrenia) and/or valproic acid (a mood stabilizer used in the treatment of mental illnesses including schizophrenia), would be, at least, as effective in preventing the development of T. gondii-associated behavioural and cognitive alterations as the standard anti-T. gondii chemotherapeutics pyrimethamine with Dapsone. We demonstrate that, while T. gondii appears to alter the rats' perception of predation risk turning their innate aversion into a 'suicidal' feline attraction, anti-psychotic drugs prove as efficient as anti-T. gondii drugs in preventing such behavioural alterations. Our results have important implications regarding the aetiology and treatment of such disorders.


The impact of physicians' brief smoking cessation counseling: a MIRNET study.
Although many family physicians may discuss smoking cessation with their patients, few do so consistently. A common belief among many physicians is that such efforts will not deter their patients from smoking. Others believe the time commitment required for a successful intervention is excessive. The present study addressed the above issues by examining the effect of a 3- to 5-minute unstructured physician discussion encouraging smoking cessation with family practice patients. Cigarette-smoking patients of two busy family practices in southeast Michigan were randomly assigned to either a control group receiving routine care or an intervention group receiving, in addition to routine care, smoking cessation counseling from their physician. A third comparison group was drawn from smokers in practices not involved in delivering the intervention. Two hundred thirty-eight patients from the intervention group, 178 from the control group, and 47 from the comparison group were followed up with a telephone interview at 6 months. Intervention group patients made significantly more quit attempts than did those in the control group (P less than .001), which was similar to the comparison group. At the 6-month follow-up, 8% of intervention group members, and 4% of both the comparison and control groups reportedly were abstinent from smoking. Among those contacted at the 1-year follow-up, the respective percentages abstinent were 8%, 3%, and 4%. Although these differences in quit rates were not statistically significant, the findings suggest that physicians can positively affect patient smoking cessation. This intervention was feasible in busy family practices, highlighting its generalizability and applicability to other family practice settings in the United States.


Amino acid biosynthesis and metabolic flux profiling of Pichia pastoris.
Amino acid biosynthesis and central carbon metabolism of Pichia pastoris were studied using biosynthetically directed fractional (13)C labeling. Cells were grown aerobically in a chemostat culture fed at two dilution rates (0.05 h(-1), 0.16 h(-1)) with glycerol as the sole carbon source. For investigation of amino acid biosynthesis and comparison with glycerol cultivations, cells were also grown at 0.16 h(-1) on glucose. Our results show that, firstly, amino acids are synthesized as in Saccharomyces cerevisiae. Secondly, biosynthesis of mitochondrial pyruvate via the malic enzyme is not registered for any of the three cultivations. Thirdly, transfer of oxaloacetate across the mitochondrial membrane appears bidirectional, with a smaller fraction of cytosolic oxaloacetate stemming from the mitochondrial pool at the higher dilution rate of 0.16 h(-1) (for glucose or glycerol cultivation) when compared to the glycerol cultivation at 0.05 h(-1). Fourthly, the fraction of anaplerotic synthesis of oxaloacetate increases from 33% to 48% when increasing the dilution rate for glycerol supply, while 38% is detected when glucose is fed. Finally, the cultivation on glucose also allowed qualitative comparison with the flux ratio profile previously published for Pichia stipitis and S. cerevisiae grown on glucose in a chemostat culture at a dilution rate of 0.1 h(-1). This provided a first indication that regulation of central carbon metabolism in P. pastoris and S. cerevisiae might be more similar to each other than to P. stipitis.


Pathophysiology and treatment of osteoporosis: challenges for clinical practice in older people.
Osteoporosis, a common chronic metabolic bone disease is associated with considerable morbidity and mortality. As the prevalence of osteoporosis increases with age, a paralleled elevation in the rate of incident fragility fractures will be observed. This narrative review explores the origins of bone and considers physiological mechanisms involved in bone homeostasis relevant to management and treatment. Secondary causes of osteoporosis, as well as osteosarcopenia are discussed followed by an overview of the commonly used pharmacological treatments for osteoporosis in older people.


Serologic cross-reactivity between Anaplasma marginale and Anaplasma phagocytophilum.
In the context of a serosurvey conducted on the Anaplasma marginale prevalence in Swiss cattle, we suspected that a serological cross-reactivity between A. marginale and A. phagocytophilum might exist. In the present study we demonstrate that cattle, sheep and horses experimentally infected with A. phagocytophilum not only develop antibodies to A. phagocytophilum (detected by immunofluorescent-antibody assay) but also to A. marginale (detected by a competitive enzyme-linked immunosorbent assay). Conversely, calves experimentally infected with A. marginale also developed antibodies to A. phagocytophilum using the same serological tests. The identity of 63% determined in silico within a 209-amino-acid sequence of major surface protein 5 of an isolate of A. marginale and one of A. phagocytophilum supported the observed immunological cross-reactivity. These observations have important consequences for the serotesting of both, A. marginale and A. phagocytophilum infection of several animal species. In view of these new findings, tests that have been considered specific for either infection must be interpreted carefully.


The evolution and function of carotenoid hydroxylases in Arabidopsis.
To gain insight into the evolution of xanthophyll synthesis in Arabidopsis thaliana, we analyzed two pairs of duplicated carotenoid hydroxylase enzymes in Arabidopsis thaliana: the cytochrome P450 enzymes CYP97A3 and CYP97C1, and non-heme di-iron enzymes, BCH1 and BCH2. Hydroxylated carotenes did not accumulate in a quadruple mutant for these four genes, demonstrating that they encode the full complement of carotenoid hydroxylases in A. thaliana. We were thus able to infer definitively the activity of each enzyme in vivo based on the phenotypes of selected double and triple mutant genotypes. The CYP97 and BCH gene pairs are primarily responsible for hydroxylation of alpha- and beta-carotenes, respectively, but exhibit some overlapping activities, most notably in hydroxylation of the beta-ring of alpha-carotene. Surprisingly, triple mutants containing only CYP97C1 or CYP97A3 activity produced 74 and 6% of the wild-type lutein level, indicating that CYP97C1 can efficiently hydroxylate both the beta- and epsilon-rings of alpha-carotene and that CYP97A3 also has low activity toward the epsilon-ring of alpha-carotene. The modes of functional divergence for the gene pairs appear distinct, with the CYP97 duplicates being strongly co-expressed but encoding enzymes with different in vivo substrates, while the BCH duplicates encode isozymes that show significant expression divergence in reproductive organs. By integrating the evolutionary history and substrate specificities of each extant enzyme with the phenotypic responses of various mutant genotypes to high light stress, we propose two likely scenarios for the evolution of alpha-xanthophyll biosynthesis in plants from ancestral organisms.


Early complications after living donor nephrectomy: analysis of the Swiss Organ Living Donor Health Registry.
We evaluated the prospectively collected data about the incidence of early peri- and postoperative complications, and potential risk factors for adverse outcomes after living kidney donation in Switzerland. Peri- and postoperative events were prospectively recorded on a questionnaire by the local transplant teams of all Swiss transplant centres and evaluated by the Swiss Organ Living Donor Health Registry. Complications were classified according to the Clavien grading system. A total of 1649 consecutive donors between 1998 and 2015 were included in the analysis. There was no perioperative mortality observed. The overall complication rate was 13.5%. Major complications defined as Clavien ≥3 occurred in 2.1% of donors. Obesity was not associated with any complications. Donor age >70years was associated with major complications (odds ratio [OR] 3.99) and genitourinary complications (urinary tract infection OR 5.85; urinary retention OR 6.61). There were more major complications observed in donors with laparoscopic surgery versus open surgery (p = 0.048), but an equal overall complication rate (p = 0.094). We found a low rate of major and minor complications, independent of surgical technique, after living donor nephrectomy. There was no elevated complication rate in obese donors. In contrast, elderly donors >70 years had an elevated risk for perioperative complications.


Inhibition of protein kinase c-Src as a therapeutic approach for cancer and bone metastases.
c-Src is a proto-oncogene involved in the genesis of and invasion by many cancers. This non-receptor tyrosine kinase also plays a crucial role in bone homeostasis, since inhibition or deletion of c-Src impairs the function of osteoclasts, the bone resorbing cells. It is thus conceivable that c-Src could be a suitable target for the pharmacological treatment of cancers, skeletal metastases and diseases of bone loss, such as osteoporosis. The pyrrolo-pyrimidines CGP77675 and CGP76030 proved to be effective in preventing bone loss in animal models, while the effect of AZD0530, a dually active inhibitor of c-Src and Bcr-ABL, on bone resorption, has been tested in a Phase I clinical trials with promising results. As far as the metastatic bone disease is concerned, c-Src inhibitors could potentially have inhibitory effects both on osteoclasts and on tumour cells, and could disrupt the vicious circle established between these cell types in the bone microenvironment. In accord with this idea, CGP76030 is able to reduce the incidence of osteolytic lesions and of visceral metastases, and to suppress morbidity and lethality in a bone metastasis mouse model without obvious adverse effects. The purine-based c-Src inhibitor AP23451 and the dual c-Src/Abl inhibitors AP22408 and AP23236 proved efficacious in reducing bone metastases in preclinical studies. These results open a new avenue for the development of innovative therapies for the treatment of bone metastatic disease.


Red/blue spectral shifts of laser-induced fluorescence emission due to different nanoparticle suspensions in various dye solutions.
Red/blue shifts of laser-induced fluorescence (LIF) are investigated using several guest dielectric nanoscatterers, such as TiO2, ZnO, Al2O3, and SiO2, in the host Rd6G, RdB, Coumarin 4, and Coumarin 7 ethanolic solutions. A couple of inflection points are identified varying nanoparticle (NP) density into dye solutions based on LIF spectroscopy. The inflection of the spectral shift exhibits that the suspension of NPs in dye solutions significantly involves a couple of competitive chemical and optical mechanisms during photon traveling in scattering media regarding ballistic and diffusive transport. It is shown that the low, medium, and high NP additives in fluorescent suspension induce blue, red, and blue spectral shifts, respectively.


Prolylcarboxypeptidase independently activates plasma prekallikrein (fletcher factor).
Prolylcarboxypeptidase isoform 1 (PRCP1) is capable of regulating numerous autocrines and hormones, such as angiotensin II, angiotensin III, αMSH1-13, and DesArg(9) bradykinin. It does so by cleaving a C-terminal PRO-X bond. Recent work also indicates that the human PRCP1 activates plasma prekallikrein (PK) to kallikrein on endothelial cells through an uncharacterized mechanism. This study aims to identify PRCP1 binding interaction and cleavage site on PK. Recently, a cDNA encoding a novel splice variant of the human PRCP1 was identified. This isoform differed only in the N-terminal region of the deduced amino acid sequence. Using structural and functional studies, a combination of peptide mapping and site-directed mutagenesis approaches were employed to investigate the interaction of PRCP1 with PK. Three PRCP peptides, in decreasing order of potency, from 1) the N-terminus of the secreted protein, 2) spanning the opening of the active site pocket, and 3) in the dimerization region inhibit PRCP activation of PK on endothelial cells. Investigations also tested the hypothesis that PRCP cleavage site on PK is between its C-terminal Pro 637 (P(637)) and Ala 638 (A(638)). Recombinant forms of PK with C-terminal alanine mutagenesis or a stop codon is activated equally as wild type PK by PRCP. In conclusion, PRCP1 interacts with PK at multiple sites for PK activation. PRCP1 also enhances FXIIa activation of PK, suggesting that its activation site on PK is not identical to that of FXIIa.


The Goal of Adequate Nutrition: Can It Be Made Affordable, Sustainable, and Universal?
Until about 1900, large proportions of the world population endured hunger and poverty. The 20th century saw world population increase from 1.6 to 6.1 billion, accompanied and to some extent made possible by rapid improvements in health standards and food supply, with associated advances in agricultural and nutrition sciences. In this paper, I use the application of linear programming (LP) in preparation of rations for farm animals to illustrate a method of calculating the lowest cost of a human diet selected from locally available food items, constrained to provide recommended levels of food energy and nutrients; then, to find a realistic minimum cost, I apply the further constraint that the main sources of food energy in the costed diet are weighted in proportion to the actual reported consumption of food items in that area. Worldwide variations in dietary preferences raise the issue as to the sustainability of popular dietary regimes, and the paper reviews the factors associated with satisfying requirements for adequate nutrition within those regimes. The ultimate physical constraints on food supply are described, together with the ways in which climate change may affect those constraints. During the 20th century, food supply increased sufficiently in most areas to keep pace with the rapid increase in world population. Many challenges will need to be overcome if food supply is to continue to meet demand, and those challenges are made more severe by rising expectations of quality of life in the developing world, as well as by the impacts of climate change on agriculture and aquaculture.


Papillary thyroid carcinoma associated with familial adenomatous polyposis: molecular analysis of pathogenesis in a family and review of the literature.
We found a case of a papillary thyroid carcinoma that was accompanied by a familial adenomatous polyposis (FAP) in a 29-year-old female. She had hundreds of adenomas inside the entire colon and a congenital hypertrophy of the retinal pigmented epithelium (CHRPE). The patient underwent a total thyroidectomy and a central compartment neck node dissection. Gross examination of the thyroid identified two solid and cystic lesions. The pathological finding of thyroid cancer revealed a mixture of a peculiar nuclear clearing, cribriform, morula formation, trabecular and papillary pattern. The patient's brother had undergone a total colectomy due to FAP at the age of 25. Genetic analyses of the patient's family members revealed that she and her brother had the same germline mutation, in which five nucleotides (AAAGA) were deleted from codon 1309 of the adenomatous polyposis coli (APC) gene exon 15. Strong and frequent immunoreactivities of beta-catenin and p53 were evident in the tumor tissue. At the time of writing, a preventive colectomy was still under consideration for the patient. Genetic counseling was given to the other family members, who were not attacked by this disease, in order to allay their fears of cancer.


Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood.
Kaposi sarcoma (KS), a human herpes virus 8 (HHV-8; also called KSHV)-induced endothelial tumor, develops only in a small fraction of individuals infected with HHV-8. We hypothesized that inborn errors of immunity to HHV-8 might underlie the exceedingly rare development of classic KS in childhood. We report here autosomal recessive OX40 deficiency in an otherwise healthy adult with childhood-onset classic KS. OX40 is a co-stimulatory receptor expressed on activated T cells. Its ligand, OX40L, is expressed on various cell types, including endothelial cells. We found OX40L was abundantly expressed in KS lesions. The mutant OX40 protein was poorly expressed on the cell surface and failed to bind OX40L, resulting in complete functional OX40 deficiency. The patient had a low proportion of effector memory CD4(+) T cells in the peripheral blood, consistent with impaired CD4(+) T cell responses to recall antigens in vitro. The proportion of effector memory CD8(+) T cells was less diminished. The proportion of circulating memory B cells was low, but the antibody response in vivo was intact, including the response to a vaccine boost. Together, these findings suggest that human OX40 is necessary for robust CD4(+) T cell memory and confers apparently selective protective immunity against HHV-8 infection in endothelial cells.


Legislative smoking bans for reducing harms from secondhand smoke exposure, smoking prevalence and tobacco consumption.
Smoking bans have been implemented in a variety of settings, as well as being part of policy in many jurisdictions to protect the public and employees from the harmful effects of secondhand smoke (SHS). They also offer the potential to influence social norms and the smoking behaviour of those populations they affect. Since the first version of this review in 2010, more countries have introduced national smoking legislation banning indoor smoking. To assess the effects of legislative smoking bans on (1) morbidity and mortality from exposure to secondhand smoke, and (2) smoking prevalence and tobacco consumption. We searched the Cochrane Tobacco Addiction Group Specialised Register, MEDLINE, EMBASE, PsycINFO, CINAHL and reference lists of included studies. We also checked websites of various organisations. Date of most recent search; February 2015. We considered studies that reported legislative smoking bans affecting populations. The minimum standard was having an indoor smoking ban explicitly in the study and a minimum of six months follow-up for measures of smoking behaviour. Our search included a broad range of research designs including: randomized controlled trials, quasi-experimental studies (i.e. non-randomized controlled studies), controlled before-and-after studies, interrupted time series as defined by the Cochrane Effective Practice and Organisation of Care Group, and uncontrolled pre- and post-ban data. One author extracted characteristics and content of the interventions, participants, outcomes and methods of the included studies and a second author checked the details. We extracted health and smoking behaviour outcomes. We did not attempt a meta-analysis due to the heterogeneity in design and content of the studies included. We evaluated the studies using qualitative narrative synthesis. There are 77 studies included in this updated review. We retained 12 studies from the original review and identified 65 new studies. Evidence from 21 countries is provided in this update, an increase of eight countries from the original review. The nature of the intervention precludes randomized controlled trials. Thirty-six studies used an interrupted time series study design, 23 studies use a controlled before-and-after design and 18 studies are before-and-after studies with no control group; six of these studies use a cohort design. Seventy-two studies reported health outcomes, including cardiovascular (44), respiratory (21), and perinatal outcomes (7). Eleven studies reported national mortality rates for smoking-related diseases. A number of the studies report multiple health outcomes. There is consistent evidence of a positive impact of national smoking bans on improving cardiovascular health outcomes, and reducing mortality for associated smoking-related illnesses. Effects on respiratory and perinatal health were less consistent. We found 24 studies evaluating the impact of national smoke-free legislation on smoking behaviour. Evidence of an impact of legislative bans on smoking prevalence and tobacco consumption is inconsistent, with some studies not detecting additional long-term change in existing trends in prevalence. Since the first version of this review was published, the current evidence provides more robust support for the previous conclusions that the introduction of a legislative smoking ban does lead to improved health outcomes through reduction in SHS for countries and their populations. The clearest evidence is observed in reduced admissions for acute coronary syndrome. There is evidence of reduced mortality from smoking-related illnesses at a national level. There is inconsistent evidence of an impact on respiratory and perinatal health outcomes, and on smoking prevalence and tobacco consumption.


Is excessive daytime sleepiness a separate manifestation in Parkinson's disease?
Excessive daytime sleepiness (EDS) is common in Parkinson's disease (PD), but its role and relation to other PD features is less well understood. To investigate potential predictors of EDS in PD and to explore how EDS relates to other motor and non-motor PD features. 118 consecutive persons with PD (54% men; mean age, 64) were assessed regarding EDS using the Epworth Sleepiness Scale (ESS) and a range of motor and non-motor symptoms. Variables significantly associated with ESS scores in bivariate analyses were used in multiple regression analyses with ESS scores as the dependent variable. Principal component analysis (PCA) was conducted to explore the interrelationships between ESS scores and other motor and non-motor PD aspects. Among 114 persons with complete ESS data, significant independent associations were found between ESS scores and axial/postural/gait impairment, depressive symptoms, and pain (R2, 0.199). ESS scores did not load significantly together with any other PD features in the PCA. Only a limited proportion of the variation in EDS could be accounted for by other symptoms, and EDS did not cluster together with any other PD features in PCAs. This suggests that EDS is a separate manifestation differing from, for example, poor sleep quality and fatigue.


Patterns of Genetic Diversification in the Invasive Hybrid Plant Pathogen Phytophthora × alni and Its Parental Species P. uniformis.
In pathogenic fungi and oomycetes, interspecific hybridization may lead to the formation of new species having a greater impact on natural ecosystems than the parental species. From the early 1990s, a severe alder (Alnus spp.) decline due to an unknown Phytophthora species was observed in several European countries. Genetic analyses revealed that the disease was caused by the triploid hybrid P. × alni, which originated in Europe from the hybridization of P. uniformis and P. × multiformis. Here, we investigated the population structure of P. × alni (158 isolates) and P. uniformis (85 isolates) in several European countries using microsatellite markers. Our analyses confirmed the genetic structure previously observed in other European populations, with P. uniformis populations consisting of at most two multilocus genotypes (MLGs) and P. × alni populations dominated by MLG Pxa-1. The genetic structure of P. × alni populations in the Czech Republic, Hungary and Sweden seemed to reflect the physical isolation of river systems. Most rare P. × alni MLGs showed a loss of heterozygosity (LOH) at one or a few microsatellite loci compared with other MLGs. This LOH may allow a stabilization within the P. × alni genome or a rapid adaptation to stress situations. Alternatively, alleles may be lost because of random genetic drift in small, isolated populations, with no effect on fitness of P. × alni. Additional studies would be necessary to confirm these patterns of population diversification and to better understand the factors driving it.


A Cross-Cultural Comparison of an Extended Planned Risk Information Seeking Model on Mental Health Among College Students: Cross-Sectional Study.
Approximately 42.5 million adults have been affected by mental illness in the United States in 2013, and 173 million people have been affected by a diagnosable psychiatric disorder in China. An increasing number of people tend to seek health information on the Web, and it is important to understand the factors associated with individuals' mental health information seeking. Identifying factors associated with mental health information seeking may influence the disease progression of potential patients. The planned risk information seeking model (PRISM) was developed in 2010 by integrating multiple information seeking models including the theory of planned behavior. Few studies have replicated PRISM outside the United States and no previous study has examined mental health as a personal risk in different cultures. This study aimed to test the planned risk information seeking model (PRISM) in China and the United States with a chronic disease, mental illness, and two additional factors, ie, media use and cultural identity, among college students. Data were collected in both countries using the same online survey through a survey management program (Qualtrics). In China, college instructors distributed the survey link among university students, and it was also posted on a leading social media site called Sina Weibo. In the United States, the data were collected in a college-wide survey pool in a large Northwestern university. The final sample size was 235 for the Chinese sample and 241 for the US sample. Media use was significantly associated with mental health information-seeking intentions in the Chinese sample (P<.001), and cultural identity was significantly associated with intentions in both samples (China: P=.02; United States: P<.001). The extended PRISM had a better model fit than the original PRISM. Cultural identity and media use should be considered when evaluating the process of mental health information seeking or when designing interventions to address mental health information seeking.


Retinal detachment in Scotland is associated with affluence.
Socio-economic deprivation plays a major role in health and disease, but its role in retinal detachment has not been studied. Data from the Scottish Retinal Detachment Study were used to investigate any association between retinal detachment, macular status at presentation and deprivation. Prospective multicentre population-based observational study. Data were collected on all patients with primary retinal detachment presenting in Scotland between 1 November 2007 and 31 October 2008. Every patient was allocated a validated deprivation ranking according to their postcodes based on the Scottish Index of Multiple Deprivation (SIMD), which takes into account income, employment, health, education, housing, geographic accessibility and crime in 6505 postcode-based datazones. The patients were divided into four quartiles according to their SIMD ranking. 572 patients were included. The annual incidence of detachment declined from 15.4/100,000 in the most affluent quartile to 13.6/100,000 in the second, 9.3/100,000 in the third and 6.9/100,000 in the most deprived (chi(2) for trend = 50.2, p<0.0001). The trend was more marked for men than for women but was present in both sexes. There were no differences in the rate of macula-off detachments or the number of quadrants detached. Rates of pseudophakic and myopic detachment were evenly distributed across all quartiles. Retinal detachment appears to be associated with affluence. This has not been previously reported and may be partly responsible for the variation in estimates of the incidence of retinal detachment. It may also have implications for service planning. The reason for this association is unknown.


A Scoping Review of Bikeability Assessment Methods.
Bicycling holds promise as a healthy and sustainable means of transportation and physical activity. Despite the growing interest in community-based environmental approaches to promoting physical activity, bikeability has received relatively little attention. This paper provides a scoping review of the instruments developed to measure bikeability along with practice-based analyses of the tools related to user expertise, estimated cost, and required time to implement. The review summarizes the literature, identifies research gaps, and informs stakeholders with articles from EBSCO and transportation databases published after 2003 when the previous bikeability instrument review paper was published. Data extraction included the tool name, data collection method, study location, data collection scale, type of measure, and description. Two reviewers independently reviewed articles included in the full text review, and the inter-rater agreement exceeded 90%. The database search yielded 388 unique articles, and 17 met the inclusion/exclusion criteria. Most of the studies, 11 of 17, were applied to settings outside of the U.S. Five studies employed a self-report survey, and five studies examined bikeability using geospatial data, like GIS. Seven studies used a direct observation audit tool-one specifically using a mobile app and another using virtual observation techniques with Google Street View. Bikeability tools are useful for assessing communities and their supports for bicycling. Our primary finding is that advances in technology over the past two decades have driven innovative and useful methodologies, in a variety of disciplines, for assessing the environment, but more consensus is needed to provide a universal definition of bikeability.


Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects.
Growing interest has been seen in using lysergic acid diethylamide (LSD) and psilocybin in psychiatric research and therapy. However, no modern studies have evaluated differences in subjective and autonomic effects of LSD and psilocybin or their similarities and dose equivalence. We used a double-blind, randomized, placebo-controlled, crossover design in 28 healthy subjects (14 women, 14 men) who underwent five 25 h sessions and received placebo, LSD (100 and 200 µg), and psilocybin (15 and 30 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics. The doses of 100 and 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. The 15 mg psilocybin dose produced clearly weaker subjective effects compared with both doses of LSD and 30 mg psilocybin. The 200 µg dose of LSD induced higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 µg dose. The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin. LSD at both doses had clearly longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. However, both LSD and psilocybin showed comparable cardiostimulant properties, assessed by the rate-pressure product. Both LSD and psilocybin had dose-proportional pharmacokinetics and first-order elimination. Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. Any differences between LSD and psilocybin are dose-dependent rather than substance-dependent. However, LSD and psilocybin differentially increased heart rate and blood pressure. These results may assist with dose finding for future psychedelic research.Trial registration: ClinicalTrials.gov identifier: NCT03604744.


Inhibitory effect of nicotinamide on enzymatic activity of selected fungal strains causing skin infection.
Pathogenicity of fungi is connected with their ability to easily penetrate the host tissues, survive in the infected host organism and use the elements of the host tissues as nutrients. Hence, the co-occurrence of pathogenic properties with the high enzymatic activity, which is manifested through the production of various enzymes including extracellular enzymes, was observed. It can be expected that it is possible to decrease fungal pathogenicity by lowering their enzymatic activity. The aim of the study was to determine the effect of nicotinamide on enzymatic activity of the fungi, which are most frequently isolated in cases of skin infection. Enzymatic activity was analysed using 15 Candida albicans, 15 Trichophyton rubrum and 15 Trichophyton mentagrophytes strains. The strains used for the study were collected from the current diagnostic material. API ZYM tests were used in diagnostic analysis. MICs of nicotinamide were determined by the macrodilution method in liquid medium. In the case of Candida strains, the presence of nicotinamide in the broth had a significant effect on the decrease of enzymatic activity (P < 0.05) of esterase (C4), esterase lipase (C-8), valin-arylamidase, acid phosphatase and alpha-glycosydase. A considerably stronger effect of nicotinamide was observed in the case of dermatophytes (P < 0.005). Its action led to a decrease in the activity of all the enzymes under study except alpha-glucosidase produced by T. rubrum strains. Thus, nicotinamide exhibited biological activity towards C. albicans, T. rubrum and Trichophyton mentagrophytes, which resulted in a decrease in the activity of enzymes produced by the fungi.


Niche segregation between wild and domestic herbivores in Chilean Patagonia.
Competition arises when two co-occuring species share a limiting resource. Potential for competition is higher when species have coexisted for a short time, as it is the case for herbivores and livestock introduced in natural systems. Sheep, introduced in the late 19(th) century in Patagonia, bear a great resemblance in size and diet to the guanaco, the main native herbivore in Patagonia. In such circumstances, it could be expected that the two species compete and one of them could be displaced. We investigated spatial overlap and habitat selection by coexisting sheep and guanaco in winter and in summer. Additionally, we studied habitat selection of the guanaco in a control situation free from sheep, both in summer and winter. We also determined overlap between species in areas with different intensity of use (named preferred and marginal areas) in order to further detect the potential level of competition in the case of overlapping. Guanaco and sheep showed significantly different habitat preferences through all seasons, in spite of their spatial overlap at landscape scale. Additionally, the habitat used by guanaco was similar regardless of the presence or absence of livestock, which further indicates that sheep is not displacing guanaco where they coexist. These results suggest that habitat segregation between guanaco and sheep is due to a differential habitat selection and not to a competitive displacement process. Therefore, the potential for competition is considered low, contrary to what has been previously observed, although this could be a density-dependent result.


DNA repair. Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links.
DNA interstrand cross-links (ICLs) block replication fork progression by inhibiting DNA strand separation. Repair of ICLs requires sequential incisions, translesion DNA synthesis, and homologous recombination, but the full set of factors involved in these transactions remains unknown. We devised a technique called chromatin mass spectrometry (CHROMASS) to study protein recruitment dynamics during perturbed DNA replication in Xenopus egg extracts. Using CHROMASS, we systematically monitored protein assembly and disassembly on ICL-containing chromatin. Among numerous prospective DNA repair factors, we identified SLF1 and SLF2, which form a complex with RAD18 and together define a pathway that suppresses genome instability by recruiting the SMC5/6 cohesion complex to DNA lesions. Our study provides a global analysis of an entire DNA repair pathway and reveals the mechanism of SMC5/6 relocalization to damaged DNA in vertebrate cells.


Analysis of the IDS gene in 38 patients with Hunter syndrome: the c.879G>A (p.Gln293Gln) synonymous variation in a female create exonic splicing.
Hunter syndrome (mucopolysaccharidosis type II, MPS II) is a rare disease inherited in an X-linked autosomal recessive pattern. It is the prevailing form of the mucopolysaccharidoses in China. Here we investigated mutations of IDS (iduronate 2-sulfatase) gene in 38 unrelated Chinese patients, one of which is a female. Peripheral leucocytes were collected from the patients and the IDS gene was amplified to looking for the variations. For a female patient, the X chromosome status was analyzed by androgen receptor X-inactivation assay and the mutation impact on RNA level was further performed by reverse transcription polymerase chain reaction. We discovered that point mutations constituted the major form while mutations in codon p.R468 defined the largest number of patients in our cohort. Consistent with data from other ethnic groups, exons 9 and 3 had comparatively more mutations, while exon 2 had quite a few mutations unique to Chinese patients. Of the 30 different mutations identified, only 9 were novel: one was a premature termination mutation, i.e., c.196C>T (p.Gln66X); three were missense mutations, i.e., c.200T>C (p.Leu67Pro), c.215T>C (p.Leu72Pro), c.389C>T (p.Thr130Ile); one was a small deletion, i.e., c.1104_1122del19 (p.Ser369ArgfsX16); and one was a deletion that spanned both exons 8 and 9 deletion leading to gross structural changes in the IDS gene. In addition, a synonymous mutation c.879G>A (p.Gln293Gln) was identified in a female Hunter disease patient, which resulted in loss of the original splicing site, activated a cryptic splicing site upstream, leading to a 28 bp deletion and a premature termination at p. Tyr285GlufsX47. Together with concurrent skewed X-inactivation this was believed to facilitate the development of Hunter disease in this girl. In conclusion, the molecular analysis of IDS gene in Chinese patients confirmed the Hunter disease diagnosis and expanded the mutation and clinical spectrum of this devastating disorder.


Polyproline and the "spectroscopic ruler" revisited with single-molecule fluorescence.
To determine whether Forster resonance energy transfer (FRET) measurements can provide quantitative distance information in single-molecule fluorescence experiments on polypeptides, we measured FRET efficiency distributions for donor and acceptor dyes attached to the ends of freely diffusing polyproline molecules of various lengths. The observed mean FRET efficiencies agree with those determined from ensemble lifetime measurements but differ considerably from the values expected from Forster theory, with polyproline treated as a rigid rod. At donor-acceptor distances much less than the Forster radius R(0), the observed efficiencies are lower than predicted, whereas at distances comparable to and greater than R(0), they are much higher. Two possible contributions to the former are incomplete orientational averaging during the donor lifetime and, because of the large size of the dyes, breakdown of the point-dipole approximation assumed in Forster theory. End-to-end distance distributions and correlation times obtained from Langevin molecular dynamics simulations suggest that the differences for the longer polyproline peptides can be explained by chain bending, which considerably shortens the donor-acceptor distances.


Parallel microdevice for high throughput analysis of levofloxacin using tris (2,2'-bipyridyl) ruthenium (II) and peroxydisulfate chemiluminescence system.
A parallel microdevice has been developed for high throughput analysis using microfluidics. The detection method is based on a chemiluminescence (CL) system based on the oxidation of tris (2,2'-bipyridyl) Ru(ll) [Ru (bipy)3(2+)] by peroxydisulfate. The device consists of a photoreactor chip and two detection chips. The sample throughput can reach up to 720 runs/h with the total reagent consumption of only 2.4 mL. The parallel microdevice was evaluated using levofloxacin (LEVO) in pharmaceutical preparations. The various factors that affect the CL signal were optimized, and the LOD was found to be 30 and 27 microg/L for the two detectors, respectively (S/N = 3), while RSD was 1.1% (n = 15) for 1.0 mg/L LEVO. Two tablet samples that contain LEVO as an active ingredient were successfully analyzed using the proposed parallel microdevice.


Investigation of depth dependent changes in cerebral haemodynamics during face perception in infants.
Near-infrared spectroscopy has been used to record oxygenation changes in the visual cortex of 4 month old infants. Our in-house topography system, with 30 channels and 3 different source-detector separations, recorded changes in the concentration of oxy-, deoxy- and total haemoglobin (HbO2, HHb and HbT) in response to visual stimuli (face, scrambled visual noise and cartoons as rest). The aim of this work was to demonstrate the capability of the system to spatially localize functional activation and study the possibility of depth discrimination in the haemodynamic response. The group data show both face stimulation and visual noise stimulation induced significant increases in HbO2 from rest, but the increase in HbO2 with face stimulation was not significantly different from that seen with visual noise stimulation. The face stimuli induced increases in HbO2 were spread across a greater area across all depths than visual noise induced changes. In results from a single subject there was a significant increase of HbO2 in the inferior area of the visual cortex in response to both types of stimuli, and a larger number of channels (source-detector pairs) showed HbO2 increase to face stimuli, especially at the greatest depth. Activation maps were obtained using 3D reconstruction methods on multi source-detector separation optical topography data.


Production of IL-16 correlates with CD4+ Th1 inflammation and phosphorylation of axonal cytoskeleton in multiple sclerosis lesions.
Multiple sclerosis (MS) is a central nervous system-specific autoimmune, demyelinating and neurodegenerative disease. Infiltration of lesions by autoaggressive, myelin-specific CD4+Th1 cells correlates with clinical manifestations of disease. The cytokine IL-16 is a CD4+ T cell-specific chemoattractant that is biased towards CD4+ Th1 cells. IL-16 precursor is constitutively expressed in lymphocytes and during CD4+ T cell activation; active caspase-3 cleaves and releases C-terminal bioactive IL-16. Previously, we used an animal model of MS to demonstrate an important role for IL-16 in regulation of autoimmune inflammation and subsequent axonal damage. This role of IL-16 in MS is largely unexplored. Here we examine the regulation of IL-16 in relation to CD4+ Th1 infiltration and inflammation-related changes of axonal cytoskeleton in MS lesions. We measured relative levels of IL-16, active caspase-3, T-bet, Stat-1 (Tyr 701), and phosphorylated NF(M+H), in brain and spinal cord lesions from MS autopsies, using western blot analysis. We examined samples from 39 MS cases, which included acute, subacute and chronic lesions, as well as adjacent, normal-appearing white and grey matter. All samples were taken from patients with relapsing remitting clinical disease. We employed two-color immunostaining and confocal microscopy to identify phenotypes of IL-16-containing cells in frozen tissue sections from MS lesions. We found markedly increased levels of pro- and secreted IL-16 (80 kD and 22 kD, respectively) in MS lesions compared to controls. Levels of IL-16 peaked in acute, diminished in subacute, and were elevated again in chronic active lesions. Compared to lesions, lower but still appreciable IL-6 levels were measured in normal-appearing white matter adjacent to active lesions. Levels of IL-16 corresponded to increases in active-caspase-3, T-bet and phosphorylated Stat-1. In MS lesions, we readily observed IL-16 immunoreactivity confined to infiltrating CD3+, T-bet+ and active caspase-3+ mononuclear cells. We present evidence suggesting that IL-16 production occurs in MS lesions. We show correlations between increased levels of secreted IL-16, CD4+ Th1 cell inflammation, and phosphorylation of axonal cytoskeleton in MS lesions. Overall, the data suggest a possible role for IL-16 in regulation of inflammation and of subsequent changes in the axonal cytoskeleton in MS.


Knee Ligament Injury and the Clinical Application of Tissue Engineering Techniques: A Systematic Review.
The incidence of knee ligament injury is increasing and represents a significant cost to healthcare providers. Current interventions include tissue grafts, suture repair and non-surgical management. These techniques have demonstrated good patient outcomes but have been associated graft rejection, infection, long term immobilization and reduced joint function. The limitations of traditional management strategies have prompted research into tissue engineering of knee ligaments. This paper aims to evaluate whether tissue engineering of knee ligaments offers a viable alternative in the clinical management of knee ligament injuries. A search of existing literature was performed using OVID Medline, Embase, AMED, PubMed and Google Scholar, and a manual review of citations identified within these papers. Silk, polymer and extracellular matrix based scaffolds can all improve graft healing and collagen production. Fibroblasts and stem cells demonstrate compatibility with scaffolds, and have been shown to increase organized collagen production. These effects can be augmented using growth factors and extracellular matrix derivatives. Animal studies have shown tissue engineered ligaments can provide the biomechanical characteristics required for effective treatment of knee ligament injuries. There is a growing clinical demand for a tissue engineered alternative to traditional management strategies. Currently, there is limited consensus regarding material selection for use in tissue engineered ligaments. Further research is required to optimize tissue engineered ligament production before clinical application. Controlled clinical trials comparing the use of tissue engineered ligaments and traditional management in patients with knee ligament injury could determine whether they can provide a cost-effective alternative.


Human Skin, Oral, and Gut Microbiomes Predict Chronological Age.
Human gut microbiomes are known to change with age, yet the relative value of human microbiomes across the body as predictors of age, and prediction robustness across populations is unknown. In this study, we tested the ability of the oral, gut, and skin (hand and forehead) microbiomes to predict age in adults using random forest regression on data combined from multiple publicly available studies, evaluating the models in each cohort individually. Intriguingly, the skin microbiome provides the best prediction of age (mean ± standard deviation, 3.8 ± 0.45 years, versus 4.5 ± 0.14 years for the oral microbiome and 11.5 ± 0.12 years for the gut microbiome). This also agrees with forensic studies showing that the skin microbiome predicts postmortem interval better than microbiomes from other body sites. Age prediction models constructed from the hand microbiome generalized to the forehead and vice versa, across cohorts, and results from the gut microbiome generalized across multiple cohorts (United States, United Kingdom, and China). Interestingly, taxa enriched in young individuals (18 to 30 years) tend to be more abundant and more prevalent than taxa enriched in elderly individuals (>60 yrs), suggesting a model in which physiological aging occurs concomitantly with the loss of key taxa over a lifetime, enabling potential microbiome-targeted therapeutic strategies to prevent aging.IMPORTANCE Considerable evidence suggests that the gut microbiome changes with age or even accelerates aging in adults. Whether the age-related changes in the gut microbiome are more or less prominent than those for other body sites and whether predictions can be made about a person's age from a microbiome sample remain unknown. We therefore combined several large studies from different countries to determine which body site's microbiome could most accurately predict age. We found that the skin was the best, on average yielding predictions within 4 years of chronological age. This study sets the stage for future research on the role of the microbiome in accelerating or decelerating the aging process and in the susceptibility for age-related diseases.


Rupture of mitral chordae tendineae: adding to the list of hypertension complications.
Many patients with chordae tendineae rupture (CTR) of the mitral valve have obscure aetiologies. The association between pre-existing hypertension and idiopathic CTR was investigated. 494 patients with CTR were identified by searching the computer database. For each patient with idiopathic CTR, three matched controls without CTR who were admitted to the same hospital for bone fractures were included. Among the 494 patients with CTR, 351 patients (71%) had idiopathic CTR, and 143 patients (29%) had secondary CTR. The prevalence of pre-existing hypertension was significantly higher in the idiopathic than in the secondary CTR group (50.9% vs 14.6%, p<0.001). The odds ratio was 6.0 (95% CI 3.6 to 10.1). The percentage of patients without adequate blood pressure control was also higher in the idiopathic than in the secondary CTR group (23.1% vs 4.9%, p<0.001). When compared with the fracture group, patients with idiopathic CTR also had a significantly higher prevalence of hypertension (50.9% vs 14.9%, p<0.001), and the odds ratio was 5.9 (95% CI 4.5 to 7.8). After correction for age, the odds ratio of having hypertension was 3.6 (95% CI 2.1 to 6.3) and 6.6 (p<0.001, 95% CI 5.0 to 8.8) when compared with the secondary CTR group and fracture group respectively. There is a strong association between pre-existing hypertension and idiopathic CTR. Whether or not this disease can be prevented by controlling hypertension deserves further investigation.


Bovine respiratory disease: efficacy of different prophylactic treatments in veal calves and antimicrobial resistance of isolated Pasteurellaceae.
The present study was conducted to evaluate the efficacy of two prophylactic antibiotic treatments against bovine respiratory disease (BRD) in veal calves. In addition, the antibiotic susceptibilities of isolated Pasteurellaceae were tested. The calves were treated either on the day of arrival by a single administration of tulathromycin (group A, n=20), by a peroral administration of chlortetracycline, sulphadimidine, and tylosin (group B, n=20) for seven consecutive days, or were not prophylactically treated (group C, n=19). On the first day of clinically diagnosed BRD, transtracheal lavage samples were obtained prior to therapeutic treatment and were subsequently cultured. Pasteurellaceae isolates were tested for their susceptibility to 12 antimicrobial agents by the determination of the minimal inhibitory concentrations. During the first 56 d after arrival, different calves in group A and B suffered from one episode of clinically diagnosed BRD while calves of group C experienced two episodes. The average daily weight gain during the same period was significantly lower in group C (0.89 ± 0.04kg/d) than in the two prophylactically treated groups (1.14 ± 0.05 and 1.15 ± 0.04 kg/d for group A and B, respectively). The improved performance of groups A and B in comparison to group C could be related to a lower incidence of respiratory disorders during the first days after arrival in the prophylactically treated animals. No differences in the clinical efficacy were seen between the two tested prophylactic treatments. The most prevalent bacterial pathogens isolated (n=79) were Pasteurella multocida (23% of isolated pathogens), Mycoplasma bovis (18%), and Mannheimia varigena (16%). For the isolated Pasteurellaceae, a high resistance pattern was observed to tylosin (83% of the tested P. multocida and 88% of the Mannheimia spp. isolates resistant) and tilmicosin (56% of the tested P. multocida isolates non-sensitive).


Pharmacological prevention of post-traumatic stress disorder and acute stress disorder: a systematic review and meta-analysis.
An increasing number of studies have investigated the pharmacological prevention of post-traumatic stress disorder (PTSD) and acute stress disorder (ASD). This is the first systematic review to examine the effects of pharmacotherapies (eg, β blockers, hydrocortisone, and selective serotonin re-uptake inhibitors) given within the first month after a traumatic or aversive event to prevent PTSD or ASD compared with no pharmacotherapy or placebo control. A systematic literature search in PubMed, PsycINFO, Embase, and the Cochrane database of randomised trials was done. Studies included randomised controlled trials, controlled clinical trials, and cohort studies; their overall quality was low to moderate. We computed the pooled incidence risk ratio (IRR): the risk of incidence of PTSD or ASD in the pharmacotherapy groups relative to the incidence of PTSD or ASD in the control groups. Additionally, we computed Hedges'g effect sizes for PTSD or ASD continuous outcomes. 15 studies met inclusion criteria (1765 individuals). Pharmacotherapy was more effective in preventing PTSD or ASD than placebo or no intervention (14 studies, 1705 individuals, IRR 0·65, 95% CI 0·55-0·78; number needed to treat 11·36), although no effect was found when only randomised controlled trials were included (ten studies, 300 individuals, IRR 0·69, 95% CI 0·40-1·21). Hydrocortisone showed a large effect in reducing the risk of PTSD (five studies, 164 individuals, IRR 0·38, 95% CI 0·16-0·92). No firm evidence was found for the efficacy of all early pharmacotherapies in the prevention of PTSD or ASD, but hydrocortisone reduced the risk of developing PTSD. The small number of studies and their limited methodological quality cast uncertainty about the effects. None.


Merkel cell carcinoma: a systematic review of ENT presentations.
The aim of this study was to perform a systematic literature review of Merkel cell carcinomas (MCCs) originating exclusively in the ear, nose and throat (ENT) district. An appropriate string was run on PubMed to retrieve articles dealing with ENT presentations of MCC. A double cross-check was performed on citations and full-text articles found using the selected inclusion and exclusion criteria. In total, 43 articles were finally included in the study, describing 51 cases of MCC involving the ENT region: 22/51 (43%) cases involving the ear; 20/51 (39%) cases involving the mucosal sites; 9/51 (18%) cases involving other ENT regions. Patients with mucosal site involvement showed a higher mortality rate from the disease (45%) in comparison with the other two groups, especially when compared with those patients having primary involvement of the ear (22%). The ENT specialist should suspect and consider MCC, especially in elderly patients presenting with a suspicious lesion of the auricular pavilion, so as to avoid misdiagnosis and delayed treatments.


A Narrative Review of the Confluence of Breast Cancer and Low-wage Employment and Its Impact on Receipt of Guideline-recommended Treatment.
Breast cancer is the leading cause of cancer among women in the United States, costing the healthcare system, employers, and society billions of dollars each year. Despite improvements in screening and treatment, significant breast cancer treatment and survivorship disparities exist among various groups of women. One variable that has not been explored extensively as a possible contributor to breast cancer treatment disparities is employment. This is concerning, given the changing economic and employment trends in the United States favoring low-wage employment. Currently, one-quarter to one-third of all US workers are considered to be working poor, and women are disproportionally represented in this group. Characteristics of low-wage work-limited paid time off, minimal health benefits, schedule inflexibility, and economic insecurity-may become even more significant in the event of a breast cancer diagnosis. To date, there has been limited research into how job conditions inherent to low-wage work may influence working poor survivors' receipt of guideline-recommended breast cancer treatment. Therefore, the purpose of this narrative review was to critically examine the current literature to further our understanding of how employment context may impact treatment decisions and adherence-and therefore receipt of guideline-recommended care-among newly diagnosed, working poor breast cancer survivors. After undertaking a comprehensive review, we failed to identify any published literature that explicitly addressed low-wage employment and receipt of guideline-recommended breast cancer treatment. Four articles reported circumstances where women delayed, missed, or quit treatments due to work interference, or alternatively, developed strategies that allowed them to continue to work and obtain their breast cancer treatment concurrent with medical and economic challenges. An additional five articles, while focused on other cancer and employment outcomes, described the need for increased patient-provider communication about the influence of work on treatment decisions and the development of alternative treatment plans. Due to the paucity of research in this area, future policy, practice, and research efforts should focus on the employment context of working poor breast cancer survivors as a potential contributor to cancer disparities. Engagement of women, employers, oncology providers, healthcare systems, and interdisciplinary researchers is warranted to improve cancer outcomes among this disparate population of working women.