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While mutational processes operating in the Escherichia coli genome have been revealed by multiple laboratory experiments, the contribution of these processes to accumulation of bacterial polymorphism and evolution in natural environments is unknown. To address this question, we reconstruct signatures of distinct mutational processes from experimental data on E. coli hypermutators, and ask how these processes contribute to differences between naturally occurring E. coli strains. We show that both mutations accumulated in the course of evolution of wild-type strains in nature and in the lab-grown nonmutator laboratory strains are explained predominantly by the low fidelity of DNA polymerases II and III. By contrast, contributions specific to disruption of DNA repair systems cannot be detected, suggesting that temporary accelerations of mutagenesis associated with such disruptions are unimportant for within-species evolution. These observations demonstrate that accumulation of diversity in bacterial strains in nature is predominantly associated with errors of DNA polymerases. [ABSTRACT FROM AUTHOR]

Context In some patients, symptoms may persist after COVID-19, defined as long COVID. Its pathogenesis is still debated and many hypotheses have been raised. Objective Our primary objective was to evaluate the corticotroph and somatotroph functions of patients previously infected with SARS-CoV-2 and experiencing post–COVID-19 syndrome to detect any deficiencies that may explain long COVID. Methods A cross-sectional study was conducted including patients who had previously contracted SARS-CoV-2 with a postinfection period of 3 months or less to 15 months, divided into 2 groups. The first group (G1) comprised fully recovered patients, while the second group (G2) included patients experiencing long COVID. The primary outcome was the comparison of corticotroph and somatotroph functions. Results A total of 64 patients were divided into 2 groups, each consisting of 32 patients. G2 exhibited more frequently anterior pituitary deficits compared to G1 (P =.045): for the corticotroph axis (G1: 6.3% vs G2: 28.1%) and for the somatotroph axis (G1: 31.3% vs G2: 59.4%). Baseline cortisol level was significantly lower in G2 (G1: 13.37 µg/dL vs G2: 11.59 µg/dL) (P =.045). The peak cortisol level was also lower in G2 (G1: 23.60 µg/dL vs G2: 19.14 µg/dL) (P =.01). For the somatotroph axis, the insulin growth factor-1 level was lower in G2 (G1: 146.03 ng/mL vs G2: 132.25 ng/mL) (P =.369). The peak growth hormone level was also lower in G2 (G1: 4.82 ng/mL vs G2: 2.89 ng/mL) (P =.041). Conclusion The results showed that long COVID patients in our cohort were more likely to have anterior pituitary deficiencies. The endocrine hypothesis involving anterior pituitary insufficiency can be considered to explain long COVID. [ABSTRACT FROM AUTHOR]

An individual's chronological age does not always correspond to the health of different tissues in their body, especially in cases of disease. Therefore, estimating and contrasting the physiological age of tissues with an individual's chronological age may be a useful tool to diagnose disease and its progression. In this study, we present novel metrics to quantify the loss of phylogenetic diversity in hematopoietic stem cells (HSCs), which are precursors to most blood cell types and are associated with many blood-related diseases. These metrics showed an excellent correspondence with an age-related increase in blood cancer incidence, enabling a model to estimate the phylogeny-derived age (phyloAge) of HSCs present in an individual. The HSC phyloAge was generally older than the chronological age of patients suffering from myeloproliferative neoplasms (MPNs). We present a model that relates excess HSC aging with increased MPN risk. It predicted an over 200 times greater risk based on the HSC phylogenies of the youngest MPN patients analyzed. Our new metrics are designed to be robust to sampling biases and do not rely on prior knowledge of driver mutations or physiological assessments. Consequently, they complement conventional biomarker-based methods to estimate physiological age and disease risk. [ABSTRACT FROM AUTHOR]

Although evolutionary biologists have long theorized that variation in DNA repair efficacy might explain some of the diversity of lifespan and cancer incidence across species, we have little data on the variability of normal germline mutagenesis outside of humans. Here, we shed light on the spectrum and etiology of mutagenesis across mammals by quantifying mutational sequence context biases using polymorphism data from thirteen species of mice, apes, bears, wolves, and cetaceans. After normalizing the mutation spectrum for reference genome accessibility and k -mer content, we use the Mantel test to deduce that mutation spectrum divergence is highly correlated with genetic divergence between species, whereas life history traits like reproductive age are weaker predictors of mutation spectrum divergence. Potential bioinformatic confounders are only weakly related to a small set of mutation spectrum features. We find that clock-like mutational signatures previously inferred from human cancers cannot explain the phylogenetic signal exhibited by the mammalian mutation spectrum, despite the ability of these signatures to fit each species' 3-mer spectrum with high cosine similarity. In contrast, parental aging signatures inferred from human de novo mutation data appear to explain much of the 1-mer spectrum's phylogenetic signal in combination with a novel mutational signature. We posit that future models purporting to explain the etiology of mammalian mutagenesis need to capture the fact that more closely related species have more similar mutation spectra; a model that fits each marginal spectrum with high cosine similarity is not guaranteed to capture this hierarchy of mutation spectrum variation among species. [ABSTRACT FROM AUTHOR]

COVID-19 is a systemic disease associated with respiratory insufficiency, systemic inflammation, as well as coagulation, neurological, and endocrine disorders. Among them pituitary apoplexy (PA) as well as, more rarely, acute hypophysitis (AH) have been reported. In the present report, we described a case of PA in an 84-year-old man with SARS-CoV-2 pneumonia, with a previous unknown pituitary adenoma and a possible but not confirmed overlap with transitory AH. After reviewing the available literature, we discuss the potential clinical and pathophysiological relationship between PA and AH. Furthermore, we focus on the neuroradiological features of pituitary lesions in the presence of SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

The ceiling of energy density of batteries in materials level motivates the innovation of cell, module and pack that constitute the battery assembly for electric vehicles (EVs). Patent analysis is a powerful means to inform technology life cycle and forecast upcoming innovations. To date, only a handful of research have quantitatively analysed and compared battery assembly in the EV field, resulting in a lack of information to discern the battery layout. Herein, battery patents are categorized into cell, module and pack levels, and are recorded with a function of timeline and technology life cycle to identify their development status. It indicates the maturity stage of the cell level while noting the growth stage of module and pack levels, which probably results from the intensive demand of large-size and high-quality batteries for EVs. Moreover, the global patent distribution reveals that China and Japan possess most patents among cell, module and pack levels, and that patent assignees are scattered in China, whereas concentrated in Japan and Korea. This work is expected to figure out the battery technology trends to construct energy-dense batteries in the EV field, as well as provide instructive information for decision-makers to lay out battery technologies in the future. [ABSTRACT FROM AUTHOR]

Background A growing number of long COVID cases after infection have been reported. By definition, long COVID is the condition whereby affected individuals do not recover for several weeks or months following the onset of symptoms suggestive of COVID-19, the profile and timeline of which remains uncertain. Methods In this work, in-home, outpatient and hospitalized COVID-19 positive patients were monitored for up to 14 mo to establish the prevalence of long COVID symptoms and their correlation with age, pre-existing comorbidities and course of acute infection. The longitudinal study included 646 positive patients who were monitored once a month. Results From the whole population, 50.2% presented with long COVID syndrome. Twenty-three different symptoms were reported. Most frequent were fatigue (35.6%), persistent cough (34.0%), dyspnea (26.5%), loss of smell/taste (20.1%) and frequent headaches (17.3%). Mental disorders (20.7%), change in blood pressure (7.4%) and thrombosis (6.2%) were also reported. Most patients presented with 2–3 symptoms at the same time. Long COVID started after mild, moderate and severe infection in 60, 13 and 27% of cases, respectively, and it was not restricted to specific age groups. Conclusions Older patients tended to have more severe symptoms, leading to a longer post-COVID-19 period. The presence of seven comorbidities was correlated with the severity of infection, and severity itself was the main factor that determined the duration of symptoms in long COVID cases. [ABSTRACT FROM AUTHOR]

Mutational processes in tumors create distinctive patterns of mutations, composed of neutral "passenger" mutations and oncogenic drivers that have quantifiable effects on the proliferation and survival of cancer cell lineages. Increases in proliferation and survival are mediated by natural selection, which can be quantified by comparing the frequency at which we detect substitutions to the frequency at which we expect to detect substitutions assuming neutrality. Most of the variants detectable with whole-exome sequencing in tumors are neutral or nearly neutral in effect, and thus the processes generating the majority of mutations may not be the primary sources of the tumorigenic mutations. Across 24 cancer types, we identify the contributions of mutational processes to each oncogenic variant and quantify the degree to which each process contributes to tumorigenesis. We demonstrate that the origination of variants driving melanomas and lung cancers is predominantly attributable to the preventable, exogenous mutational processes associated with ultraviolet light and tobacco exposure, respectively, whereas the origination of selected variants in gliomas and prostate adenocarcinomas is largely attributable to endogenous processes associated with aging. Preventable mutations associated with pathogen exposure and apolipoprotein B mRNA-editing enzyme activity account for a large proportion of the cancer effect within head-and-neck, bladder, cervical, and breast cancers. These attributions complement epidemiological approaches—revealing the burden of cancer driven by single-nucleotide variants caused by either endogenous or exogenous, nonpreventable, or preventable processes, and crucially inform public health strategies. [ABSTRACT FROM AUTHOR]

Stenotrophomonas maltophilia is an underappreciated source of morbidity and mortality among gram-negative pathogens. Effective treatment options with acceptable toxicity profiles are limited. Phenotypic susceptibility testing via commercial automated test systems is problematic and no Food and Drug Administration breakpoints are approved for any of the first-line treatment options for S maltophilia. The lack of modern pharmacokinetic/pharmacodynamic data for many agents impedes dose optimization, and the lack of robust efficacy and safety data limits their clinical utility. Levofloxacin has demonstrated similar efficacy to trimethoprim-sulfamethoxazole, although rapid development of resistance is a concern. Minocycline demonstrates the highest rate of in vitro susceptibility, however, evidence to support its clinical use are scant. Novel agents such as cefiderocol have exhibited promising activity in preclinical investigations, though additional outcomes data are needed to determine its place in therapy for S maltophilia. Combination therapy is often employed despite the dearth of adequate supporting data. [ABSTRACT FROM AUTHOR]

Spatial genetic and phenotypic diversity within solid tumors has been well documented. Nevertheless, how this heterogeneity affects temporal dynamics of tumorigenesis has not been rigorously examined because solid tumors do not evolve as the standard population genetic model due to the spatial constraint. We therefore, propose a neutral spatial (NS) model whereby the mutation accumulation increases toward the periphery; the genealogical relationship is spatially determined and the selection efficacy is blunted (due to kin competition). In this model, neutral mutations are accrued and spatially distributed in manners different from those of advantageous mutations. Importantly, the distinctions could be blurred in the conventional model. To test the NS model, we performed a three-dimensional multiple microsampling of two hepatocellular carcinomas. Whole-genome sequencing (WGS) revealed a 2-fold increase in mutations going from the center to the periphery. The operation of natural selection can then be tested by examining the spatially determined clonal relationships and the clonal sizes. Due to limited migration, only the expansion of highly advantageous clones can sweep through a large part of the tumor to reveal the selective advantages. Hence, even multiregional sampling can only reveal a fraction of fitness differences in solid tumors. Our results suggest that the NS patterns are crucial for testing the influence of natural selection during tumorigenesis, especially for small solid tumors. [ABSTRACT FROM AUTHOR]

From the earliest days of the coronavirus disease 2019 (COVID-19) pandemic, there have been reports of significant neurological and psychological symptoms following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. This narrative review is designed to examine the potential psychoneuroendocrine pathogenic mechanisms by which SARS-CoV-2 elicits psychiatric sequelae as well as to posit potential pharmacologic strategies to address and reverse these pathologies. Following a brief overview of neurological and psychological sequelae from previous viral pandemics, we address mechanisms by which SARS-CoV-2 could enter or otherwise elicit changes in the CNS. We then examine the hypothesis that COVID-19–induced psychiatric disorders result from challenges to the neuroendocrine system, in particular the hypothalamic-pituitary-adrenal stress axis and monoamine synthesis, physiological mechanisms that are only further enhanced by the pandemic-induced social environment of fear, isolation, and socioeconomic pressure. Finally, we evaluate several FDA-approved therapeutics in the context of COVID-19–induced psychoneuroendocrine disorders. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic continues to exert a significant impact on global health care systems, causing devastating mortality and morbidity. As time passes and our understanding of this novel respiratory virus deepens, it is increasingly clear that its effects extend beyond that of the respiratory system. The coronavirus responsible for COVID-19, severe acute respiratory syndrome coronavirus 2, obtains cellular access through the angiotensin-converting enzyme 2 (ACE2) receptor in a process requiring the transmembrane serine protease 2 (TMPRSS2) protein. Both ACE2 and TMPRSS2 are widely expressed in many endocrine glands. This, along with several case reports of thyroid and pituitary disruption in patients with COVID-19, has resulted in significant interest in its impact on the endocrine system. Indeed, as mortality is abated by the increasing availability of effective vaccines, there is increasing focus on the long-term effects on health in COVID-19 survivors. This review summarizes data investigating the effects of COVID-19 on each of the endocrine axes to guide appropriate investigations and optimal management. [ABSTRACT FROM AUTHOR]

Context: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe chronic illness that reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized.Objective: This work aims to investigate the occurrence of antipituitary (APA) and antihypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients.Methods: This is a case-control study conducted in a university hospital setting (Stanford, California, USA; and Naples, Italy). Thirty women with ME/CSF (group 1) diagnosed according to Fukuda, Canadian, and Institute of Medicine criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls. APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands. APA and AHA titers both were assessed and the prevalence of pituitary hormone deficiencies was also investigated.Results: Patients in group 1 showed a high prevalence of AHA (33%) and APA (56%) and significantly lower levels of adrenocorticotropin (ACTH)/cortisol, and growth hormone (GH) peak/insulin-like growth factor-1 (IGF-1) vs controls (all AHA/APA negative). Patients in group 1A (13 patients positive at high titers, ≥ 1:32) showed ACTH/cortisol and GH peak/IGF-1 levels significantly lower and more severe forms of ME/CFS with respect to patients in group 1B (7 positive at middle/low titers, 1:16-1:8) and 1C (10 antibody-negative patients).Conclusion: Both AHA and/or APA at high titers were associated with hypothalamic/pituitary dysfunction, suggesting that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms. [ABSTRACT FROM AUTHOR]

Context: The COVID-19 pandemic continues to exert an immense burden on global health services. Moreover, up to 63% of patients experience persistent symptoms, including fatigue, after acute illness. Endocrine systems are vulnerable to the effects of COVID-19 as many glands express the ACE2 receptor, used by the SARS-CoV-2 virion for cellular access. However, the effects of COVID-19 on adrenal and thyroid gland function after acute COVID-19 remain unknown.Objective: Our objectives were to evaluate adrenal and thyroid gland function in COVID-19 survivors.Methods: A prospective, observational study was undertaken at the Clinical Research Facility, Imperial College NHS Healthcare Trust, including 70 patients ≥18 years of age, at least 3 months after diagnosis of COVID-19. Participants attended a research study visit (8:00-9:30 am), during which a short Synacthen test (250 µg IV bolus) and thyroid function assessments were performed.Results: All patients had a peak cortisol ≥450 nmol/L after Synacthen, consistent with adequate adrenal reserve. Basal and peak serum cortisol did not differ according to disease severity or history of dexamethasone treatment during COVID-19. There was no difference in baseline or peak cortisol after Synacthen or in thyroid function tests, or thyroid status, in patients with fatigue (n = 44) compared to those without (n = 26).Conclusion: Adrenal and thyroid function ≥3 months after presentation with COVID-19 was preserved. While a significant proportion of patients experienced persistent fatigue, their symptoms were not accounted for by alterations in adrenal or thyroid function. These findings have important implications for the clinical care of patients after COVID-19. [ABSTRACT FROM AUTHOR]

Pituitary apoplexy is a medical and surgical emergency caused by hemorrhage or infarction of the hypophysis, which typically occurs within a pituitary adenoma. It is usually characterized by severe (often thunderclap) headache, visual disturbances, cranial nerve impairments, and hormonal deficiencies. We herein report a case of a previously healthy woman with severe acute respiratory syndrome coronavirus 2 infection associated with pituitary apoplexy. The plausible pathophysiological mechanisms of pituitary apoplexy in infectious coronavirus disease 2019 are discussed. [ABSTRACT FROM AUTHOR]

The novel coronavirus disease 2019 (COVID-19) produced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sweeping the world in a very short time. Although much has been learned about the clinical course, prognostic inflammatory markers, and disease complications of COVID-19, the potential interaction between SARS-CoV-2 and the thyroid is poorly understood. In contrast to SARS-CoV-1, limited available evidence indicates there is no pathological evidence of thyroid injury caused by SARS-CoV-2. However, subacute thyroiditis caused by SARS-CoV-2 has been reported for the first time. Thyroid dysfunction is common in patients with COVID-19 infection. By contrast, certain thyroid diseases may have a negative impact on the prevention and control of COVID-19. In addition, some anti–COVID-19 agents may cause thyroid injury or affect its metabolism. COVID-19 and thyroid disease may mutually aggravate the disease burden. Patients with SARS-CoV-2 infection should not ignore the effect on thyroid function, especially when there are obvious related symptoms. In addition, patients with thyroid diseases should follow specific management principles during the epidemic period. [ABSTRACT FROM AUTHOR]

As SARS-CoV-2 (COVID-19) overtakes the world, causing moderate to severe disease in about 15% of infected patients, COVID-19 is also found to have widespread effects throughout the body with a myriad of clinical manifestations including the endocrine system. This manuscript reviews what is known about the impact of COVID-19 on the pathophysiology and management of diabetes (both outpatient and inpatient) as well as pituitary, adrenal, thyroid, bone, and gonadal function. Findings in this area are evolving, and long-term effects of infection remain an active area of further research. [ABSTRACT FROM AUTHOR]

Objective: This study assessed thyroid function in patients affected by the coronavirus disease-19 (COVID-19), based on the hypothesis that the cytokine storm associated with COVID-19 may influence thyroid function and/or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may directly act on thyroid cells, such as previously demonstrated for SARS-CoV-1 infection. Design and methods: This single-center study was retrospective and consisted in evaluating thyroid function tests and serum interleukin-6 (IL-6) values in 287 consecutive patients (193 males, median age: 66 years, range: 27–92) hospitalized for COVID-19 in non-intensive care units. Results: Fifty-eight patients (20.2%) were found with thyrotoxicosis (overt in 31 cases), 15 (5.2%) with hypothyroidism (overt in only 2 cases), and 214 (74.6%) with normal thyroid function. Serum thyrotropin (TSH) values were inversely correlated with age of patients (rho −0.27; P < 0.001) and IL-6 (rho −0.41; P < 0.001). In the multivariate analysis, thyrotoxicosis resulted to be significantly associated with higher IL-6 (odds ratio: 3.25, 95% confidence interval: 1.97–5.36; P < 0.001), whereas the association with age of patients was lost (P = 0.09). Conclusions: This study provides first evidence that COVID-19 may be associated with high risk of thyrotoxicosis in relationship with systemic immune activation induced by the SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has spread across the globe rapidly causing an unprecedented pandemic. Because of the novelty of the disease, the possible impact on the endocrine system is not clear. To compile a mini-review describing possible endocrine consequences of SARS-CoV-2 infection, we performed a literature survey using the key words Covid-19, Coronavirus, SARS CoV-1, SARS Cov-2, Endocrine, and related terms in medical databases including PubMed, Google Scholar, and MedARXiv from the year 2000. Additional references were identified through manual screening of bibliographies and via citations in the selected articles. The literature review is current until April 28, 2020. In light of the literature, we discuss SARS-CoV-2 and explore the endocrine consequences based on the experience with structurally-similar SARS-CoV-1. Studies from the SARS -CoV-1 epidemic have reported variable changes in the endocrine organs. SARS-CoV-2 attaches to the ACE2 system in the pancreas causing perturbation of insulin production resulting in hyperglycemic emergencies. In patients with preexisting endocrine disorders who develop COVID-19, several factors warrant management decisions. Hydrocortisone dose adjustments are required in patients with adrenal insufficiency. Identification and management of critical illness-related corticosteroid insufficiency is crucial. Patients with Cushing syndrome may have poorer outcomes because of the associated immunodeficiency and coagulopathy. Vitamin D deficiency appears to be associated with increased susceptibility or severity to SARS-CoV-2 infection, and replacement may improve outcomes. Robust strategies required for the optimal management of endocrinopathies in COVID-19 are discussed extensively in this mini-review. [ABSTRACT FROM AUTHOR]

Coronavirus infection outbreaks have occurred frequently in the last two decades and have led to significant mortality. Despite the focus on reducing mortality by preventing the spread of the virus, patients have died due to several other complications of the illness. The understanding of pathological mechanisms and their implications is continuously evolving. A number of symptoms occur in these patients due to the involvement of various endocrine glands. These clinical presentations went largely unnoticed during the first outbreak of severe acute respiratory syndrome (SARS) in 2002-2003. A few of these derangements continued during the convalescence phase and sometimes occurred after recovery. Similar pathological and biochemical changes are being reported with the novel coronavirus disease outbreak in 2020. In this review, we focus on these endocrine changes that have been reported in both SARS coronavirus and SARS coronavirus-2. As we battle the pandemic, it becomes imperative to address these underlying endocrine disturbances that are contributing towards or predicting mortality of these patients. [ABSTRACT FROM AUTHOR]

This article introduces the dialogical nature of self to study consumers' inner dialogs in order to understand consumers' marketplace decisions and conflicts. The authors explore the meaning of consumption at multiple self levels and dialogical relationships to manage differences. The study uses mixed methods including in-depth interviews, multidimensional scaling, cluster analysis, and metaphors to distill important voices in their informants. They find that the consumption stories vary across self levels. The meta-self level reflects a dispassionate representation of the primary I-positions in consumers and does not explain what the consumers experience at the time of actual consumption. An examination of inconsistent consumption preferences at the level of I-positions reveals that dialogical relationships labeled compartmentalization, compassion, negotiation, and coalition can avoid and manage conflicts, while relationships involving opposition and domination reflect unresolved conflicts. Suggestions to use the dialogical self model for addressing issues of negative selves, addictions, and domination in future research are provided. [ABSTRACT FROM AUTHOR]

Objectives: Optimal dosing for nebulized gentamicin is unknown. We compared the pulmonary and systemic pharmacokinetics (PK) of gentamicin following intravenous and nebulized administration in mechanically ventilated patients.Methods: Twelve critically ill male patients with ventilator-associated pneumonia received a 30 min intravenous infusion of 8 mg/kg gentamicin , followed 48 h afterwards by the same dose nebulized. Blood samples were collected immediately before and until 24 h after intravenous and nebulized administration; mini-bronchoalveolar lavages (mini-BALs) were performed at 3 and 7 h or 5 and 10 h (six patients each) after each intravenous and nebulized administration. The PK analysis was conducted using a population approach.Results: After intravenous administration, concentrations of gentamicin measured in epithelial lining fluid (ELF) were very variable, and overall in the same range of magnitude (from 0.3 to 28 mg/L) as in plasma. After nebulization, gentamicin concentrations were much higher (∼3800-fold) in ELF than in plasma. The average systemic bioavailability of nebulized gentamicin was estimated to be 5%, with considerable inter-individual variability. Compared with intravenous administration, after nebulization the exposure (expressed as AUC) to gentamicin was 276-fold greater in ELF and 18-fold lower in plasma.Conclusions: Compared with intravenous administration, nebulization of gentamicin in patients with ventilator-associated pneumonia provides higher pulmonary concentrations and lower systemic concentrations but the inter-individual variability is large. [ABSTRACT FROM AUTHOR]

Patient misunderstandings of healthcare-related instructions result in significant health, social and economic consequences. Pushing the boundaries of traditional academic methods may offer strategies that promote new ways to improve communication and understanding between healthcare providers, caregivers and patients. Comics can be an educational tool, offering an innovative strategy to communicate health-related information. Our study objective was to compare parents' understanding of health-related instructions (i.e. prescription labels, medical instructions and emergency situation scenarios) that were presented using two different formats--sequential pictorial instructions (SPIs) versus written text instructions (WRIs). This was a cross-sectional study to compare parents' understanding of health-related instructions for pediatric patients using structured SPIs versus WRIs. Parents (n=359, 18-82 years old) of pediatric patients were given a card with instructions that were presented as SPIs (n=195, 54.3%) or WRIs (n=164, 45.7%), and then they completed a questionnaire. Total (14 questions) and grouped scores (10 questions) for parental comprehension of prescription and medical emergency instructions were significantly higher among participants viewing the SPIs than those viewing the WRIs in both English and Spanish. The mean understanding of instructions significantly increased from 6% to 12.2% when comparing the WRI versus the SPI. Our initial findings indicate that parents and caregivers of pediatric patients had significantly better understanding and recall of instructions delivered using SPIs than using WRIs. [ABSTRACT FROM AUTHOR]

The article focuses on the diagnosis of shoulder pain including bicep tendon tear and dislocation of the tendon. It discusses the use of magnetic resonance imaging and arthroscopic surgery for the diagnosis and treatment. It also discusses topics including subluxation of the long head of the biceps tendon (SLBT), bicipital groove, and rotator cuff tears.

In a transgenic model of spontaneous experimental autoimmune encephalomyelitis, autoimmune attack against the CNS requires the presence of an intact commensal gut flora. Extending this observation to human autoimmune disease, such as multiple sclerosis, we postulate that the pathogenic reaction requires the coincidence of at least three factors: a permissive genetic disposition, a pro-inflammatory intestinal microbial profile, and the accumulation of autoreactive T cells in the gut-associated lymphatic tissue. This concept may offer new approaches to diagnostic markers and non-invasive therapies. [ABSTRACT FROM AUTHOR]

Objective: We investigated the impact of deep inspiration breath-hold (DIBH) and tumour baseline shifts on image quality and registration uncertainty in image-guided DIBH radiotherapy (RT) for locally advanced lung cancer. Methods: Patients treated with daily cone beam CT (CBCT)-guided free-breathing (FB) RT had an additional CBCT in DIBH at three fractions. These CBCT scans were offline rigidly registered (on tumour) to FB and DIBH CT scans acquired at planning. All registrations were repeated to evaluate the intraobserver uncertainty. CBCT scans were scored on degree of streak artefacts and visualization of tumour and anatomical structures. We examined the impact of tumour baseline shift between consecutive DIBHs on CBCT image quality. Results: CBCT scans from 15 patients were analysed. Intraobserver image registration uncertainty was approximately 2 mm in both FB and DIBH, except for the craniocaudal direction in FB, where it was >3 mm. On the 31st fraction, the intraobserver uncertainty increased compared with the second fraction. This increase was more pronounced in FB. Image quality scores improved in DIBH compared with FB for all parameters in all patients. Simulated tumour baseline shifts ≤2 mm did not affect the CBCT image quality considerably. Conclusion: DIBH CBCT improved image quality and reduced registration uncertainty in the craniocaudal direction in image-guided RT of locally advanced lung cancer. Baseline shifts ≤2 mm in DIBH during CBCT acquisition did not affect image quality. Advances in knowledge: DIBH RT has dosimetric advantages over FB; this work demonstrates an additional benefit of DIBH in terms of registration accuracy because of improved image quality. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of axial traction during MR arthrography (MRA) of the elbow joint on joint space widening, contrast dispersion between opposing cartilage surfaces and cartilage surface visibility. Methods: 11 patients with elbow MRA with and without axial traction were prospectively studied. Two radiologists independently measured the elbow joint space width and semi-quantitatively graded contrast material dispersion between the opposing cartilage surfaces as well as the articular cartilage surface visibility before and after traction. The detection and visibility of articular cartilage defects were also compared before and after traction. Patients were instructed to report on pain or any other symptoms during elbow traction. Results: No patient reported discomfort, pain or any other symptoms related to traction on immediate and intermediate-term follow-up. Joint space width increased, more at the radiocapitellar joint space (Δ = 0.63 mm, p = 0.005) than at the ulnotrochlear joint space (Δ = 0.17 mm, p = 0.012), with contrast dispersion into the radiocapitellar joint and cartilage visibility of the radiocapitellar joint space significantly improving after traction (all p < 0.05). All of these parameters also improved at the ulnotrochlear joint, although this did not reach statistical significance. Traction improved the visibility of cartilage defects. Conclusion: This is the first study to evaluate the effect of traction on MRA of the elbow joint. This technique is safe and technically feasible. Traction MRA improves the cartilage surface visibility and cartilage defect visibility. [ABSTRACT FROM AUTHOR]

Objective: To compare the quality of two different imaging methods, three-point Dixon (mDixon) and fast spin-echo (FSE) T2 weighted image (T2WI) [and fat suppression (FS) T2WI], and to assess the utility of mDixon for the imaging of knee joint pathology. Methods: This retrospective study included 66 patients who underwent both mDixon and FSE T2WI (and FS T2W1) of the knee joint. Signal-to-noise ratio (SNR) and contrast-tonoise ratio (CNR) of the two sequences at the articular cartilage and ligament were measured. Two radiologists independently evaluated the anatomic identification score and diagnostic performances of the two sequences. Results: The mean SNRs and CNRs of the patellar cartilage, femoral cartilage and anterior cruciate ligament (ACL) were significantly higher on T2WI and FS T2WI than on mDixon imaging, with the exception of the mean SNR of ACL on in-phase images. Most of the anatomic identification scores did not show significant differences, except for inferiorities of the in-phase mDixon in the evaluation of the cruciate ligament. There were no significant differences in sensitivity, specificity and accuracy between mDixon and T2WI regarding diagnostic performance. Conclusion: mDixon images have equivalent anatomic identification ability with the exception of cruciate ligament delineation on in-phase images and have a diagnostic performance comparable with that of FSE T2WI for meniscal, cartilage and ligament injuries of the knee joint. There would be a net saving in time, if mDixon was the only sequence used. Advances in knowledge: The mDixon images have equivalent anatomic identification abilities, with the exception of cruciate ligament delineation on in-phase images and have a diagnostic performance comparable with that of FSE T2WI for meniscal, cartilage and ligament injuries of the knee joint. [ABSTRACT FROM AUTHOR]

Ultrasound-guided needle biopsy of synovium is an increasingly performed procedure with a high diagnostic yield. In this review, we discuss the normal synovium, as well as the indications, technique, tissue handling and clinical applications of ultrasound-guided synovial biopsy. [ABSTRACT FROM AUTHOR]

Objective To assess the current state of ultrasound training in U.S. and Canadian Chronic Pain Fellowship programs. Design U.S. as well as Canadian chronic pain fellowship programs were contacted via email and program directors were asked to complete a survey. The surveys were completed online using a questionnaire. Setting Questionnaire via email. Patients None. Interventions None. Outcome To assess the current state of ultrasound training in U.S. and Canadian Chronic Pain Fellowship programs. Measures Current teaching structure, types, and numbers of ultrasound-guided interventional pain procedures. Results Thirty-one responses (30.7%) from the 97 U.S. and four Canadian programs surveyed. Of the 31 programs that responded, 26 offered ultrasound training; five did not. These 31 programs averaged 4.1 fellows per year, majority 96.2% of the 26 programs taught ultrasound throughout the fellowship year. The type of ultrasound training varied, with the large majority 96.2% being patient based. Among 26 programs, 96.2% used ultrasound for peripheral nerve blocks, 76.9% used ultrasound for non-axial musculoskeletal injections, and 53.8% used ultrasound for axial nerve blocks. Conclusions Chronic pain fellowships were teaching ultrasound-guided procedures to their fellows. The majority of the fellowships offered ultrasound training throughout the fellowship year. A majority of training was accomplished via hands-on experience with patients. Chronic pain fellows were receiving a majority of ultrasound training for peripheral nerve blocks, followed by nonaxial musculoskeletal blocks, with few axial nerve blocks being taught. [ABSTRACT FROM AUTHOR]

Until now, the culture of sulphur-oxidizing bacterial symbionts associated with marine invertebrates remains impossible. Therefore, few studies focused on symbiont's physiology under stress conditions. In this study, we carried out a comparative experiment based on two different species of lucinid bivalves ( Codakia orbiculata and Lucina pensylvanica) under comparable stress factors. The bivalves were starved for 6 months in sulphide-free filtered seawater. For C. orbiculata only, starved individuals were then put back to the field, in natural sediment. We used in situ hybridization, flow cytometry and X-ray fluorescence to characterize the symbiont population hosted in the gills of both species. In L. pensylvanica, no decrease in symbiont abundance was observed throughout the starvation experiment, whereas elemental sulphur slowly decreased to zero after 3 months of starvation. Conversely, in C. orbiculata, symbiont abundance within bacteriocytes decreased rapidly and sulphur from symbionts disappeared during the first weeks of the experiment. The modifications of the cellular characteristics ( SSC - relative cell size and FL1 - genomic content) of the symbiotic populations along starvation were not comparable between species. Return to the sediment of starved C. orbiculata individuals led to a rapid (2-4 weeks) recovery of symbiotic cellular characteristics, comparable with unstressed symbionts. These results suggest that endosymbiotic population regulation is host-species-dependent in lucinids. [ABSTRACT FROM AUTHOR]

Background Although laparoscopic adjustable gastric bands ( LAGBs) have been shown to be efficacious, their long-term usefulness has been questioned. This study examined the fate of LAGBs in a unit with over a decade of experience in their use. Patient factors related to the need for, and timing of, band removal were investigated. Methods A prospectively maintained database was used to identify all patients with a LAGB. Patient demographics, need for band removal and band survival were examined. Logistic regression modelling was done and Kaplan-Meier curves were calculated for band survival. Results Between 2000 and 2012, 674 bands were placed in 665 patients. Of these, 143 (21·2 per cent) were removed. There was no difference in rates of removal by sex ( P = 0·910). The highest rates of removal were in patients aged less than 40 years (26·7 per cent), and those with a BMI greater than 60 kg/m2 (28·6 per cent). Earlier band removal was seen in younger patients ( P = 0·002). Rates of removal increased linearly by earlier year of placement. Of bands placed 4 or more years previously, 35·0 per cent required removal. Eighty-three patients (58·0 per cent) who had a LAGB removed went on to have a further bariatric procedure (band to bypass, 66; band to sleeve, 17). Conclusion Even in experienced hands LAGB does not appear to be a definitive solution. In a large number of patients there appears to be a finite 'band life', with the majority of patients requiring conversion to a further bariatric procedure. Presented in part to a meeting of the British Obesity and Metabolic Surgery Society, Glasgow, UK, January 2013, as an oral presentation for which it was awarded the council prize; published in abstract form as Br J Surg 2013; 100(Suppl 3): 2 [ABSTRACT FROM AUTHOR]

A novel lipid formulation of Nystatin (NYT), Nystatin-Intralipid (NYT-IL), which was found to be more active and less toxic in vitro and in vivo, was developed in our laboratory. The aim of the present study was to explore the possible mechanisms underlying its biological activity. To assess mechanisms affecting fungal cells we conducted the following experiments: killing kinetics, scanning and transmission electron microscopy (EM), measurements of potassium ion leakage and susceptibility in the presence of ergosterol. To study mechanisms affecting mammalian cells, we evaluated the effect of NYT-IL on a kidney cell line, with respect to viability, metabolic activity, potassium leakage and internalization of FITC-labeled human transferrin. NYT-IL exhibited killing kinetics patterns against Candida albicans similar to those of NYT and caused disruption of fungal cells and potassium ion leakage. Susceptibility tests showed that NYT-IL had lower antifungal activity in the presence of ergosterol. Thus, NYT-IL acts apparently by damaging fungal membrane, possibly through interaction with ergosterol, and maybe by additional modes of action. NYT-IL did not cause potassium leakage from mammalian kidney cells at any tested concentration and was not cytotoxic, whereas NYT, at high concentrations, led to K+ leakage and was cytotoxic. Furthermore, the high NYT concentration interfered in the internalization process of human transferrin receptor (hTfnR) while NYT-IL did not. In summary, the Intralipid formulation of NYT diminishes the mechanisms responsible for toxicity to mammalian cells but preserves mechanisms of action against fungi, thereby suggesting superiority of NYT-IL as compared to NYT as an antifungal agent. [ABSTRACT FROM AUTHOR]

Objectives We developed a novel lipid formulation of nystatin suitable for parenteral administration, nystatin–intralipid (NYT-IL), with antifungal activity and reduced toxicity in mice. We investigated the pharmacokinetics, tissue distribution and immunomodulatory effect of NYT-IL in mice. Methods Nystatin levels in serum and organs were determined using HPLC after NYT-IL or nystatin administration in mice. The levels of the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) and the anti-inflammatory cytokine interleukin 10 (IL-10) produced by splenocytes from mice injected with NYT-IL or nystatin were evaluated by an ELISA assay. Results Injection of NYT-IL resulted in similar levels and similar kinetics of nystatin in serum, higher concentrations in the liver and lower concentrations in the kidneys, in comparison with nystatin injection. Injection of mice with NYT-IL yielded higher levels of IL-10 than that of nystatin, whereas the levels of TNF-α and IFN-γ induced by NYT-IL were lower than those elicited by nystatin. Conclusions Since polyene treatment is associated with nephrotoxicity, lower levels of nystatin in the kidneys following NYT-IL injection suggest the possibility of reduced toxicity. As the acute infusion-related adverse effects associated with polyene treatment are considered to be induced by pro-inflammatory cytokines, a higher level of anti-inflammatory and lower levels of pro-inflammatory cytokines elicited by NYT-IL administration suggest the possibility of amelioration of such effects. In summary, the altered pharmacokinetics, tissue distribution and immune response due to the use of this intralipid formulation of nystatin merit further research towards the development of a therapeutic agent against invasive mycoses. [ABSTRACT FROM PUBLISHER]

Objectives: We describe the spectrum of findings and the diagnostic value of MR defecography in patients referred with suspicion of dyssynergic defecation. Methods: 48 patients (34 females, 14 males; mean age 48 years) with constipation and clinically suspected dyssynergic defecation underwent MR defecography. Patients were divided into patients with dyssynergic defecation (n=18) and constipated patients without dyssynergic defecation (control group, n=30). MRIs were analysed for evacuation ability, time to initiate evacuation, time of evacuation, changes in the anorectal angle (ARA-change), presence of paradoxical sphincter contraction and presence of additional pelvic floor abnormalities. Sensitivity, specificity, positive and negative predictive values and accuracy for the diagnosis of dyssynergic defecation were calculated. Results: The most frequent finding was impaired evacuation, which was seen in 100% of patients with dyssynergic defecation and in 83% of the control group, yielding a sensitivity for MR defecography for the diagnosis of dyssynergic defecation of 100% (95% confidence interval (CI) 97-100%), but a specificity of only 23% (95% CI 7-40%). A lower sensitivity (50%; 95% CI 24-76%) and a high specificity (97%; 95% CI 89-100%) were seen with abnormal ARA-change. The sensitivity of paradoxical sphincter contraction was relatively high (83%; 95% CI 63-100%). A combined analysis of abnormal ARA-change and paradoxical sphincter contraction allowed for the detection of 94% (95% CI 81-100%) of the patients with dyssynergic defecation. Conclusion: MR defecography detects functional and structural abnormal findings in patients with clinically suspected dyssynergic defecation. Impaired evacuation is seen in patients with functional constipation owing to other pelvic floor abnormalities than dyssynergic defecation. [ABSTRACT FROM AUTHOR]

Radiation recall is an acute inflammatory reaction confined to previously irradiated areas that can be triggered when chemotherapy agents are administered after radiotherapy. It remains a poorly understood phenomenon, but increased awareness may aid early diagnosis and appropriate management. A diverse range of drugs used in the treatment of cancer has been associated with radiation recall. As most data come from case reports, it is not possible to determine the true incidence, but to date the antineoplastic drugs for which radiation recall reactions have been most commonly reported include the anthracycline doxorubicin, the taxanes docetaxel and paclitaxel, and the antimetabolites gemcitabine and capecitabine. Radiation recall is drug-specific for any individual patient; it is not possible to predict which patients will react to which drugs, and rechallenge does not uniformly induce a reaction. There are no identifiable characteristics of drugs that cause radiation recall, and thus, it is a possibility that must be kept in mind with use of any drug after radiotherapy, including those from new drug classes. Although it is not yet possible to design treatment regimens to eliminate the risk of radiation recall, it seems likely that risks can be minimized by prolonging the interval between completion of radiotherapy and initiation of chemotherapy. [ABSTRACT FROM AUTHOR]

Background: To assess the participation rate and results of cytological assessment in the context of cervical cancer screening activities in an area of Barcelona (Spain) with a large immigrant population. Methods: Descriptive retrospective study of cytologies performed between 2001 and 2006 in women ≥14 years of age living in 2 out of 10 districts of Barcelona (n = 129 327) and participating in cervical cancer screening activities within a sexual and reproductive health care programme. Results: Between 2001 and 2006, overall participation among women aged 20- to 64-years old was 50.7%, with higher participation among women aged 20–34 years than among those aged 50–64 years (63.8 and 36.0%, respectively; P < 0.01). The median frequency was 0.5 cytologies/year. The rate of pathological results increased from 11.4‰ in 2001 to 29.0‰ in 2006 (P < 0.001). This increase was higher among younger women and was mainly due to an increase in the rate of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (L-SIL). Conclusions: These results show a low rate of participation in the public cervical cancer screening programme and an increase in the number of pathological results during the study period. These results provide useful information at a time when significant changes in the prevention of cervical cancer are being planned. [ABSTRACT FROM PUBLISHER]

Specimens of Lamellibrachia ( Annelida: Siboglinidae) were recently discovered at cold seeps in the eastern Mediterranean. In this study, we have investigated the phylogeny and function of intracellular bacterial symbionts inhabiting the trophosome of specimens of Lamellibrachia sp. from the Amon mud volcano, as well as the bacterial assemblages associated with their tube. The dominant intracellular symbiont of Lamellibrachia sp. is a gammaproteobacterium closely related to other sulfide-oxidizing tubeworm symbionts. In vivo uptake experiments show that the tubeworm relies on sulfide for its metabolism, and does not utilize methane. Bacterial communities associated with the tube form biofilms and occur from the anterior to the posterior end of the tube. The diversity of 16S rRNA gene phylotypes includes representatives from the same divisions previously identified from the tube of the vent species Riftia pachyptila, and others commonly found at seeps and vents. [ABSTRACT FROM AUTHOR]

A systematic review was performed to examine renal function in patients with invasive fungal infections, comparing the nephrotoxicity caused by conventional amphotericin B deoxycholate (c-AmB) with that induced by the use of lipid-based amphotericin B formulations. The analysis considered all comparative studies published in the literature between January 1996 and May 2007. The outcome data reviewed herein focused on renal toxicity as measured by serum creatinine (S-Cr) and the doubling or the mean difference in S-Cr levels from baseline to the end of therapy or the need for dialysis. We found that AmB lipid complex (ABLC), liposomal AmB (L-AmB) and AmB colloidal dispersion (ABCD) were significantly less nephrotoxic than c-AmB in all reported studies. ABLC and L-AmB caused low and comparable nephrotoxicity in nine studies. In one randomized study, L-AmB was significantly less nephrotoxic than ABLC. No studies compared ABCD nephrotoxicity to the other lipid formulations. Based on our review we conclude that lipid formulations of amphotericin B are an important strategy to preserve renal function and improve survival in critically ill patients who require treatment for systemic fungal infections. [ABSTRACT FROM AUTHOR]

Pneumothorax is a relatively common clinical problem which can occur in individuals of any age. Irrespective of aetiology (primary, or secondary to antecedent lung disorders or injury), immediate management depends on the extent of cardiorespiratory impairment, degree of symptoms and size of pneumothorax. Guidelines have been produced which outline appropriate strategies in the care of patients with a pneumothorax, while the emergence of video-assisted thoracoscopic surgery has created a more accessible and successful tool by which to prevent recurrence in selected individuals. This evidence based review highlights current practices involved in the management of patients with a pneumothorax. [ABSTRACT FROM AUTHOR]

A rapidly expanding literature on firm heterogeneity and firm level globalisation strategies has developed over the last decade. There are new insights on why some firms export and others do not, why some firms fail to survive in export markets and some choose to produce overseas rather than export. This article provides a synthesis and evaluation of this literature. It reviews both new theories of firms in an open economy context and the extensive microeconometric evidence base, which has now developed. It highlights the implications of this evidence base for policy and includes an assessment of how the research agenda may evolve. [ABSTRACT FROM AUTHOR]

To develop a model for predicting the dose absorbed by organ at risk (OAR) during intensity modulated radiation therapy for nasopharyngeal carcinoma (NPC). 55 patients underwent intensity modulated radiation therapy for NPC. The OARs were divided into several suborgans, and SPSS software was used to evaluate multiple linear method for fitting the normalized volume for each suborgan, normalized mean dose (Dmean) Dnm (Dnm = Dmean/Dprescription), and normalized D10%−D100% values Dn10%−n100%(Dn10%−n100% = D10%−D100%/Dprescription) for each OAR. Based on the Matlab software, the predicted Dn10%−n100% value was fitted to obtain the predicted DVH curve. The multiple linear fitting formulas revealed significant results for the oral cavity Dn100% (p = 0.017), the parotid gland Dn100% (p = 0.001), and the remaining OAR (all p < 0.0001). The correlation coefficients and p values indicated that the fitting formula was a good fit. The p values for the White test show that the prediction model is robust. This method was successfully used for verification cases. The present study provided a simple and effective model for predicting the dose absorbed by OAR for NPC. This method is a relatively simple mathematical model, just use prescription dose and V0–Vn to predict the Dmean and D10%−100%, which predict does not require buying new modules of treatment planning software or extracting the distance of each sampling point of the OAR with the dose information. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Differential cell line susceptibility to the emerging novel human betacoronavirus 2c EMC/2012: Implications for disease pathogenesis and clinical manifestation" by J. F. Chan and colleagues in a 2013 issue.