Practice-Level Variation in Telemedicine Use in a Pediatric Primary Care Network During the COVID-19 Pandemic: Retrospective Analysis and Survey Study.
Telehealth, the delivery of health care through telecommunication technology, has potential to address multiple health system concerns. Despite this potential, only 15% of pediatric primary care clinicians reported using telemedicine as of 2016, with the majority identifying inadequate payment for these services as the largest barrier to their adoption. The COVID-19 pandemic led to rapid changes in payment and regulations surrounding telehealth, enabling its integration into primary care pediatrics. Due to limited use of telemedicine in primary care pediatrics prior to the COVID-19 pandemic, much is unknown about the role of telemedicine in pediatric primary care. To address this gap in knowledge, we examined the association between practice-level telemedicine use within a large pediatric primary care network and practice characteristics, telemedicine visit diagnoses, in-person visit volumes, child-level variations in telemedicine use, and clinician attitudes toward telemedicine. We analyzed electronic health record data from 45 primary care practices and administered a clinician survey to practice clinicians. Practices were stratified into tertiles based on rates of telemedicine use (low, intermediate, high) per 1000 patients per week during a two-week period (April 19 to May 2, 2020). By practice tertile, we compared (1) practice characteristics, (2) telemedicine visit diagnoses, (3) rates of in-person visits to the office, urgent care, and the emergency department, (4) child-level variation in telemedicine use, and (5) clinician attitudes toward telemedicine across these practices. Across pediatric primary care practices, telemedicine visit rates ranged from 5 to 23 telemedicine visits per 1000 patients per week. Across all tertiles, the most frequent telemedicine visit diagnoses were mental health (28%-36% of visits) and dermatologic (15%-28%). Compared to low telemedicine use practices, high telemedicine use practices had fewer in-person office visits (10 vs 16 visits per 1000 patients per week, P=.005) but more total encounters overall (in-office and telemedicine: 28 vs 22 visits per 1000 patients per week, P=.006). Telemedicine use varied with child age, race and ethnicity, and recent preventive care; however, no significant interactions existed between these characteristics and practice-level telemedicine use. Finally, clinician attitudes regarding the usability and impact of telemedicine did not vary significantly across tertiles. Across a network of pediatric practices, we identified significant practice-level variation in telemedicine use, with increased use associated with more varied telemedicine diagnoses, fewer in-person office visits, and increased overall primary care encounter volume. Thus, in the context of the pandemic, when underutilization of primary care was prevalent, higher practice-level telemedicine use supported pediatric primary care encounter volume closer to usual rates. Child-level telemedicine use differed by child age, race and ethnicity, and recent preventive care, building upon prior concerns about differences in access to telemedicine. However, increased practice-level use of telemedicine services was not associated with reduced or increased differences in use, suggesting that further work is needed to promote equitable access to primary care telemedicine.


Impact of prone positioning on patients with COVID-19 and ARDS on invasive mechanical ventilation: a multicenter cohort study.
To identify factors that lead to a positive oxygenation response and predictive factors of mortality after prone positioning. This was a retrospective, multicenter, cohort study involving seven hospitals in Brazil. Inclusion criteria were being > 18 years of age with a suspected or confirmed diagnosis of COVID-19, being on invasive mechanical ventilation, having a PaO2/FIO2 ratio < 150 mmHg, and being submitted to prone positioning. After the first prone positioning session, a 20 mmHg improvement in the PaO2/FIO2 ratio was defined as a positive response. The study involved 574 patients, 412 (72%) of whom responded positively to the first prone positioning session. Multiple logistic regression showed that responders had lower Simplified Acute Physiology Score III (SAPS III)/SOFA scores and lower D-dimer levels (p = 0.01; p = 0.04; and p = 0.04, respectively). It was suggested that initial SAPS III and initial PaO2/FIO2 were predictors of oxygenation response. The mortality rate was 69.3%. Increased risk of mortality was associated with age (OR = 1.04 [95 CI: 1.01-1.06]), time to first prone positioning session (OR = 1.18 [95 CI: 1.06-1.31]), number of sessions (OR = 1.31 [95% CI: 1.00-1.72]), proportion of pulmonary impairment (OR = 1.55 [95% CI: 1.02-2.35]), and immunosuppression (OR = 3.83 [95% CI: 1.35-10.86]). Our results show that most patients in our sample had a positive oxygenation response after the first prone positioning session. However, the mortality rate was high, probably due to the health status and the number of comorbidities of the patients, as well as the severity of their disease. Our results also suggest that SAPS III and the initial PaO2/FIO2 predict the oxygenation response; in addition, age, time to first prone positioning, number of sessions, pulmonary impairment, and immunosuppression can predict mortality.


The solution structure of BmTx3B, a member of the scorpion toxin subfamily alpha-KTx 16.
This article reports the solution structure of BmTx3B (alpha-KTx16.2), a potassium channel blocker belonging to the subfamily alpha-KTx16, purified from the venom of the Chinese scorpion Buthus martensi Karsch. In solution, BmTx3B assumes a typical CSalphabeta motif, with an alpha-helix connected to a triple-stranded beta-sheet by 3 disulfide bridges, which belongs to the first structural group of short-chain scorpion toxins. On the other hand, BmTx3B is quite different from other toxins (such as ChTx and AgTx2) of this group in terms of the electrostatic and hydrophobic surface distribution. The functional surface (beta-face) of the molecule is characterized by less basic residues (only 2: Lys28 and Arg35) and extra aromatic residues (Phe1, Phe9, Trp15, and Tyr37). The peptide shows a great preference for the Kca1.1 channel over the Kv channel (about a 10(3)-fold difference). The model of BmTx3B/Kca1.1 channel complex generated by docking and dynamic simulation reveals that the stable binding between the BmTx3B and Kca1.1 channel is favored by a number of aromatic pi-pi stacking interactions. The influences of these structural features on the kinetic behavior of the toxin binding to Kca1.1 channel are also discussed.


Effect of Lifestyle Changes after Percutaneous Coronary Intervention on Revascularization.
Whether optimal cardiovascular health metrics may reduce the risk of cardiovascular events in secondary prevention is uncertain. The study was conducted to evaluate the influence of lifestyle changes on clinical outcomes among the subjects underwent percutaneous coronary intervention (PCI). The study group consists of 17,099 consecutive PCI patients. We recorded data on subject lifestyle behavior changes after their procedure. Patients were categorized as ideal, intermediate, or poor CV health according to a modified Life's Simple 7 score (on body mass, smoking, physical activity, diet, cholesterol, blood pressure, and glucose). Multivariable COX regression was used to evaluate the association between CV health and revascularization event. We also tested the impact of cumulative cardiovascular health score on reoccurrence of cardiovascular event. During a 3-year median follow-up, 1,583 revascularization events were identified. The observed revascularization rate was 8.0%, 9.3%, and 10.6% in the group of patients with optimal (a modified Life's Simple 7 score of 11-14), average (score = 9 or 10), or inadequate (less or equal than 8) CV health, respectively. After multivariable analysis, the adjusted hazard ratios were 0.83 (95% CI: 0.73-0.94) and 0.89 (95% CI: 0.79-0.99) for patients with optimal and average lifestyle changes comparing with the inadequate tertile (P for trend = 0.003). In addition, each unit increase in above metrics was associated with a decrease risk of revascularization (HR, 0.96; 95% confidence interval, 0.93-0.98; P for trend = 0.003). In addition, each unit increase in above metrics was associated with a decrease risk of revascularization (HR, 0.96; 95% confidence interval, 0.93-0.98. Ideal CV health related to lower incidence of cardiovascular events, even after the percutaneous coronary intervention. Revascularization can be reduced by lifestyle changes. The cardiovascular health metrics could be extrapolated to secondary prevention and need for further validation.


An autoinhibitory effect of the homothorax domain of Meis2.
Myeloid ecotropic insertion site (Meis)2 is a homeodomain protein containing a conserved homothorax (Hth) domain that is present in all Meis and Prep family proteins and in the Drosophila Hth protein. The Hth domain mediates interaction with Pbx homeodomain proteins, allowing for efficient DNA binding. Here we show that, like Meis1, Meis2 has a strong C-terminal transcriptional activation domain, which is required for full activation of transcription by homeodomain protein complexes composed of Meis2 and Pbx1. We also show that the activity of the activation domain is inhibited by the Hth domain, and that this autoinhibition can be partially relieved by the interaction of Pbx1 with the Hth domain of Meis2. Targeting of the Hth domain to DNA suggests that it is not a portable trans-acting repression domain. However, the Hth domain can inhibit a linked activation domain, and this inhibition is not limited to the Meis2 activation domain. Database searching reveals that the Meis3.2 splice variant, which is found in several vertebrate species, disrupts the Hth domain by removing 17 codons from the 5'-end of exon 6. We show that the equivalent deletion in Meis2 derepresses the C-terminal activation domain and weakens interaction with Pbx1. This work suggests that the transcriptional activity of all members of the Meis/Prep Hth protein family is subject to autoinhibition by their Hth domains, and that the Meis3.2 splice variant encodes a protein that bypasses this autoinhibitory effect.


Platelet Rich Plasma Injection for Soft Tissue Musculoskeletal Pain.
Treating soft tissue injuries can be a challenge for physicians as it can be overlooked which can lead to more problems. In recent studies, the use of Platelet Rich Plasma (PRP) has been gaining popularity for soft tissue injuries because of its benefits and minimal side effects. This study aims to evaluate the effect of PRP injection on various musculoskeletal soft tissues inflammation. This is a retrospective study of patients with soft tissue injury who underwent PRP therapy between 2015 and 2018 at an orthopaedic and traumatology hospital. The study collected demographic data including the type of soft tissue injury and Visual Analog Scale (VAS) before and after the PRP injection. Those data were statistically analysed to identify the significance of PRP. Seventy-six patients were included, predominantly female, middle aged (40-69 years old) and class one obesity. Most of the complaints (61.8%) were in the lower extremity region. Pain improvements measured with mean VAS score were observed in both acute (3.06±1.28 to 0.8±0.65) and chronic (4±1.75 to 0.97±0.62) cases. There was a significant decrease of VAS score before and after the PRP injection (p < 0.000). PRP injection is able to alleviate both acute and chronic pain in soft tissue injuries without additional analgesic.


Quantum mechanics/molecular mechanics study of the catalytic cycle of water splitting in photosystem II.
This paper investigates the mechanism of water splitting in photosystem II (PSII) as described by chemically sensible models of the oxygen-evolving complex (OEC) in the S0-S4 states. The reaction is the paradigm for engineering direct solar fuel production systems since it is driven by solar light and the catalyst involves inexpensive and abundant metals (calcium and manganese). Molecular models of the OEC Mn3CaO4Mn catalytic cluster are constructed by explicitly considering the perturbational influence of the surrounding protein environment according to state-of-the-art quantum mechanics/molecular mechanics (QM/MM) hybrid methods, in conjunction with the X-ray diffraction (XRD) structure of PSII from the cyanobacterium Thermosynechococcus elongatus. The resulting models are validated through direct comparisons with high-resolution extended X-ray absorption fine structure spectroscopic data. Structures of the S3, S4, and S0 states include an additional mu-oxo bridge between Mn(3) and Mn(4), not present in XRD structures, found to be essential for the deprotonation of substrate water molecules. The structures of reaction intermediates suggest a detailed mechanism of dioxygen evolution based on changes in oxidization and protonation states and structural rearrangements of the oxomanganese cluster and surrounding water molecules. The catalytic reaction is consistent with substrate water molecules coordinated as terminal ligands to Mn(4) and calcium and requires the formation of an oxyl radical by deprotonation of the substrate water molecule ligated to Mn(4) and the accumulation of four oxidizing equivalents. The oxyl radical is susceptible to nucleophilic attack by a substrate water molecule initially coordinated to calcium and activated by two basic species, including CP43-R357 and the mu-oxo bridge between Mn(3) and Mn(4). The reaction is concerted with water ligand exchange, swapping the activated water by a water molecule in the second coordination shell of calcium.


Telomere length - a cellular aging marker for depression and Post-traumatic Stress Disorder.
Telomeres play a central role in cell fate and aging by adjusting the cellular response to both biological and psychological stress. Human telomeres are regions of tandem TTAGGG repeats at chromosomal ends that protect chromosomes from degradation, fusion, and recombination. They are made up of approximately 1000-2500 copies of the repeated DNA sequence. Over time, at each cell division, the telomere ends become shorter. Thus, telomere length (TL) has been considered a cellular marker for age-related diseases. In addition to biochemical stressors such as oxidation and inflammation, psychosocial traumatic stress has also been linked to shorter telomeres. TL is significantly inversely correlated with long-term depression, even after controlling for age. Average TL in depressed subjects, who were above the median of lifetime depression, was 281 base pairs shorter than that in controls, corresponding to approximately 7years of accelerated cell aging. Several recent studies have also demonstrated an inverse relationship between leukocyte telomere length (LTL) and the risk of PTSD. TL was inversely correlated with the duration of caregiving and PTSD. Here, we focus on the discussion of findings in studies of the relationships between stress-related disorders (e.g., depression and PTSD) and telomeres. We also present direct evidence that TL is associated with traumatic stress, depression, and PTSD, and hypothesize that traumatic stress affects not only mental disorders but also cellular aging. The nature of this relationship between stress and TL warrants further evaluation in psychiatry.


Increased acylated plasma ghrelin, but improved lipid profiles 24-h after consumption of carob pulp preparation rich in dietary fibre and polyphenols.
We have recently shown that a polyphenol-rich insoluble dietary fibre preparation from carob pulp (Ceratonia siliqua L; carob fibre) decreased postprandial acylated ghrelin, TAG and NEFA during an acute liquid meal challenge test. However, delayed effects of carob fibre consumption are unknown. Therefore, a randomized controlled crossover study in nineteen healthy volunteers consuming foods with or without 50 g carob fibre was conducted. On the subsequent day (day 2), glucose, TAG, total and acylated ghrelin as well as insulin, NEFA and leptin were assessed at baseline and at timed intervals for 300 min after ingestion of standardized bread. Consumption of carob fibre-enriched foods did not affect fasting concentrations of glucose, TAG, total ghrelin, NEFA, insulin and leptin. Fasting acylated ghrelin was increased on the day subsequent to carob fibre consumption compared with control (P = 0.046). After consumption of the standard bread on day 2, glucose response (P = 0.029) was increased, and TAG (P = 0.033) and NEFA (P < 0.001) responses were decreased compared with control. Postprandial responses of total and acylated ghrelin, insulin and leptin on day 2 were unaffected by carob fibre consumption the previous day. In conclusion, an increase in total and acylated plasma ghrelin accompanied by enhanced lipid metabolism after carob fibre consumption suggests higher lipid utilization and suppressed lipolysis on the day subsequent to carob fibre consumption. However, elevated glucose levels after carob fibre consumption need to be addressed in future studies.


High insulinlike growth factor I is associated with cognitive decline in Huntington disease.
The somatotropic axis (growth hormone [GH] and insulinlike growth factor I [IGFI]) play a role in the cognitive deficits seen with aging, GH deficiency, and neurodegenerative disorders such as Alzheimer disease. We recently reported elevations in basal plasma GH and IGFI levels in patients with Huntington disease (HD). Here, our objective was to determine whether somatotropic axis abnormalities predicted cognitive dysfunction in HD. In this prospective cohort study of 109 patients with genetically documented HD, aged 21 to 85 years, we determined fasting blood levels of total IGFI, GH, and insulinlike factor binding protein 3 at baseline, and we used the cognitive Unified Huntington's Disease Rating Scale to assess cognitive impairment at baseline and for up to 5 years subsequently. Associations were evaluated using mixed linear model analysis. Higher plasma IGFI concentrations were associated with greater cognitive decline (beta Stroop Words, -6.01, p = 0.003; beta Stroop Color, -4.41, p = 0.01; beta Stroop Color/Words, -3.86, p = 0.02; beta Symbol Digit Modalities, -3.69, p = 0.03; and beta verbal fluency, -5.01, p = 0.03). Higher free IGFI concentrations and higher GH concentrations in men also predicted greater cognitive decline. Our findings in patients with HD suggest that a high IGFI level at baseline may be associated with greater subsequent declines in executive function and attention.


Spatial Distribution and Characterization of the Small-Molecule Metabolites and In Situ Hydrolyzed Oligosaccharides in the Rhizome of Glycyrrhiza uralensis by Desorption Electrospray Ionization-Mass Spectrometry Imaging and High-Resolution Liquid Chromatography-Mass Spectrometry.
Characterization and spatial distribution studies of the metabolome in plants are crucial for revealing the physiology of plants and developing functional foods. Using the rhizome of Glycyrrhiza uralensis as a case, we integrated desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) and high-resolution liquid chromatography/mass spectrometry approaches aimed at characterizing and locating both the small molecules and the macromolecular polysaccharides. Under the optimal conditions, 21 flavonoids and 12 triterpenoids were detected and characterized in different tissues of the rhizome and another 19 components were characterized exclusively by DESI-MSI. Combined with hydrophilic interaction chromatography/ion mobility-quadrupole time-of-flight mass spectrometry, eight different degrees of polymerization of oligosaccharides (after in situ acid hydrolysis) were characterized from the rhizome of G. uralensis. Majority of these metabolites are located in the cortex, phloem, and medulla, which lays the foundation for understanding the physiology of G. uralensis. The useful information can benefit the sustainable utilization and further development of Glycyrrhiza resource.


Direct Quantification of Nanoplastics Neurotoxicity by Single-Vesicle Electrochemistry.
Nanoplastics are recently recognized as neurotoxic factors for the nervous systems. However, whether and how they affect vesicle chemistry (i.e., vesicular catecholamine content and exocytosis) remains unclear. This study offers the first direct evidence for the nanoplastics-induced neurotoxicity by single-vesicle electrochemistry. We observe the cellular uptake of polystyrene (PS) nanoplastics into model neuronal cells and mouse primary neurons, leading to cell viability loss depending on nanoplastics exposure time and concentration. By using single-vesicle electrochemistry, we find the reductions in the vesicular catecholamine content, the frequency of stimulated exocytotic spikes, the neurotransmitter release amount of single exocytotic event, and the membrane-vesicle fusion pore opening-closing speed. Mechanistic investigations suggest that PS nanoplastics can cause disruption of filamentous actin (F-actin) assemblies at cytomembrane zones and change the kinetic patterns of vesicle exocytosis. Our finding shapes the first quantitative picture of neurotoxicity induced by high-concentration nanoplastics exposure at a single-cell level.


A randomized controlled trial of a combined self-management and exercise intervention for elderly people with osteoarthritis of the knee: the PLE2NO program.
To assess the effectiveness of a 12-week self-management and exercise intervention (the PLE2NO program) in elderly individuals with knee osteoarthritis. Randomized controlled trial. Four different community settings. Eighty individuals aged 60 years or older with clinical and radiographic knee osteoarthritis enrolled in the study. A combined self-management and exercise intervention (treatment group) and an educational intervention (control group). The primary outcomes were pain and other knee osteoarthritis symptoms (swelling, crackling, limitation on movement, and stiffness), self-management behaviors (communication with physician and cognitive symptom management), and functional lower limb strength. Secondary outcomes were knee osteoarthritis-specific health-related quality of life, self-perceived health, aerobic capacity, lower and upper limb flexibility, and handgrip strength. In all, 67 participants, mean age 69.1 ± 5.8 years, completed the study: 32 in the Educational Group and 35 in the Self-Management and Exercise Group. A significant group effect favorable to the Self-Management and Exercise Group was observed in the following variables: communication with the physicians ( P = .048), aerobic capacity ( P = .035), and functional lower limb strength ( P = .015). Although no significant group effect was detected, clinical improvements in pain (31%) and knee osteoarthritis symptoms (29%) were observed in the experimental group. No improvements regarding cognitive symptom management, self-perceived health, lower limb flexibility, and handgrip strength were found. This study supports the importance of a combined self-management and exercise intervention to improve functional lower limb strength and aerobic capacity in a Portuguese sample. Additionally, pain and other symptoms have improved clinically.


A comparison of telephone and texting interventions for persons with schizophrenia spectrum disorders.
Problem-solving interventions are not routinely offered to persons with schizophrenia spectrum disorders (SSDs). Telephone calls and text messages are potential avenues to offer problem solving support. This study compared the effect of telephone calls only, text messages only, and both telephone calls and text messages on individuals' symptoms and medication adherence. Thirty outpatient participants with SSDs were randomly assigned to weekly telephone calls, daily text messages, or both for three months. Participants received monthly in-home pill counts and symptom assessments. Repeated measures ANOVA was significant (F (4,26) = 4.2, p = 0.005) for symptom scores. Further work with larger, more diverse, samples is needed.


Bridging the gap: implementation of an online induction course to support students' transition into first year medicine.
This article was migrated. The article was marked as recommended. Introduction Students transitioning into medical school encounter a series of transitions on their journey towards graduation. In the context of undergraduate medicine, students must develop new skills common to all incoming undergraduates (e.g., academic writing, digital skills), as well as subject-specific knowledge, e.g., regarding professionalism or anatomical dissection governance. Whilst the University of Glasgow School of Medicine provides on-campus induction activities, e.g., to prepare students to participate in problem-based learning, other induction material has traditionally been delivered in a didactic manner. Methods We developed a five-unit online induction course using existing resources available under creative commons licensing. The course used an interactive approach to deliver teaching and signpost key resources related to digital and academic skills and professionalism. The course was released to incoming students ( n = 316) via the institutional public Moodle site prior to their arrival at Glasgow. Student engagement and perception was assessed using quizzes, an online anonymous survey ( n = 133) and focus group ( n = 2). Results Student engagement with the induction course was high: 95% (301/316) of students accessed the course, and 89% (280/316) of students completed the course by achieving 100% in all five end-of-unit quizzes. Students placed particular value on content relating to professional expectations and highlighted that inclusion of current students' testimonies would improve the course. However, the requirement to engage with sections relating to fundamental digital skills was sometimes a barrier to engagement. Discussion Overall, the online induction course benefitted students by helping them understand institutional expectations and creating an opportunity to identify their digital skills needs for them to succeed in their studies. These insights will be of key importance in supporting transition as we prepare for remote induction of our students in September 2020 and should be applicable to others interested in adapting and implementing this induction course in their own settings.


A brief review on the immunological scenario and recent developmental status of vaccines against enteric fever.
Enteric fever has been one of the leading causes of severe illness and deaths worldwide. S. Typhi and S. Paratyphi A, B and C are important enteric fever-causing organisms globally. This infection causes about 21 million cases among which 222,000 typhoid related deaths occurred in 2015. These estimates do not reflect the ultimate and real status of the disease due to the lack of unified diagnostic and proper reporting system from typhoid endemic and other regions. Current control strategies have become increasingly ineffective due to the emergence of multi-drug resistance among the strains. This situation worsens the disease-burden in developing as well as in developed countries. Moreover the emergence of S. Paratyphi A as a major enteric fever-causing organism in several Asian countries, demands a prophylactic measure at this hour. Other than two licensed vaccines of S. Typhi, there are no exsisting vaccines for S. Paratyphi A. Moreover, travelers returning from endemic regions are becoming more susceptible to have these infections. In this situation, a need for bivalent approach is required where a single immunogen (consisting from each organism) will be effective against the disease. In this review, we have focused on the general information about typhoidal fever, its spread and epidemiology in brief and the present status of typhoidal vaccines and its future. This review highlights existing gaps in the typhoidal salmonellae research with a special emphasis on the status of present typhoidal salmonellae vaccine research.


Metabolic connectivity as a predictor of surgical outcome in mesial temporal lobe epilepsy.
The study investigated metabolic connectivity (MC) differences between patients with unilateral drug-resistant mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) and healthy controls (HC), based on [18 F]-fluorodeoxyglucose (FDG)-PET data. We focused on the MC changes dependent on the lateralization of the epileptogenic lobe and on correlations with postoperative outcome. FDG-PET scans of 47 patients with unilateral MTLE with histopathologically proven HS and 25 HC were included in the study. All the patients underwent a standard anterior temporal lobectomy and were more than two years after the surgery. MC changes were compared between the two HS groups (left HS, right HS) and HC. Differences between the metabolic network of seizure-free and non-seizure-free patients after surgery were depicted afterward. Network changes were correlated with clinical characteristics. The study showed widespread metabolic network changes in the HS patients as compared to HC. The changes were more extensive in right HS than in left HS. Unfavorable surgical outcomes were found in patients with decreased MC within the network including both the lesional and contralesional hippocampus, ipsilesional frontal operculum, and contralesional insula. Favorable outcomes correlated with decreased MC within the network involving both orbitofrontal cortices and the ipsilesional temporal lobe. There are major differences in the metabolic networks of left and right HS, with more extensive changes in right HS. The changes within the metabolic network could help predict surgical outcomes in patients with HS. MC may identify patients with potentially unfavorable outcomes and direct them to a more detailed presurgical evaluation.


The First Case of Cutaneous Acanthamoebiasis Caused by Acanthamoeba triangularis in Korea.
A 62-year-old man with multiple myeloma visited our clinic with multiple painful erythematous to purpuric nodules on his whole body. He received a skin biopsy which showed septal and lobular inflammation with vasculitis, and multiple amoebic organisms were found. Polymerase chain reaction and culture were performed and an Acanthamoeba triangularis infection was diagnosed. This is the first report on cutaneous acanthamoebiasis caused by A. triangularis, suggesting that A. triangularis should be regarded as a clinical pathogen that can cause ocular as well as disseminated infection.


Imaging cellular ultrastructures using expansion microscopy (U-ExM).
Determining the structure and composition of macromolecular assemblies is a major challenge in biology. Here we describe ultrastructure expansion microscopy (U-ExM), an extension of expansion microscopy that allows the visualization of preserved ultrastructures by optical microscopy. This method allows for near-native expansion of diverse structures in vitro and in cells; when combined with super-resolution microscopy, it unveiled details of ultrastructural organization, such as centriolar chirality, that could otherwise be observed only by electron microscopy.


Tomato consumption and intake of lycopene as predictors of the incidence of prostate cancer: the Adventist Health Study-2.
Studies have controversially suggested that prostate cancer, the most common cancer among Western men, is less common among those with a high intake of tomato products and lycopene. We examine multivariable associations between the intake of tomatoes and lycopene, and risk of prostate cancer. In a prospective study of 27,934 Adventist men without prevalent cancer, Cox proportional hazard regression analyses were used to address the objectives. Dietary measurement error was partially corrected with regression calibration. 1226 incident cases of prostate cancer, 355 of them aggressive, were identified during 7.9 years of follow-up. Consumption of canned and cooked tomatoes more than four times a week was associated with a HR = 0.72 (95% CI 0.55, 0.94, P = 0.02) comparing to risk in those never consuming this food. Treating this as a continuous variable, adjusting for confounders, produces a similar result, HR = 0.86 (95% CI 0.75, 0.99), comparing 64 g/day with zero intakes (questionnaire data). Regression calibration, although less precise, suggests a yet stronger and statistically significant inverse relationship, comparing a 24-h dietary recall intake of 71 g/day canned and cooked tomato product, with zero intake. Uncalibrated multivariable-adjusted competing risk analyses do not find differences in tomato associations between aggressive and non-aggressive prostate cancers although power for aggressive cancers is limited. Consumption of canned and cooked tomatoes may reduce the risk of prostate cancer. These products contain more available lycopene. However, an observational study cannot exclude confounding by some unidentified, prostate cancer preventive factor. Clinical Trial Registry: ClinicalTrials.gov Identifier: NCT03615599.


A Web-Based Intervention to Reduce Indoor Tanning Motivations in Adolescents: a Randomized Controlled Trial.
Youthful indoor tanning as few as ten sessions can increase the risk of melanoma by two to four times with each additional session adding another 2 % to the risk. Recent research estimates that indoor tanning can be linked to approximately 450,000 cases of skin cancer annually in the USA, Europe, and Australia. Despite these risks, indoor tanning remains popular with adolescents. This study tested the efficacy of a web-based skin cancer prevention intervention designed to reduce indoor tanning motivations in adolescent females. A nationally representative sample of 443 female teens was enrolled from an online panel into a two-arm, parallel group design, randomized controlled trial. Treatment participants received an appearance-focused intervention grounded in established health behavior change models. Controls viewed a teen alcohol prevention website. Outcome variables included willingness and intentions to indoor tan, willingness to sunless tan, and measures of indoor tanning attitudes and beliefs. The intervention decreased willingness and intentions to indoor tan and increased sunless tanning willingness relative to controls. We also examined indirect mechanisms of change through intervening variables (e.g., indoor tanning attitudes, norms, positive and negative expectancies) using the product of coefficient approach. The web-based intervention demonstrated efficacy in changing adolescent indoor tanning motivations and improving their orientation toward healthier alternatives. Results from the intervening variable analyses give guidance to future adolescent skin cancer prevention interventions.


Coding of significant comorbidities and complications for stroke in rehabilitation.
Comorbidities and complications of stroke have implications for level of care and hospital resources. It is critical, therefore, that hospital morbidity data accurately reflect the prevalence of these additional diagnoses. This study aimed to measure and describe the concordance between stroke clinicians/researchers and medical record coders when recording stroke and related diagnoses. Diagnoses recorded prospectively, according to defined criteria by a clinical research team, were compared with the coding of stroke comorbidities and complications as per the Australian Coding Standards (ACS) from the separations of 100 inpatients from three rehabilitation facilities in South Australia. Percentage agreement, kappa coefficient, sensitivity and specificity values were calculated. Kappa coefficients for agreement of prospective diagnoses with coding ranged from 0.08 to 0.819. The diagnoses with the highest agreement were stroke, aspiration pneumonia (nil cases), aphasia and dysphagia. The diagnoses with the lowest agreement were apraxia, cognitive impairment, constipation and dehydration. Not all stroke comorbidities are represented accurately in hospital morbidity datasets. Education of stroke clinicians about the current ACS may clarify expectations about medical record documentation for coding purposes which in turn may result in more accurate morbidity data and therefore costings for the rehabilitation sector.


Comprehensive analysis of 34 MiT family translocation renal cell carcinomas and review of the literature: investigating prognostic markers and therapy targets.
Recently cabozantinib, a tyrosine kinase inhibitor with activity against VEGF, MET, AXL, and downregulating cathepsin K in vitro, has been proposed for the treatment of advanced clear and non-clear renal cell carcinomas. Since it is well known that cathepsin K is expressed in the majority of MiT family translocation renal cell carcinomas, we investigated cathepsin K, MET, AXL, and VEGF in a large series of those tumours, looking for possible predictive markers. We collected the clinicopathological features of 34 genetically confirmed MiT family translocation renal cell carcinomas [26 Xp11 and 8 t(6;11) renal cell carcinomas] and studied them using an immunohistochemical panel including PAX8, cathepsin K, HMB45, Melan-A, CD68 (PG-M1), CK7, CA9, MET, AXL and by FISH for VEGFA and MET. Cathepsin K was expressed in 14 of 26, HMB45 in 8 of 25, and Melan-A in 4 of 23 Xp11 renal cell carcinomas, whereas labelling for CK7 and CA9 was minimal. In t(6;11) renal cell carcinoma, cathepsin K and melanogenesis markers were constantly positive, whereas CK7 and CA9 were negative. None of the 34 carcinomas showed CD68 (PG-M1) and AXL expression. One aggressive Xp11 renal cell carcinoma showed increased VEGFA gene copy number (4-5 copies) with concurrent gains of TFE3 and TFEB. None of the 34 carcinomas showed MET gene amplification, whereas staining for MET was found in 7 of 8 t(6;11) and in 16 of 24 Xp11 renal cell carcinomas, and in the latter cases, when the expression was >50%, correlated with aggressiveness (p=0.0049). In Xp11 renal cell carcinomas, the aggressiveness was also correlated with larger tumour size (p=0.0008) and the presence of necrosis (p=0.027) but not nucleolar grading (p=1). Interestingly, in patients with tumours exhibiting two of three parameters (necrosis, larger tumour size and MET immunolabelling >50%) an aggressive clinical behaviour was observed in 88% of cases. In conclusion, cathepsin K, CD68 (PG-M1), CK7, CA9, and PAX8 is a useful panel for the diagnosis. Larger tumour size, the presence of necrosis and MET immunohistochemical expression correlate with aggressive behaviour in Xp11 renal cell carcinomas, especially in combination. VEGF, MET, cathepsin K but not AXL may be potential predictive markers for targeted therapy in MiT family translocation renal cell carcinomas.


Factors predicting local recurrence, metastasis, and survival in pediatric soft tissue sarcoma in extremities.
Pediatric soft tissue sarcomas are rare and differ from those in adults regarding the spectrum of diagnoses and treatment. Sarcomas in extremities may have different prognoses from those located elsewhere. We sought risk factors predicting local recurrence, metastasis, and overall survival and asked whether radiation and chemotherapy influenced local recurrence, metastasis, and overall survival. We retrospectively reviewed all 98 patients aged 18 years or younger diagnosed with soft tissue sarcomas in extremities from 1990 to 2008. Age, tumor size, depth, location, bone or neurovascular involvement, histologic subtypes, unplanned excision, surgical margins, metastasis at diagnosis, and adjuvant treatments were reviewed for each patient. We determined the effect of each prognostic variable on local recurrence, metastasis, and overall survival. Ninety-four patients underwent surgical excision and seven patients had local recurrence at a median time of 18.6 months. Radiation therapy reduced the rate of local recurrence. Fourteen patients had metastasis at diagnosis and seven patients later developed metastasis. The median time to metastasis was 20.9 months. Six patients died and the median time to death was 28.0 months. Metastasis at diagnosis was a predictive factor for death. When limited to extremities, radiation therapy reduced the rate of local recurrence in pediatric soft tissue sarcomas. Metastases at diagnosis predict death.


A journey in quest of meaning: a hermeneutic-phenomenological study on living with memories from intensive care.
In a short-term perspective, a high incidence of psychological problems linked to memories from intensive care has been found in survivors of critical illness. Little is known about what kinds of memories patients might carry with them and what it is like to live with memories from intensive care as years go by. The aim of this study was to explore the meaning of living with memories from intensive care. A hermeneutic-phenomenological approach. In-depth interviews with ten former intensive care patients 10 years after their admission. Memories of bodily sensations and memories containing strong emotions were surprisingly well kept. Memories residing in the body at a prereflective level and that could be awakened without being triggered by will or conscious thought comprised an important segment of the memory spectrum. Complaints such as panic attacks and anxiety were strongly linked to these kinds of memories and experienced as flashbacks of frightening experiences that entailed strong emotions. Some informants still strove to understand experiences and reactions. Living with these memories and flashbacks was interpreted as a journey in quest of meaning. Having someone and something to live for implied strength on the journey. The presence of close relatives at the bedside provided strength to go on and someone with whom to share experiences afterwards. A period of critical illness and intensive care stay for treatment may leave durable traces in the patient's life. Finding meaning of existential and ontological nature seems to be of decisive significance for how people fare in their lives after having lived through intensive care treatment. The identified journey in quest of meaning points to the need for follow-up programmes, and we must acknowledge close relatives as important resources for the patient both at the bedside and in the subsequent process of discovering meaning in lived experience.


Interaction of human papillomavirus type 16 and adeno-associated virus type 2 co-infecting human cervical epithelium.
Recently, we hypothesized that the tumour-suppressive, human helper-virus-dependent, adeno-associated parvoviruses (AAV) may interfere with transforming functions of human papillomaviruses (HPV) in the development of cervical carcinoma. Here, we demonstrate that in cervical epithelium containing papillomavirus DNA, AAV DNA can be detected in a replication-competent form and that AAV proteins are expressed. In cultured cells containing integrated AAV-2 DNA, transfection of HPV-16 DNA induced rescue of infectious AAV-2, revealing helper functions of HPV-16. Similarly, cotransfection of HPV-16 and AAV-2 DNAs into human epithelial cell lines led to replication of AAV-2, and, in keratinocytes, to a cytopathic effect. These data suggest an interaction of the two viruses, possibly influencing the development of HPV-related lesions.


CD100 is associated with CD45 at the surface of human T lymphocytes. Role in T cell homotypic adhesion.
CD100 is a 150-kDa human surface glycoprotein implicated in T cell activation. Using BB18 and BD16 mAbs to two discrete epitopes of the CD100 molecule, we have shown previously that triggering the CD100 molecule through the BB18 epitope is comitogenic with PMA, whereas it lacks a detectable effect on CD2- and CD3-induced PBMC proliferation. Conversely, triggering the CD100 molecule through the BD16-defined epitope only exerts an effect on CD2- and CD3-induced PBMC proliferation. In the present study, we investigated the molecular relationship between CD100 and another surface structure involved in human T cell proliferation, the CD45 phosphatase. We show in this study that CD100 is associated with CD45 and that this association has functional significance. The association was demonstrated using coimmunoprecipitation and detection of CD45 enzymatic PTPase activity. Furthermore, we show that the association is increased during T cell activation and that triggering CD45 molecules through discrete epitopes induces the down-modulation of CD100 molecules at the cell surface. Interestingly, we demonstrate that this modulation could be attributed to the shedding of a soluble form of CD100 in the culture supernatant. Finally, one of the functional consequences of this T cell activation-induced CD100-CD45 association is revealed by the finding that CD100 mAbs have an effect on CD45-induced T cell aggregation.


Virtual morphometric method using seven cervical vertebrae for sex estimation on the Turkish population.
Sex estimation from skeletal remains is crucial for the estimation of the biological profile of an individual. Although the most commonly used bones for means of sex estimation are the pelvis and the skull, research has shown that acceptable accuracy rates might be achieved by using other skeletal elements such as vertebrae. This study aims to contribute to the development of sex estimation standards from a Turkish population through the examination of CT scans from the seven cervical vertebrae. A total of 294 individuals were included in this study. The CT scans were obtained from patients attending the Bakirkoy Training and Research Hospital (Turkey) and the data was collected retrospectively by virtually taking measurements from each cervical vertebrae. The full database was divided into a training set (N = 210) and a validation set (N = 84) to test the fit of the models. Observer error was assessed through technical error of measurement and sex differences were explored using parametric and non-parametric approaches. Logistic regression was applied in order to explore different combinations of vertebral parameters. The results showed low intra- and inter-observer errors. All parameters presented statistically significant differences between the sexes and a total of 15 univariate and multivariate models were generated producing accuracies ranging from a minimum of 83.30% to a maximum of 91.40% for a model including three parameters collected from four vertebrae. This study presents a virtual method using cervical vertebrae for sex estimation on the Turkish population providing error rates comparable to other metric studies conducted on the postcranial skeleton. The presented results contribute not only to the development of population-specific standards but also to the generation of virtual methods that can be tested, validated, and further examined in future forensic cases.


Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer.
In a previous study (J Clin Oncol 7:1407-1417, 1989), we identified two dosage administration schedules of fluorouracil (5FU) combined with leucovorin that were superior to single-agent 5FU for the treatment of advanced colorectal cancer. In this same study, a regimen of 5FU plus high-dose methotrexate (MTX) demonstrated a suggestive advantage over 5FU alone. To permit a more definitive comparison, we have extended our evaluation of these three regimens to involve an additional 259 patients. In all, 457 patients with advanced colorectal cancer were randomly assigned to one of the following regimens: 5FU plus low-dose leucovorin, 5FU plus high-dose leucovorin, or 5FU plus high-dose MTX with leucovorin rescue. We have found that each of the 5FU/leucovorin regimens demonstrates a significant (P less than or equal to .01) advantage over 5FU plus high-dose MTX for objective tumor response and interval to tumor progression. Moreover, 5FU plus low-dose leucovorin confers a significant survival benefit (P less than or equal to .01) compared with 5FU plus high-dose MTX. The 5FU plus high-dose leucovorin regimen shows a survival benefit only in unadjusted analyses (P = .04), but this difference is not significant when adjusted for imbalances in prognostic variables (P = .44). Evaluation of the two 5FU/leucovorin regimens rules out a 10% decrease in death rate for the high-dose leucovorin regimen compared with the low-dose leucovorin regimen (P less than .05). The regimen of 5FU plus low-dose leucovorin has now been shown to offer a statistically significant survival advantage versus 5FU alone and versus 5FU plus high-dose MTX, a regimen that had shown promise in earlier trials. These data confirm the efficacy of leucovorin combined with 5FU in patients with advanced colorectal cancer and establish that it is not necessary to use high doses of leucovorin to achieve these results.


Evaluation and Comparison of Spray Equipment for Indoor Residual Spraying.
The World Health Organization (WHO) has recently recommended indoor residual spraying (IRS) as part of a vector control strategy to combat Aedes-borne diseases, including dengue, chikungunya, and Zika viruses. Hand compression sprayers have been used in malaria prevention and control programs worldwide since the 1950s and are a standard for IRS application. However, there are technological advances that should be considered to improve IRS application (e.g., flow-control valves, rechargeable-battery equipment, reduced-drift nozzles, etc.), particularly if interventions are performed in urban areas to target Aedes aegypti. Using WHO guidelines, we contrasted technical characteristics of potential IRS equipment including hand compression sprayers (Hudson X-pert, Goizper IK Vector Control Super), rechargeable-battery sprayers (Solo 416, Birchmeier REC 15ABZ, Hudson NeverPump), and motorized sprayers (Honda WJR 2525, Kawashima AK35GX). Measurements included flow rate, droplet size, battery/fuel life, and technical/physical characteristics. Flow rate, the most important parameter, of the Hudson X-pert was stabilized at 550 ml/min by the use of a control flow valve (CFV). The IK Vector Control Super had integrated CFVs and produced a similar flow as the Hudson X-pert. Rechargeable-battery equipment provided consistent flow as well as negligible noise. Motorized sprayers also produced consistent flow, but their weight, high noise pollution when used indoors, and high engine temperature made them highly unpleasant for technicians. We identify alternatives to the more traditional hand compression Hudson X-pert sprayer with technical and operational considerations for performing IRS.


Redefining the role of clinical nurse specialists.
Leadership in a time of change requires personal and professional skills. As nursing responds to the evolving health care environment, the advanced skills of the clinical nurse specialist (CNS) are needed to promote a relationship with the client that is holistic and fiscally responsible. Positioned within vertically integrated corporations as community case manager, the CNS has an opportunity to bring innovative interpretations to the roles of practitioner, consultant, educator, and researcher.


Measuring activity and participation in children and adolescents with disabilities: a literature review of available instruments.
This article aims to (1) identify instruments available to measure activity and participation in children with disabilities; (2) describe the reliability and validity of these instruments; and (3) consider whether the available instruments capture the extent of involvement, as well as the difficulty and satisfaction/enjoyment associated with performance in all life areas. A literature review was completed by undertaking an electronic search to identify instruments that measure activity and participation in children with disabilities. A further electronic search was conducted to obtain an adequate description of the instruments, including psychometric properties. The search identified 20 instruments purporting to measure activity and participation, however, no single instrument measured extent of involvement, difficulty and satisfaction/enjoyment in all life areas. There were instances in which each of these aspects was captured, but not within the one instrument. Instruments assessed combinations of frequency, difficulty, assistance, environment and satisfaction across varying contexts, for example, school, domestic life, recreational tasks, leisure tasks or all life areas. Although a large number of instruments exist to measure varying aspects of activity and participation, there is currently no single instrument available to measure the extent of involvement, difficulty and satisfaction/enjoyment in all life areas. This finding indicates that there is the opportunity to develop a single instrument to measure activity and participation across all life areas.


[Fracture of the femoral neck and osteoporosis].
The authors have established that osteoporosis is noted in the age above 70 years old--in 70-80% and above 80 years old--in all of the patients. That's why while treating the fractures of neck of the femur (NF) in the patients aged older than 60 years the osteosynthesis is not recommended. The stump joint endoprosthesis may be a method of choice. It is expedient to prescribe antiresorptive preparations phosamax, myacalcique and preparations of calcium in the complex of treatment.


A method for S- and O-palmitoylation of peptides: synthesis of pulmonary surfactant protein-C models.
A method for O- and S-palmitoylation of non-protected peptides has been developed. The peptides are treated with excess of palmitoyl chloride in 100% trifluoroacetic acid for 10 min at room temperature. The acidic conditions prevent acylation of amino groups, which is only significant after prolonged treatment (hours to days). The tripeptides Gly-Cys-Phe and Gly-Ser-Phe were converted into the respective S- and O-palmitoylated compounds, and the hydrophobic pulmonary surfactant protein-C model peptides, LRIPCCPVNLKRLLVVV [SP-C(1-17)] and FGIPSSPVLKRLLILLLLLLLILLLILGALLMGL [SP-C(Leu)] were converted into their respective S,S- and O,O-dipalmitoylated peptides. The reactions were virtually quantitative, and the palmitoylated peptides were isolated in about 75-80% yield after reversed-phase HPLC purification. CD spectroscopy showed that S, S-dipalmitoylation of SP-C(1-17) affects the peptide secondary structure (substantial increase in the alpha-helix content) in dodecylphosphocholine micelles.


Diagnostic and outcome differences between heterosexual and nonheterosexual men treated for prostate cancer.
To determine if heterosexual and nonheterosexual men treated for prostate cancer differ in diagnostic and treatment outcomes and in various measures of physical health, sexual function, and well being, before and after the treatment. Four hundred sixty self-identified heterosexual and 96 self-identified nonheterosexual men completed an anonymous online survey. The men in the 2 groups were then compared using logistic regressions that controlled for differences among countries. There were no significant differences in age at diagnosis for men in the 2 groups. However, Gleason scores at diagnosis were significantly lower for the nonheterosexual men (P = .02). There were no significant differences among men in the 2 groups in the proportion who receive different treatment modalities or in the incidence of urinary incontinence, who experience bone pain (as a marker of disease progression), who take antidepressants (as a proxy measure for mental health), or who experience erectile dysfunction after the treatment. However, nonheterosexual men rated the degree to which they were bothered by an inability to ejaculate significantly higher than did the heterosexual men (P = .04). This is the first set of findings from a survey that compares heterosexual and nonheterosexual men treated for prostate cancer. Although the groups were generally similar, nonheterosexual men might experience more intensive screening for disease, as indicated by lower Gleason scores at diagnosis. Nonheterosexual men appear more distressed by loss of ejaculation after prostatectomy.


[Communication management of collaborative networks of science, technology and innovation in health].
The objective of the article was to propose a model of communication management of networks for the Health Innovation System in Brazil. The health production complex and its relationship with the nation's development are addressed and some suggestions for operationalization of the proposed model are also presented. The discussion is based on Habermas' theory and similar cases from other countries. Communication strategies and approaches to commitment dialogue for concerted actions and consensus-building based on critical reasoning may help strengthen democratic networks.


Equivalence of regression curves sharing common parameters.
In clinical trials, the comparison of two different populations is a common problem. Nonlinear (parametric) regression models are commonly used to describe the relationship between covariates, such as concentration or dose, and a response variable in the two groups. In some situations, it is reasonable to assume some model parameters to be the same, for instance, the placebo effect or the maximum treatment effect. In this paper, we develop a (parametric) bootstrap test to establish the similarity of two regression curves sharing some common parameters. We show by theoretical arguments and by means of a simulation study that the new test controls its significance level and achieves a reasonable power. Moreover, it is demonstrated that under the assumption of common parameters, a considerably more powerful test can be constructed compared with the test that does not use this assumption. Finally, we illustrate the potential applications of the new methodology by a clinical trial example.


Successful pregnancies on nocturnal home hemodialysis.
Women of childbearing age on conventional hemodialysis (CHD) have decreased fertility when compared with the general population. Even in women who conceived, maternal morbidity and fetal mortality remained elevated. We hypothesized that nocturnal hemodialysis (NHD) (3 to 6 sessions per week, 6 to 8 h per treatment), by augmenting uremic clearance, leads to a more hospitable maternal environment and therefore superior outcomes in fertility and pregnancy compared with CHD. This is a descriptive cohort study of all female patients achieving pregnancy and delivering a live infant while on NHD at the University Health Network, St. Michael's Hospital, and Humber River Regional Hospital from 2001 to 2006 in Toronto, Canada. Our primary objective was to describe maternal and fetal outcomes in addition to the changes in biochemical parameters after conception in our cohort. Our cohort included five patients (age range, 31 to 37 yr) who had seven pregnancies while on NHD and delivered six live infants. All had previously been on CHD, but none conceived during that time. In all patients, the amount of hemodialysis was increased (from a weekly mean of 36 +/- 10 to 48 +/- 5 h; P < 0.01) after pregnancy was diagnosed. Mean predialysis blood urea and mean arterial BP were maintained within normal physiological parameters. The mean gestational age of the cohort was 36.2 +/- 3 wk and the mean birth weight was 2417.5 +/- 657 g. The maternal and fetal complications observed in the cohort included intrauterine growth restriction or small for gestational age (n = 2), preterm delivery (<32 wk) (n = 1), and shortened cervix threatened labor (n = 1). Anemia was accentuated during pregnancy, and intravenous iron and erythropoietin requirements were increased. To maintain normal physiological indices for plasma phosphate, an augmented dialysate phosphate supplementation regimen was required. NHD may allow for improved fertility. Delivering a live infant at a mature gestational age is feasible for patients on NHD. Our cohort tended to have fewer maternal and fetal complications compared with historical controls. Hemoglobin and phosphate levels must be monitored with treatment adjusted accordingly.


Recent advances in neuraminidase inhibitor development as anti-influenza drugs.
The recent emergence of the highly pathogenic H5N1 subtype of avian influenza virus (AIV) and of the new type of human influenza A (H1N1) have emphasized the need for the development of effective anti-influenza drugs. Presently, neuraminidase (NA) inhibitors are widely used in the treatment and prophylaxis of human influenza virus infection, and tremendous efforts have been made to develop more potent NA inhibitors to combat resistance and new influenza viruses. In this review, we discuss the structural characteristics of NA catalytic domains and the recent developments of new NA inhibitors using structure-based drug design strategies. These drugs include analogues of zanamivir, analogues of oseltamivir, analogues of peramivir, and analogues of aromatic carboxylic acid and present promising options for therapeutics or leads for further development of NA inhibitors that may be useful in the event of a future influenza pandemic.


Naringenin inhibits migration of lung cancer cells via the inhibition of matrix metalloproteinases-2 and -9.
Lung cancer is among the most common causes of cancer-related mortality. It has a high mortality rate and resistance to chemotherapy due to its high metastatic potential. Naringenin, a bioactive compound identified in several fruits, displays anti-inflammatory and antitumor effects. Furthermore, naringenin mitigates the migration of several human cancer cell types. However, the effects of naringenin on lung cancer remain unclear. The current study investigated the mechanisms of naringenin on the migration of lung cancer A549 cells. The results indicate that significant alteration in A549 cell proliferation was observed in response to naringenin (0-300 µM) treatment for 24 and 48 h. Furthermore, a dose-dependent migration inhibition of A549 in the presence of naringenin was observed by healing and transwell migration assays. In addition, a zymography assay revealed that naringenin exhibited a concentration-dependent inhibition of matrix metalloproteinase (MMP)-2 and -9 activities. Furthermore, naringenin also inhibited the activities of AKT in a dose-dependent manner. These observations indicated that naringenin inhibited the migration of lung cancer A549 cells through several mechanisms, including the inhibition of AKT activities and reduction of MMP-2 and -9 activities.


Effect of adverse environmental conditions and protective clothing on temperature rise in a human body exposed to radiofrequency electromagnetic fields.
This study considers the computationally determined thermal profile of a finely discretized, heterogeneous human body model, simulating a radiofrequency electromagnetic field (RF-EMF) worker wearing protective clothing subject to RF-EMF exposure, and subject to various environmental conditions including high ambient temperature and high humidity, with full thermoregulatory mechanisms in place. How the human body responds in various scenarios was investigated, and the information was used to consider safety limits in current international RF-EMF safety guidelines and standards. It was found that different environmental conditions had minimal impact on the magnitude of the thermal response due to RF-EMF exposure, and that the current safety factor of 10 applied in international RF-EMF safety guidelines and standards for RF-EMF workers is generally conservative, though it is only narrowly so when workers are subjected to the most adverse environmental conditions. Bioelectromagnetics. 38:356-363, 2017. © 2017 Wiley Periodicals, Inc.


A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan, and the penetrance rates in children with WT1 germline mutation.
Bilateral Wilms tumours (BWTs) occur by germline mutation of various predisposing genes; one of which is WT1 whose abnormality was reported in 17-38% of BWTs in Caucasians, whereas no such studies have been conducted in East-Asians. Carriers with WT1 mutations are increasing because of improved survival. Statuses of WT1 and IGF2 were examined in 45 BWTs from 31 patients with WT1 sequencing and SNP array-based genomic analyses. The penetrance rates were estimated in WT1-mutant familial Wilms tumours collected from the present and previous studies. We detected WT1 abnormalities in 25 (81%) of 31 patients and two families, which were included in the penetrance rate analysis of familial Wilms tumour. Of 35 BWTs from the 25 patients, 31 had small homozygous WT1 mutations and uniparental disomy of IGF2, while 4 had large 11p13 deletions with the retention of 11p heterozygosity. The penetrance rate was 100% if children inherited small WT1 mutations from their fathers, and 67% if inherited the mutations from their mothers, or inherited or had de novo 11p13 deletions irrespective of parental origin (P=0.057). The high incidence of WT1 abnormalities in Japanese BWTs sharply contrasts with the lower incidence in Caucasian counterparts, and the penetrance rates should be clarified for genetic counselling of survivors with WT1 mutations.


Relationships: importance for patients with cerebral tumours.
To investigate the influence of relationships on psychosocial status in patients with Stage III and IV brain tumours. Thirty-three outpatients at a university medical centre were referred to the study by their treating physician prior to the initiation of aggressive chemotherapy. All subjects underwent a comprehensive psychosocial assessment. Depressive and anxious complaints were common, but not related to gender. Single/divorced status suggested greater vulnerability to anxiety as 88% of singles and only 48% of patients with partners reported clinical levels of anxiety. Single patients' anxiety was related to inactivity (r = 0.78, p < 0.05) and fears of financial difficulties (r = 0.72, p < 0.05). State and trait anxiety related differently to married patients' complaints. Married patients more frequently reported clinical levels of depressive symptoms (44% partnered vs 28% singles). Depression among married patients was predicted by problems with sex, finances, marital difficulties, and inactivity [R2 = 0.803; F = 20.420, df(4,20), p < 0.0001)]. Problems with relationships were disassociated from problems with sex. Married patients' problematic relationships were predicted by overprotection, inactivity, concerns of bodily deterioration, depression, and anxiety [R2 = 0.775, F = 13.060, df(5, 19) < 0.0001]. Married neuro-oncology patients may experience depressive symptoms arising from the marriage, but appear to be buffered from anxiety when compared with single/divorced patients. The prevalence of anxiety among single patients suggests modifications of interventions by relationship status.


Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma.
Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)-expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs). To test this hypothesis in our in vivo preclinical model, we treated mice bearing intracranial gliomas with DC vaccination ± murine anti-PD-1 monoclonal antibody (mAb) blockade or a colony stimulating factor 1 receptor inhibitor (CSF-1Ri) (PLX3397) and measured overall survival. We then harvested and characterized the PD-L1+ TIM population and its role in TIL activation and tumor cytolysis in vitro. Our data indicated that the majority of PD-L1 expression in the GBM environment is contributed by TIMs rather than by tumor cells themselves. While PD-1 blockade partially reversed the TIL dysfunction, targeting TIMs directly with CSF-1Ri altered TIM expression of key chemotactic factors associated with promoting increased TIL infiltration after vaccination. Neither PD-1 mAb nor CSF-1Ri had a demonstrable therapeutic benefit alone, but when combined with DC vaccination, a significant survival benefit was observed. When the tripartite regimen was given (DC vaccine, PD-1 mAb, PLX3397), long-term survival was noted together with an increase in the number of TILs and TIL activation. Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.


Hippocampal place cells: the "where" of episodic memory?
Neuropsychologists have clearly implicated the hippocampus in the consolidation of memory, particularly episodic memory, the mental replay of past experiences. When recorded from behaving animals, by far the most obvious firing pattern of the primary neurons of the hippocampus is the place field: a cell tends to fire only when the animal's head is in a particular part of its environment. It seems reasonable to suspect that the primary firing correlate of the primary neurons of a structure should underlie the primary function of that structure as revealed by behavioral lesion experiments. However, we are currently still at a loss to explain how the firing of hippocampal neurons contributes to hippocampal function. This review seeks to examine the commonalities between place cells and episodic memory, and posits that an analogy can be made between the stabilization of place fields and the consolidation of memory.


GC-MS profiling of Pistachio vera L., and effect of antioxidant and antimicrobial compounds of it's essential oil compared to chemical counterparts.
All elements of the pistachio tree are considered raw pistachio by-products. The soft hull makes up the majority of these by-products. It contains proteins, fats, minerals, vitamins, phenolics contents (TPC), and antioxidants. Early smiling pistachios are one of the most important sources of pistachio contamination with aflatoxin in the garden and processing stages. The present study aimed to evaluate pistachio hull essential oil (EO) composition, and antioxidant and antimicrobial properties under in vitro conditions. TPC, antioxidant, and antimicrobial activity were measured using the Folin-Ciocalteu reagent, 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging method, and serial dilution titration method, respectively. A gas chromatography system with a mass spectrometer (GC-MS) was utilized to determine the chemical components of the EO. The findings revealed that the quantity of TPC and anti-radical activity in IC50 were 245.43 mg gallic acid/mL and 206.32 µL/L, respectively. The free radical absorption activity of DPPH (%) increased with EO content. The inhibitory activity of EO on Staphylococcus aureus and Bacillus subtilis was much lower than that of streptomycin and penicillin. Aspergillus flavus was effectively inhibited by pistachio hull EO, comparable to fluconazole. The results obtained from GC-MS showed that the major compounds in pistachio hull essential oil include α-pinene (47.36%), terpinolene (10.57%), limonene (9.13%), and L-bornyl acetate (8.57%). The findings indicated that pistachio hull EO has potent antibacterial and antioxidant components and can be employed as a natural antimicrobial and antioxidant in food systems.


BRAF Mutation Testing and Metastatic Colorectal Cancer in the Community Setting: Is There an Urgent Need for More Education?
Patients with metastatic colorectal cancer (mCRC) with BRAF mutation (BRAF MT) generally have a poorer prognosis. BRAF MT may also have implications for treatment strategy. Despite this, inclusion of BRAF in routine molecular testing varies. Here we report the frequency of BRAF reporting in the South Australian (SA) mCRC registry reflecting community practice, together with the survival outcomes based on mutation status. The SA population-based mCRC registry was analysed to assess the number of patients where a BRAF MT result was available. The patient characteristics are reported and overall survival was analysed using the Kaplan-Meier method. Of the 3639 patients who have been entered in the registry, only 6.2% (227) have BRAF MT results available. Of the patients tested, the BRAF MT rate is 12.7%. The mutation rate was highest in rightsided primary; right colon 23 versus left colon 8.9% and rectum 7%. There was no significant difference in median age or male/female proportion. The median overall survival (mOS) for BRAF MT versus wild-type (WT) patients is 14.0 versus 32.9 months (p = 0.003). For patients who have chemotherapy (plus or minus surgery) the mOS is 14.6 months BRAF MT versus 36.1 months (p ≤ 0.001) WT. Liver or lung resection was performed on only 8% of the BRAF MT group versus 26.5% of the WT group. Results in a population setting confirm our understanding that BRAF MT is more frequently right sided and of lower frequency in rectal cancer. Survival is lower for patients with mCRC that have BRAF MT, regardless of the therapy. BRAF testing is currently performed infrequently in an Australian setting despite its importance as a significant prognostic factor, and the implications for alternate therapeutic approaches.


Generation of Human Fatty Livers Using Custom-Engineered Induced Pluripotent Stem Cells with Modifiable SIRT1 Metabolism.
The mechanisms by which steatosis of the liver progresses to non-alcoholic steatohepatitis and end-stage liver disease remain elusive. Metabolic derangements in hepatocytes controlled by SIRT1 play a role in the development of fatty liver in inbred animals. The ability to perform similar studies using human tissue has been limited by the genetic variability in man. We generated human induced pluripotent stem cells (iPSCs) with controllable expression of SIRT1. By differentiating edited iPSCs into hepatocytes and knocking down SIRT1, we found increased fatty acid biosynthesis that exacerbates fat accumulation. To model human fatty livers, we repopulated decellularized rat livers with human mesenchymal cells, fibroblasts, macrophages, and human SIRT1 knockdown iPSC-derived hepatocytes and found that the human iPSC-derived liver tissue developed macrosteatosis, acquired proinflammatory phenotype, and shared a similar lipid and metabolic profiling to human fatty livers. Biofabrication of genetically edited human liver tissue may become an important tool for investigating human liver biology and disease.


Heterogenous Effect of Risk Factors on Breast Cancer across the Breast Density Categories in a Korean Screening Population.
We evaluated the heterogeneity of the effect of known risk factors on breast cancer development based on breast density by using the Breast Imaging-Reporting and Data System (BI-RADS). In total, 4,898,880 women, aged 40-74 years, who participated in the national breast cancer screening program in 2009-2010 were followed up to December 2018. Increased age showed a heterogeneous association with breast cancer (1-year hazard ratio (HR) = 0.92, 1.00 (reference), 1.03, and 1.03 in women with BI-RADS density category 1, 2, 3, and 4, respectively; P-heterogeneity < 0.001). More advanced age at menopause increased breast cancer risk in all BI-RADS categories. This was more prominent in women with BI-RADS density category 1 but less prominent in women in other BI-RADS categories (P-heterogeneity = 0.009). In postmenopausal women, a family history of breast cancer, body mass index ≥ 25 kg/m2, and smoking showed a heterogeneous association with breast cancer across all BI-RADS categories. Other risk factors including age at menarche, menopause, hormone replacement therapy after menopause, oral contraceptive use, and alcohol consumption did not show a heterogeneous association with breast cancer across the BI-RADS categories. Several known risk factors of breast cancer had a heterogeneous effect on breast cancer development across breast density categories, especially in postmenopausal women.


The PilA protein of non-typeable Haemophilus influenzae plays a role in biofilm formation, adherence to epithelial cells and colonization of the mammalian upper respiratory tract.
We recently described the expression of type IV pili (Tfp) by non-typeable Haemophilus influenzae (NTHI), a common respiratory tract pathogen. Prior to that report, Tfp were not thought to be produced by NTHI as they are not observed on NTHI when grown on chocolate agar or other commonly used growth media. To further characterize growth conditions permissive for the expression of NTHI Tfp, as well as determine their role in colonization and virulence, we transformed an NTHI otitis media isolate with a reporter plasmid containing the lux gene cluster driven by the pilA promoter. Transcription from the pilA promoter was demonstrated under a variety of in vitro growth conditions and, importantly, by ex vivo imaging of luciferase-producing NTHI in infected chinchillas. Luciferase-producing NTHI were also identified within a biofilm formed by NTHI in vivo. We further demonstrated a role for NTHI PilA in adherence to human respiratory epithelial cells, in colonization of the chinchilla respiratory tract as well as a requirement for PilA in biofilm development, both in vitro and in vivo. Collectively, our data demonstrate that NTHI express PilA in vivo, and that PilA plays an important role in the pathogenesis of an upper respiratory tract infection induced by NTHI.


Do Health Care Providers Use Online Patient Ratings to Improve the Quality of Care? Results From an Online-Based Cross-Sectional Study.
Physician-rating websites have become a popular tool to create more transparency about the quality of health care providers. So far, it remains unknown whether online-based rating websites have the potential to contribute to a better standard of care. Our goal was to examine which health care providers use online rating websites and for what purposes, and whether health care providers use online patient ratings to improve patient care. We conducted an online-based cross-sectional study by surveying 2360 physicians and other health care providers (September 2015). In addition to descriptive statistics, we performed multilevel logistic regression models to ascertain the effects of providers' demographics as well as report card-related variables on the likelihood that providers implement measures to improve patient care. Overall, more than half of the responding providers surveyed (54.66%, 1290/2360) used online ratings to derive measures to improve patient care (implemented measures: mean 3.06, SD 2.29). Ophthalmologists (68%, 40/59) and gynecologists (65.4%, 123/188) were most likely to implement any measures. The most widely implemented quality measures were related to communication with patients (28.77%, 679/2360), the appointment scheduling process (23.60%, 557/2360), and office workflow (21.23%, 501/2360). Scaled-survey results had a greater impact on deriving measures than narrative comments. Multilevel logistic regression models revealed medical specialty, the frequency of report card use, and the appraisal of the trustworthiness of scaled-survey ratings to be significantly associated predictors for implementing measures to improve patient care because of online ratings. Our results suggest that online ratings displayed on physician-rating websites have an impact on patient care. Despite the limitations of our study and unintended consequences of physician-rating websites, they still may have the potential to improve patient care.


Evidence for particle-induced horizontal gene transfer and serial transduction between bacteria.
Incubation of the amino acid-deficient strain Escherichia coli AB1157 with particles harvested from an oligotrophic environment revealed evidence of horizontal gene transfer (HGT) with restoration of all deficiencies in revertant cells with frequencies up to 1.94 × 10(-5). None of the markers were preferentially transferred, indicating that the DNA transfer is performed by generalized transduction. The highest gene transfer frequencies were obtained for single markers, with values up to 1.04 × 10(-2). All revertants were able to produce particles of comparable size, appearing at the beginning of the stationary phase. Examination of the revertants using electron microscopy showed bud-like structures with electron-dense bodies. The particles that display the structural features of membrane vesicles were again infectious to E. coli AB1157, producing new infectious particles able to transduce genetic information, a phenomenon termed serial transduction. Thus, the <0.2-μm particle fraction from seawater contains a particle size fraction with high potential for gene transfer. Biased sinusoidal field gel electrophoresis indicated a DNA content for the particles of 370 kbp, which was higher than that of known membrane vesicles. These findings provide evidence of a new method of HGT, in which mobilizable DNA is trafficked from donor to recipient cells via particles.


Changes in dispositional empathy in American college students over time: a meta-analysis.
The current study examines changes over time in a commonly used measure of dispositional empathy. A cross-temporal meta-analysis was conducted on 72 samples of American college students who completed at least one of the four subscales (Empathic Concern, Perspective Taking, Fantasy, and Personal Distress) of the Interpersonal Reactivity Index (IRI) between 1979 and 2009 (total N = 13,737). Overall, the authors found changes in the most prototypically empathic subscales of the IRI: Empathic Concern was most sharply dropping, followed by Perspective Taking. The IRI Fantasy and Personal Distress subscales exhibited no changes over time. Additional analyses found that the declines in Perspective Taking and Empathic Concern are relatively recent phenomena and are most pronounced in samples from after 2000.


The impact of bio-logging on body weight change of the Eurasian beaver.
Bio-logging is a common method to collect ecological data on wild animals, but might also induce stress, reduce body condition, and alter behavior. Eurasian beavers (Castor fiber) are a semi-aquatic and nocturnal species that are challenging to observe in the wild. Bio-loggers are hence useful tools to study their behaviour and movements, but this raises concerns of potential negative impacts of tagging. To investigate the potential negative impacts of glue-on tags, we compared body weight change for tagged and untagged Eurasian beavers. We hypothesized that tagged beavers would gain less body weight compared to untagged beavers, and that weight change might be affected by tagging length, tag weight, water temperature and the season of tagging. Daily percentage body weight change in relation to initial body weight during the first capture was compared during 57 tagging periods (18±7 days) and 32 controls periods (64±47 days). Body weight change varied between the two groups, with untagged beavers on average gaining daily weight whilst tagged beavers on average lost weight daily, indicating a negative effect of tagging. The average reduction in percentage body weight change per day for tagged beavers was small (0.1 ± 0.3%), and with large individual variation. Neither tag weight, number of tagging days, nor season were important in explaining body weight change of tagged animals. In other words, we found that tagging reduced daily body weight during the tagging period but were unable to determine the mechanism(s) responsible for this decline. Detrimental effects of tagging have important implications for animal welfare and can introduce bias in data that are collected. This calls for careful consideration in the use of tags. We conclude that studies investigating the effects of tagging should consider individual variation in the effects of tagging and, where possible, compare tagged animals with a control group.


Impact of race and ethnicity on outcomes after autologous stem cell transplantation for patients with newly diagnosed multiple myeloma.
Non-Hispanic Black patients are disproportionally affected by multiple myeloma (MM) and whether efficacy outcomes after autologous stem cell transplant (ASCT) differ by race and ethnicity remains an area of active investigation. This study included 449 patients enriched with a large proportion of non-Hispanic Black patients and sought to highlight the impact of race and ethnicity on outcomes after HDT-ASCT for patients with newly diagnosed MM. We found induction chemotherapy followed by high-dose therapy-ASCT and maintenance chemotherapy is associated with long-term PFS and OS, regardless of race or ethnicity.


Ischemic Stroke or Systemic Embolism After Transseptal Ablation of Arrhythmias in Patients With Cardiac Implantable Electronic Devices.
Incidental mobile thrombi are commonly found on endovascular leads of cardiac implantable electronic devices (CIEDs). Transseptal puncture for catheter ablation of arrhythmia poses a risk for paradoxical embolism. We examined risk of ischemic stroke, transient ischemic attack (TIA), or systemic embolism after transseptal ablation in patients with and without CIEDs. Using a national administrative claims database, 31 720 patients who underwent a transseptal catheter ablation between January 2004 and September 2014 were identified. Two propensity-matched cohorts were created by matching demographic variables, administrative variables, Charlson Comorbidity Index, CHA2DS2-Vasc score, and year and indication for ablation (5533 and 11 300 patients with and without CIEDs). Incidence rates and Cox proportional hazards models were used to estimate risk of ischemic stroke, TIA, or systemic embolism for patients with and without CIEDs. Impact of oral anticoagulation (OAC) use on the endpoint was examined. Over a mean follow-up of 2.1 years, the incidence of the combined endpoint was 1.9 per 100 person-years in patients with CIEDs and 1.5 per 100 person-years in patients without CIEDs (P=0.03). Among patients not on OAC, presence of a cardiac device was associated with an increased risk (hazard ratio [HR], 1.71 [1.24-2.35]; P<0.01), whereas there was no association noted among patients treated with OAC (HR, 0.98 [0.75-1.28]). CIEDs are associated with an increased risk of stroke, TIA, or systemic embolism after transseptal ablation, but this risk is attenuated with postablation OAC use. Role of anticoagulation post-transseptal ablation in patients with CIED warrants further investigation.


Suicide mortality by occupation in Canada, 1991-2001.
To describe the association between occupation and risk of suicide among working-age men and women in Canada. This study of suicide mortality over an 11-year period is based on a broadly representative 15% sample of the noninstitutionalized population of Canada aged 30 to 69 years at cohort inception. Age-standardized mortality rates (ASMRs) and rate ratios were calculated for men and women in 5 categories of skill level and 80 specific occupational groups, as well as for people not occupationally active. The suicide mortality rate was 20.1/100 000 person years for occupationally active men (during 9 600 000 person years of follow-up) and 5.3/100 000 person years for occupationally active women (during 8 100 000 person years of follow-up). Among occupationally active men, elevated rates of suicide mortality were observed for 9 occupational groups and protective effects were observed for 6 occupational groups. Among women, elevated rates of suicide were observed in 4 occupational groups and no protective effects were observed. For men and women, ASMRs for suicide were inversely related to skill level. The limited number of associations between occupational groups and suicide risk observed in this study suggests that, with few exceptions, the characteristics of specific occupations do not substantially influence the risk for suicide. There was a moderate gradient in suicide mortality risk relative to occupational skill level. Suicide prevention strategies in occupational settings should continue to emphasize efforts to restrict and limit access to lethal means, one of the few suicide prevention policies with proven effectiveness.


Improving the availability of antihypertensive drugs in the India Hypertension Control Initiative, India, 2019-2020.
Antihypertensive drug supply is sometimes inadequate in public sector health facilities in India. One of the core strategies of the India Hypertension Control Initiative (IHCI) is to improve the availability of antihypertensive drugs in primary and secondary care facilities. We quantified the availability of antihypertensive drugs in 2019-20 and described the practices in supply chain management in 22 districts across four states of India. Twenty-two districts from 4 states (Punjab, Madhya Pradesh, Telangana, and Maharashtra) were studied. We described the practices and challenges in supply chain management. We collected data on drug procurement from 2018 to 2020 and drug availability from April 2019 to March 2020. Quantity procured, the proportion of facilities with stockout at the end of each quarter, and availability of drugs in patient days were tabulated. All states selected drug- and dose-specific protocols with Amlodipine as the initial drug and shifted to morbidity-based forecasting. The total number of antihypertensive tablets procured for the 22 districts increased from 16 million in 2017-2018 to 160 million in 2019-2020. The proportion of facilities with Amlodipine stock-out was below 5% during the study period. Amlodipine stock was available for at least 60 patient days from the third quarter of 2019 onward in all districts. This study demonstrates that including best practices can gradually strengthen the procurement and supply chain for antihypertensives in a low-resource setting. As the program was rapidly growing, there were still gaps in the procurement and distribution system which needed to be addressed to ensure the adequacy of drugs. We recommend that best practices, including choosing a single protocol, basing supply on projected patient load rather than an increment from historical levels, and using simple stock management tools, be replicated in other districts in India to increase and sustain coverage of hypertension treatment.


Free-radical side-chain bromination of alkylaromatics in supercritical carbon dioxide.
Free-radical side-chain brominations of alkylaromatics in supercritical carbon dioxide (SC-CO(2)) are reported. Direct bromination of toluene and ethylbenzene form the corresponding benzyl bromides in high yield. The observed selectivity in SC-CO(2) is similar to that observed in conventional organic solvents. Also, SC-CO(2) is an effective alternative to carbon tetrachloride for use in the classical Ziegler bromination with N-bromosuccinimide. Reaction yields are high, side products are minimized, and bromine-atom selectivities are observed. Thus, SC-CO(2) must be useful as a viable, environmentally benign substitute for many of the solvents typically used for free-radical reactions.


Coherent imaging using laser feedback interferometry with pulsed-mode terahertz quantum cascade lasers.
We report a coherent terahertz (THz) imaging system that utilises a quantum cascade laser (QCL) operating in pulsed-mode as both the source and detector. The realisation of a short-pulsed THz QCL feedback interferometer permits both high peak powers and improved thermal efficiency, which enables the cryogen-free operation of the system. In this work, we demonstrated pulsed-mode swept-frequency laser feedback interferometry experimentally. Our interferometric detection scheme not only permits the simultaneous creation of both amplitude and phase images, but inherently suppresses unwanted background radiation. We demonstrate that the proposed system utilising microsecond pulses has the potential to achieve 0.25 mega-pixel per second acquisition rates, paving the pathway to video frame rate THz imaging.


Can incubators work in Africa? Acorn Technologies and the entrepreneur-centric model.
Incubators are organizations that support the growth of new and typically technology-based enterprises, by providing business support services that bring together human and financial capital. Although the traditional role of incubators has been for economic development, they may also be a useful policy lever to tackle global health, by fostering the development and delivery of local health innovation.Given its high disease burden, life sciences incubators hold particular potential for Africa. As the most industrially advanced African nation, South Africa serves as a litmus test for identifying effective incubator policies. The case study method was used to illustrate how one such publicly funded incubator founded in 2002, Acorn Technologies, helped to catalyze local health product innovation. Acorn helped to support twelve biomedical device firms. One of them, Real World Diagnostics, was founded by a trainee from Acorn's innovative internship program (Hellfire). It developed rapid strip diagnostic tests for locally prevalent diseases including schistosomiasis and HIV, and reported $2 million (USD) in revenue in 2009.Acorn achieved this success by operating as a non-profit virtual incubator with little physical infrastructure. Employing a virtual model in combination with stringent selection criteria of capital efficiency for clients proved to be effective in reducing its own fixed costs. Acorn focused on entrepreneurship training and networking, both critical at an early stage in an environment dominated by multinational biomedical device companies.Acorn and its clients learned that employing a cross-subsidy business model allowed one to generate royalty revenue through imports to subsidize R&D for local diseases. However, funding constraints and government expectations for rapid self-sustainability forced Acorn to merge with its sister biotechnology incubator in 2009. A key to Acorn's achievements was identifying entrepreneurs with technologies with health and economic impact, and providing them with flexible support from an early stage. A virtual organizational model helped Acorn to focus on supporting entrepreneurs. Governments and funders may wish to consider incubation strategies that draw from these good practices. With the right policies and business models, incubators have the potential to generate both health and economic benefits for Africa.


Sialic acid-dependent recognition of laminin and fibrinogen by Aspergillus fumigatus conidia.
In an attempt to define the molecular basis of the adherence of Aspergillus fumigatus conidia to the host tissues, a step which might be mediated by the recognition of basement membrane laminin or fibrinogen, we analyzed the binding of these glycoproteins by flow cytometry and a microtiter plate adherence assay. Flow cytometry revealed that the binding of fluorescein isothiocyanate-labeled laminin to conidia was saturable and specific. Moreover, the ability of conidia to bind laminin increased with their maturation. Competition experiments showed a cross-reactivity between laminin and fibrinogen binding and a lack of interactions with glycosaminoglycans. In addition, the binding of laminin was not inhibited by the different adhesive synthetic peptides tested. Furthermore, the microtiter plate assay of adherence to chymotrypsin degradation products of laminin or fibrinogen purified by gel filtration suggested a unique binding site common to sequential degradation fragments or the presence of multiple binding sites on the two ligands. Therefore, the role of carbohydrates in the recognition process was investigated. Among the carbohydrates tested, constitutive of the conidial wall or of the oligosaccharide side chains of laminin and fibrinogen, only N-acetylneuraminic acid and sialyllactose inhibited the binding of these glycoproteins to conidia. In conclusion, these results strengthen the idea that the laminin and fibrinogen receptors in A. fumigatus are identical and suggest an interaction mediated by a sialic acid-specific lectin of the conidial wall.


Multiple endocrine neoplasia: types 1 and 2.
Multiple endocrine neoplasia type 1 (MEN 1) and type 2 (MEN 2) are autosomal-dominantly inherited syndromes where highly penetrant germline mutations predispose patients to the development of tumours in hormone-secreting cells. In the case of MEN 1, loss-of-function germline mutations in the tumour suppressor gene MEN1 increase the risk of developing pituitary, parathyroid and pancreatic islet tumours, and less commonly thymic carcinoids, lipomas and benign adrenocortical tumours. In the case of MEN 2, gain-of-function germline mutations clustered in specific codons of the RET proto-oncogene increase the risk of developing medullary thyroid carcinoma (MTC), phaeochromocytoma and parathyroid tumours. Offering RET testing is best practice for the clinical management of patients at-risk of MEN 2, and MEN 2 has become a classic model for the integration of molecular medicine into patient care. Prophylactic thyroidectomy in an asymptomatic RET mutation carrier to address the risk of developing MTC can prevent or cure this malignancy. No similar preventative strategies can be employed to prevent or cure MEN 1-associated tumours. Genetic testing for MEN 1 is therefore both more complex due to a general lack of mutational hotspots, and the benefit to patients is less straight forward. While a number of genotype-phenotype correlations exist in MEN 2, providing further rationale for performing genetic testing in this condition, these correlations are absent in MEN 1. This review summarises our current knowledge of these two syndromes with emphasis on those aspects with specific relevance to the otorhinolaryngologist.