Effects of lesions of temporal-parietal junction on perceptual and attentional processing in humans.
When stimuli with larger forms (global) containing smaller forms (local) are presented to subjects with large lesions in the right hemisphere, they are more likely to miss the global form than the local form, whereas subjects with large lesions in the left are more likely to miss the local than the global form. The present study tested whether the global/local impairment in subjects with posterior lesions was due to deficits in controlled attentional processes, passive perceptual processes, or both. Attentional control was examined by measuring reaction time changes when the probability of a target appearing at either the global or local level was varied. Patients with unilateral right or left lesions centered in temporal-parietal regions and age-matched controls served as subjects. Because neurophysiological and neuropsychological evidence have implicated temporal regions in visual discrimination and inferior parietal regions in the allocation of attention to locations in the visual field, patients with left hemisphere lesions were further subdivided into those with lesions centered in the superior temporal gyrus (LSTG) or rostral inferior parietal lobule (LIPL). Patients with right hemisphere injury could not be analogously subdivided. The results revealed that the LSTG group was able to control the allocation of attention to global and local levels normally, while the LIPL group was not. In contrast, the LSTG group showed a strong baseline reaction time advantage toward global targets, while normals and the LIPL group showed no advantage toward one level or the other. Finally, the perceptual component was affected differentially by lesions in the right hemisphere and LSTG, with lesions in the left favoring global targets and lesions in the right favoring local targets. These findings indicate that the hemispheric global/local asymmetry is due to a perceptual mechanism with a critical anatomical locus centered in the STG.


Two Modes of Evolution: Optimization and Expansion.
We document and discuss two different modes of evolution across multiple systems, optimization and expansion. The former suffices in systems whose size and interactions do not change substantially over time, while the latter is a key property of open-ended evolution, where new players and interaction types enter the game. We first investigate systems from physics, biology, and engineering and argue that their evolutionary optimization dynamics is the cumulative effect of multiple independent events, or quakes, which are uniformly distributed on a logarithmic time scale and produce a decelerating fitness improvement when using the appropriate independent variable. The appropriate independent variable can be physical time for a disordered magnetic system, the number of generations for a bacterial system, or the number of produced units for a particular technological product. We then derive and discuss a simple microscopic theory that explains the nature of the involved optimization processes, and provide simulation results as illustration. Finally, we explore the evolution of human culture and technology, using empirical economic data as a proxy for human fitness. Assuming the overall dynamics is a combined optimization and expansion process, the two processes can be separated and quantified by superimposing the mathematical form of an optimization process on the empirical data and thereby transforming the independent variable. This variable turns out to increase faster than any exponential function of time, a property likely due to strong historical changes in the web of human interactions and to the associated increase in the amount of available knowledge. A microscopic theory for this time dependence remains, however, a challenging open problem.


Central substitution of azacalixphyrins: a strategy towards acidochromic NIR dyes.
Azacalixphyrin derivatives constitute one of the most intriguing class of macrocyclic compounds. Indeed, these isostructural and isoelectronic analogues of porphyrins intensively absorb light up to the near infrared region, exist in several tautomeric forms and present a bis-zwitterionic structure, with a central dianionic core surrounded by positively-charged trimethine cyanines. However, control of the position of the absorption bands of azacalixphyrin remains an important challenge, as the experimental attempts reported to date have led to very modest auxochromic shifts only. Inspired by previous work demonstrating that the optical signatures of cyanines can be strongly modified by using central substituents, we have evaluated the validity of this strategy for azacalixphyrin considering several substituents positioned in symmetric or asymmetric manners around the core and linked through both single and double bonds, as well as several protonation states of the macrocycles. It turns out that bromine and dimethylamino substituents have a negligible or weak impact on the optical properties of azacalixphyrins with maximal redshifts smaller than 0.10 eV. The imino substitution induces strong geometrical deformations that counterbalance the electronic effects leading to rather modest variations of the optical signatures. In contrast, for keto-substituted macrocycles, electronic effects dominate and very strong acidochromic shifts are predicted with absorption wavelengths going from 811 to 1095 nm upon double deprotonation.


Can the ability to adapt to exercise be considered a talent-and if so, can we test for it?
Talent identification (TI) is a popular and hugely important topic within sports performance, with an ever-increasing amount of resources dedicated to unveiling the next sporting star. However, at present, most TI processes appear to select high-performing individuals at the present point in time, as opposed to identifying those individuals with the greatest capacity to improve. This represents a potential inefficiency within the TI process, reducing its effectiveness. In this article, we discuss whether the ability to adapt favorably, and with a large magnitude, to physical training can be considered a talent, testing it against proposed criteria. We also discuss whether, if such an ability can be considered a talent, being able to test for it as part of the TI process would be advantageous. Given that such a capacity is partially heritable, driven by genetic variation between individuals that mediate the adaptive response, we also explore whether the information gained from genetic profiling can be used to identify those with the greatest capacity to improve. Although there are some ethical hurdles which must be considered, the use of genetic information to identify those individuals with the greatest capacity appears to hold promise and may improve both the efficiency and effectiveness of contemporary TI programmes.


Health professionals' involvement of parents in decision-making in interprofessional practice at the hospital.
Health professionals have the responsibility of involving parents in decision-making regarding children's healthcare. This is to ensure that healthcare is customised to meet children's and families' needs and preferences. There is inadequate knowledge about health professionals' role in involving parents in these decisions in interprofessional practice in hospital settings. The aim of this study was to explore health professionals' construction of the phenomenon of parental involvement in decision-making about children's healthcare at the hospital and to identify how parental involvement can be improved. This explorative, descriptive qualitative study within a constructivist research paradigm selected a purposive sample of 12 health professionals who participated in individual semi-structured interviews. This qualitative data was used to construct a description of this phenomenon. The health professionals described ethical dilemmas and challenges related to parental involvement in decision-making while also providing technically safe, justifiable healthcare. Individual health professionals' involvement of parents in decision-making and the intra- and interprofessional collaboration between health professionals seemed to be of great importance to increase parents' active involvement in the co-production of children's healthcare. Further research is required to confirm the findings for generalisation.


Variable region sequences of murine IgM anti-IgG monoclonal autoantibodies (rheumatoid factors). II. Comparison of hybridomas derived by lipopolysaccharide stimulation and secondary protein immunization.
We have obtained the complete variable region mRNA sequences of 11 LPS-derived and 14 secondary immunization-derived monoclonal IgM anti-IgG antibodies (rheumatoid factors, RFs). A comparative analysis of these sequences showed that monoclonal RFs derived after polyclonal activation are structurally very similar to RFs derived after secondary protein immunization. This study was undertaken to evaluate the potential relationship between two previously described phenomena: (a) during a secondary response to a protein antigen, RF is produced in quantities that equal or exceed the immunogen-specific antibody; and (b) the frequency of B cells that make RF after polyclonal activation is quite high; 3-10%. It has been unclear whether LPS-stimulated cells that produce IgM anti-IgG that is detected by an in vitro assay are related to the cells that produce RF after in vivo stimulation. The similarity of the antigen receptors found in the two types of RF, however, suggests that most or all of the RF-producing B cells detected after LPS stimulation would also be stimulated during the secondary immune response. Thus, the presence of relatively large number of B cells that can make RF after nonspecific stimulation provides an explanation for the magnitude of RF production accompanying the secondary immune response.


Wearable and telemedicine innovations for Olympic events and elite sport.
Rapid advances in wearable technologies and real-time monitoring have resulted in major inroads in the world of recreational and elite sport. One such innovation is the application of real-time monitoring, which comprises a smartwatch application and ecosystem, designed to collect, process and transmit a wide range of physiological, biomechanical, bioenergetic and environmental data using cloud-based services. We plan to assess the impact of this wireless technology during Tokyo 2020, where this technology could help characterize the physiological and thermal strain experienced by an athlete, as well as determine future management of athletes during a medical emergency as a result of a more timely and accurate diagnosis. Here we describe some of the innovative technologies developed for numerous sports at Tokyo 2020 ranging from race walking (20 km and 50 km events), marathon, triathlon, road cycling (including the time trial event), mountain biking, to potentially team sports played outdoors. A more symbiotic relationship between sport, health and technology needs to be encouraged that harnesses the unique demands of elite sport (e.g., the need for unobtrusive devices that provide real-time feedback) and serves as medical and preventive support for the athlete's care. The implementation of such applications would be particularly welcome in the field of medicine (i.e., telemedicine applications) and the workplace (with particular relevance to emergency services, the military and generally workers under extreme environmental conditions). Laboratory and field-based studies are required in simulated scenarios to validate such emerging technologies, with the field of sport serving as an excellent model to understand and impact disease.


HIF-1α Reduction by Lowering Intraocular Pressure Alleviated Retinal Neovascularization.
Hypoxia-induced retinal neovascularization is a leading cause of blindness worldwide. Oxygen-induced retinopathy (OIR) mouse, a well-established angiogenesis model, has been extensively used to evaluate the effect of anti-angiogenic agents through intravitreal injection. Here, we serendipitously found that the needles used for intravitreal injection caused an unexpected "anti-angiogenic" effect in the OIR mice. To evaluate the effects of various intravitreal puncture sizes on retinal neovascularization and explore the potential underlying mechanism, intravitreal punctures using 0.5 mm (25 G), 0.3 mm (30 G), or 0.21 mm (33 G) needles were performed in OIR mice. Compared with 0.3 mm and 0.21 mm puncture, the 0.5 mm puncture remarkably suppressed the formation of pathological angiogenesis, inhibited vascular leakage, and remodeled the retinal vasculature. Mechanistically, the 0.5 mm puncture induced a substantial reduction in intraocular pressure (IOP), leading to an improvement in oxygen partial pressure (pO2) and significant reduction in Hif1a expression, resulting in resolution of angiogenic and inflammatory responses. Furthermore, IOP-lowering drugs, Travatan or Azarga, also promoted the alleviation of hypoxia and exhibited a potent anti-angiogenesis efficacy. Our study revealed an acute and significant reduction in IOP caused by a large puncture, which could remarkably suppress HIF-1α-mediated retinal neovascularization, indicating that lowering IOP may be a promising therapeutic avenue for treating retinal neovascular diseases.


The beneficial influence of inattention on visual interference in schizophrenia.
Schizophrenia is associated with poor spatial attention. However, although this deficit undermines the perception of target information, it may be helpful for ignoring irrelevant inputs. The present study examined whether event-related brain potential (ERP) indices of visual spatial attention predicted the magnitude of the brain response to interference in schizophrenia. ERPs were recorded in 16 schizophrenia patients and 20 healthy control participants who had to indicate whether the target E was global or local in compound letter stimuli. The nontarget could be either highly similar to the target (i.e., a global E composed of local Ss and vice versa) and thus produce more interference, or it could be dissimilar (i.e., a global E composed of local Hs and vice versa) and generate less interference. Both groups' responses were slowed by interference. Voltage amplitudes of the P1, and of ERP interference effects from 300-500 ms after stimulus onset, were significantly smaller in schizophrenia patients than in healthy participants when the target was global. In patients, larger P1 amplitudes were correlated with larger interference effects and with more severe symptoms of attentional deficits and conceptual disorganization. Schizophrenia participants thus exhibited abnormal ERPs to interference despite normal behavioral performance. Schizophrenia patients likely pay less attention to stimuli in general; however, the impact of this impairment on target detection is compensated by relatively greater inattention to irrelevant components of the stimuli, and this explains why they are not more influenced by interference than healthy participants at the behavioral level. (PsycINFO Database Record


Population demography of an endangered lizard, the Blue Mountains Water Skink.
Information on the age structure within populations of an endangered species can facilitate effective management. The Blue Mountains Water Skink (Eulamprus leuraensis) is a viviparous scincid lizard that is restricted to < 40 isolated montane swamps in south-eastern Australia. We used skeletochronology of phalanges (corroborated by mark-recapture data) to estimate ages of 222 individuals from 13 populations. These lizards grow rapidly, from neonatal size (30 mm snout-vent length) to adult size (about 70 mm SVL) within two to three years. Fecundity is low (mean 2.9 offspring per litter) and is affected by maternal body length and age. Offspring quality may decline with maternal age, based upon captive-born neonates (older females gave birth to slower offspring). In contrast to its broadly sympatric (and abundant) congener E. tympanum, E. leuraensis is short-lived (maximum 6 years, vs 15 years for E. tympanum). Litter size and offspring size are similar in the two species, but female E. leuraensis reproduce annually whereas many E. tympanum produce litters biennially. Thus, a low survival rate (rather than delayed maturation or low annual fecundity) is the key reason why E. leuraensis is endangered. Our 13 populations exhibited similar growth rates and population age structures despite substantial variation in elevation, geographic location and swamp size. However, larger populations (based on a genetic estimate of effective population size) contained older lizards, and thus a wider variance in ages. Our study suggests that low adult survival rates, as well as specialisation on a rare and fragmented habitat type (montane swamps) contribute to the endangered status of the Blue Mountains Water Skink.


Chaperone-assisted crystallography with DARPins.
The structure of proteins that are difficult to crystallize can often be solved by forming a noncovalent complex with a helper protein--a crystallization "chaperone." Although several such applications have been described to date, their handling usually is still very laborious. A valuable addition to the present repertoire of binding proteins is the recently developed designed ankyrin repeat protein (DARPin) technology. DARPins are built based on the natural ankyrin repeat protein fold with randomized surface residue positions allowing specific binding to virtually any target protein. The broad potential of these binding proteins for X-ray crystallography is illustrated by five cocrystal structures that have been determined recently comprising target proteins from distinct families, namely a sugar binding protein, two kinases, a caspase, and a membrane protein. This article reviews the opportunities of this technology for structural biology and the structural aspects of the DARPin-protein complexes.


Soil carbon is a useful surrogate for conservation planning in developing nations.
Defining the optimal placement of areas for biodiversity conservation in developing nations remains a significant challenge. Our best methods for spatially targeting potential locations for biodiversity conservation rely heavily on extensive georeferenced species observation data which is often incomplete or lacking in developing nations. One possible solution is the use of surrogates that enable site assessments of potential biodiversity values which use either indicator taxa or abiotic variables, or both. Among the plethora of abiotic variables, soil carbon has previously been identified as a potentially powerful predictor for threatened biodiversity, but this has not yet been confirmed with direct observational data. Here we assess the potential value of soil carbon for spatial prediction of threatened species using direct measurements as well as a wide range of GIS derived abiotic values as surrogates for threatened plant species in the PEBANPA network of permanent plots in Southern Patagonia. We find that soil carbon significantly improves the performance of a biodiversity surrogate elaborated using abiotic variables to predict the presence of threatened species. Soil carbon could thus help to prioritize sites in conservation planning. Further, the results suggest that soil carbon on its own can be a much better surrogate than other abiotic variables when prioritization of sites for conservation are calibrated on increasingly small sets of observation plots. We call for the inclusion of soil carbon data in the elaboration of surrogates used to optimize conservation investments in the developing world.


A mentorship model for neurosurgical training: the Mayo Clinic experience.
Neurosurgical education is a continually developing field with an aim of training competent and compassionate surgeons who can care for the needs of their patients. The Mayo Clinic utilizes a unique mentorship model for neurosurgical training. In this paper, the authors detail the historical roots as well as the logistical and experiential characteristics of this teaching model. This model was first established in the late 1890s by the Mayo brothers and then adopted by the Mayo Clinic Department of Neurological Surgery at its inception in 1919. It has since been implemented enterprise-wide at the Minnesota, Florida, and Arizona residency programs. The mentorship model is focused on honing resident skills through individualized attention and guidance from an attending physician. Each resident is closely mentored by a consultant during a 2- or 3-month rotation, which allows for exposure to more complex cases early in their training. In this model, residents take ownership of their patients' care, following them longitudinally during their hospital course with guided oversight from their mentors. During the chief year, residents have their own clinic, operating room (OR) schedule, and OR team and service nurse. In this model, chief residents conduct themselves more in the manner of an attending physician than a trainee but continue to have oversight from staff to provide a "safety net." The longitudinal care of patients provided by the residents under the mentorship model is not only beneficial for the trainee and the hospital, but also has a positive impact on patient satisfaction and safety. The Mayo Clinic Mentorship Model is one of many educational models that has demonstrated itself to be an excellent approach for resident education.


The Experiences of Primary Healthcare Nurses During the COVID-19 Pandemic in Australia.
The COVID-19 pandemic has presented an international health crisis of a scope not seen in our lifetime. While much attention has been paid to health workers in critical care and acute areas, nurses working outside of hospitals are also significantly affected. This study sought to investigate the experience of nurses working in Australian primary healthcare during the COVID-19 pandemic. In particular, it sought to understand the implications on their employment status, role, and access to personal protective equipment. Nurses employed in primary healthcare across Australia were invited to participate in a cross-sectional online survey through social media and professional organizations. The survey tool was composed of demographics, and of questions about the nurses' employment, work role, and access to personal protective equipment. Of the 637 responses received, nearly half (43.7%) reported a decrease in hours and threatened or actual loss of employment. While most respondents felt that they had sufficient knowledge about COVID-19, they expressed concern about work-related risks to themselves and their family. Most respondents described never or only sometimes having sufficient personal protective equipment in their workplace. Just over half of respondents (54.8%) felt well supported by their employer. A third of respondents (34%) perceived that care provided in their workplace was significantly or slightly worse than before the pandemic. This is the first study of primary healthcare nurses' experiences during the COVID-19 pandemic. The study findings highlighted a concerning level of insecurity around primary healthcare nursing employment, as well as issues with the availability of personal protective equipment for these nurses. The perception that the pandemic has resulted in reduced quality of care needs further exploration to ensure that those with chronic conditions are supported to maintain and promote health. Understanding the implications of COVID-19 on the primary healthcare nursing workforce is vital to ensure staff retention and care quality. Ensuring that the community remains healthy and supported at home is vital to both reduce the burden on the health system and reduce secondary mortality.


Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203).
Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial. In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m2 intravenous bolus on day 1 and 10 mg/m2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037. Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively). Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial. US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.


Menopause and cognitive complaints: are ovarian hormones linked with subjective cognitive decline?
Subjective cognitive decline (SCD) and the loss of ovarian hormones after menopause have been independently linked to later-life Alzheimer's disease (AD). The objective of this review was to determine whether menopause and the loss of ovarian hormones contribute to cognitive complaints and SCD in women. This would suggest that SCD at the menopausal transition might be an important marker of eventual cognitive decline and AD. We conducted a literature search using PubMed, PsycINFO and Web of Science in July 2020. All English-language studies assessing SCD and cognitive complaints with respect to menopause and ovarian hormones were included. A total of 19 studies were included. Studies found that cognitive complaints increased across the menopause transition and were associated with reductions in attention, verbal and working memory, and medial temporal lobe volume. Women taking estrogen-decreasing treatments also had increased cognitive complaints and reduced working memory and executive function. The current literature provides impetus for further research on whether menopause and the loss of ovarian hormones are associated with cognitive complaints and SCD. Clinicians may take particular note of cognitive complaints after menopause or ovarian hormone loss, as they might presage future cognitive decline.


Assessing the academic and professional needs of trauma nurse practitioners and physician assistants.
Because of multiple changes in the health care environment, the use of services of physician assistants (PAs) and nurse practitioners (NPs) in trauma and critical care has expanded. Appropriate training and ongoing professional development for these providers are essential to optimize clinical outcomes. This study offers a baseline assessment of the academic and professional needs of the contemporary trauma PAs/NPs in the United States. A 14-question electronic survey, using SurveyMonkey, was distributed to PAs/NPs at trauma centers identified through the American College of Surgeons Web site and other online resources. Demographic questions included trauma center level, provider type, level of education, and professional affiliations. Likert scale questions were incorporated to assess level of mentorship, comfort level with training, and individual perceived needs for academic and professional development. There were 120 survey respondents: 60 NPs and 60 PAs. Sixty-two respondents (52%) worked at level I trauma centers and 95 (79%) were hospital-employed. Nearly half (49%) reported working in trauma centers for 3 years or less. One hundred nineteen respondents (99%) acknowledged the importance of trauma-specific education; 98 (82%) were required by their institution to obtain such training. Thirty-five respondents (32%) reported receiving $1000 per year or less as a continuing medical education benefit. Insufficient mentorship, professional development, and academic development were identified by 22 (18%), 16 (13%), and 30 (25%) respondents, respectively. Opportunities to network with trauma PAs/NPs outside their home institution were identified as insufficient by 79 (66%). While PAs/NPs in trauma centers recognize the importance of continued contemporary trauma care and evidence-based practices, attending trauma-related education is not universally required by their employers. Financial restrictions may pose an additional impediment to academic development. Therefore, resource-efficient opportunities should be a prime consideration for advanced practitioners education, especially since half of the reported workforce has 3 years or less experience. The Eastern Association of Trauma and other organizations can provide an ideal venue for mentorship, academic development, and networking that is vital to PA/NP professional development and, ultimately, quality patient care.


UM171-Expanded Cord Blood Transplants Support Robust T Cell Reconstitution with Low Rates of Severe Infections.
Rapid T cell reconstitution following hematopoietic stem cell transplantation (HSCT) is essential for protection against infections and has been associated with lower incidence of chronic graft-versus-host disease (cGVHD), relapse, and transplant-related mortality (TRM). While cord blood (CB) transplants are associated with lower rates of cGVHD and relapse, their low stem cell content results in slower immune reconstitution and higher risk of graft failure, severe infections, and TRM. Recently, results of a phase I/II trial revealed that single UM171-expanded CB transplant allowed the use of smaller CB units without compromising engraftment (www.clinicaltrials.gov, NCT02668315). We assessed T cell reconstitution in patients who underwent transplantation with UM171-expanded CB grafts and retrospectively compared it to that of patients receiving unmanipulated CB transplants. While median T cell dose infused was at least 2 to 3 times lower than that of unmanipulated CB, numbers and phenotype of T cells at 3, 6, and 12 months post-transplant were similar between the 2 cohorts. T cell receptor sequencing analyses revealed that UM171 patients had greater T cell diversity and higher numbers of clonotypes at 12 months post-transplant. This was associated with higher counts of naive T cells and recent thymic emigrants, suggesting active thymopoiesis and correlating with the demonstration that UM171 expands common lymphoid progenitors in vitro. UM171 patients also showed rapid virus-specific T cell reactivity and significantly reduced incidence of severe infections. These results suggest that UM171 patients benefit from rapid T cell reconstitution, which likely contributes to the absence of moderate/severe cGVHD, infection-related mortality, and late TRM observed in this cohort.


Hand disinfectant practice: the impact of an education intervention.
The primary hypothesis of this study was that a lecture on basic hygiene routines could be associated with an increase in the use of disinfectant for hand hygiene. A secondary hypothesis was that the lecture could positively affect the staff's knowledge of and attitudes toward basic hygiene routines.A quasi-experimental design including one ward of the department of orthopedics in a Swedish university hospital was adopted.During the pre-intervention test period the consumption of hand disinfectant was measured for 30 days and a questionnaire was distributed to all staff. The hospital hygiene nurse subsequently provided a lecture on basic hygiene routines to all employees on the ward. During the post-intervention test period the hand disinfectant consumption was measured for another 30 days, and the questionnaire was distributed once again. A follow-up measurement was performed 9 months after the intervention.After the lecture on hygiene routines, the consumption of hand disinfectant increased by 93%. Nine months after the intervention, the consumption was still 21% higher than before the intervention. The result of the questionnaire showed that the employees considered themselves applying the disinfectant more thoroughly after the intervention. Some employees changed their perspective on basic hygiene routines after the lecture and stopped using watches and private clothes at work.Our findings suggest that a single education session, a hygiene lecture, could be a simple and cost-effective method to increase the use of hand disinfectant, thereby reducing the number of nosocomial infections on the wards.


On the application of a monolithic array for detecting intensity-correlated photons emitted by different source types.
It is not widely appreciated that many subtleties are involved in the accurate measurement of intensity-correlated photons; even for the original experiments of Hanbury Brown and Twiss (HBT). Using a monolithic 4 x 4 array of single-photon avalanche diodes (SPADs), together with an off-chip algorithm for processing streaming data, we investigate the difficulties of measuring second-order photon correlations g((2))(x(iota), t(iota),x, t) in a wide variety of light fields that exhibit dramatically different correlation statistics: a multimode He-Ne laser, an incoherent intensity-modulated lamp-light source and a thermal light source. Our off-chip algorithm treats multiple photon-arrivals at pixel-array pairs, in any observation interval, with photon fluxes limited by detector saturation, in such a way that a correctly normalized g((2)) function is guaranteed. The impact of detector background correlations between SPAD pixels and afterpulsing effects on second-order coherence measurements is discussed. These results demonstrate that our monolithic SPAD array enables access to effects that are otherwise impossible to measure with stand-alone detectors.


Polymer photonic crystal dye lasers as Optofluidic Cell Sensors.
Dye doped hybrid polymer lasers are implemented as label free evanescent field biosensors for detection of cells. It is demonstrated that although the coverage is irregular and the cells extend over several lattice constants, the emission wavelength depends linearly on the fraction of the surface covered by the HeLa cells used as model system. Design parameters relating to photonic crystal sensing of large objects are identified and discussed. The lasers are chemically modified to bind cells and molecules with flexible UV activated linker molecules.


Perspective: Theory and simulation of hybrid halide perovskites.
Organic-inorganic halide perovskites present a number of challenges for first-principles atomistic materials modeling. Such "plastic crystals" feature dynamic processes across multiple length and time scales. These include the following: (i) transport of slow ions and fast electrons; (ii) highly anharmonic lattice dynamics with short phonon lifetimes; (iii) local symmetry breaking of the average crystallographic space group; (iv) strong relativistic (spin-orbit coupling) effects on the electronic band structure; and (v) thermodynamic metastability and rapid chemical breakdown. These issues, which affect the operation of solar cells, are outlined in this perspective. We also discuss general guidelines for performing quantitative and predictive simulations of these materials, which are relevant to metal-organic frameworks and other hybrid semiconducting, dielectric and ferroelectric compounds.


An optical marker based on the UV-induced green-to-red photoconversion of a fluorescent protein.
We have cloned a gene encoding a fluorescent protein from a stony coral, Trachyphyllia geoffroyi, which emits green, yellow, and red light. The protein, named Kaede, includes a tripeptide, His-Tyr-Gly, that acts as a green chromophore that can be converted to red. The red fluorescence is comparable in intensity to the green and is stable under usual aerobic conditions. We found that the green-red conversion is highly sensitive to irradiation with UV or violet light (350-400 nm), which excites the protonated form of the chromophore. The excitation lights used to elicit red and green fluorescence do not induce photoconversion. Under a conventional epifluorescence microscope, Kaede protein expressed in HeLa cells turned red in a graded fashion in response to UV illumination; maximal illumination resulted in a 2,000-fold increase in the ratio of red-to-green signal. These color-changing properties provide a simple and powerful technique for regional optical marking. A focused UV pulse creates an instantaneous plane source of red Kaede within the cytosol. The red spot spreads rapidly throughout the cytosol, indicating its free diffusibility in the compartment. The extensive diffusion allows us to delineate a single neuron in a dense culture, where processes originating from many different somata are present. Illumination of a focused UV pulse onto the soma of a Kaede-expressing neuron resulted in filling of all processes with red fluorescence, allowing visualization of contact sites between the red and green neurons of interest.


Benign notochordal cell tumor of the clivus with chordoma component: report of 2 cases.
Benign notochordal cell tumors (BNCTs) are considered to be benign intraosseous lesions of notochord origin; however, recent spine studies have suggested the possibility that some chordomas arise from BNCTs. Here, the authors describe two cases demonstrating histological features of BNCT and concomitant chordoma involving the clivus, which, to the best of the authors' knowledge, have not been previously documented at this anatomical site.An 18-year-old female presented with an incidentally discovered clival mass. Magnetic resonance imaging revealed a 2.8-cm nonenhancing lesion in the upper clivus that was T2 hyperintense and T1 hypointense. She underwent an uneventful endoscopic transsphenoidal resection. Histologically, the tumor demonstrated areas of classic chordoma and a distinct intraosseous BNCT component. The patient completed adjuvant radiation therapy. Follow-up showed no recurrence at 18 months.A 39-year-old male presented with an incidentally discovered 2.8-cm clival lesion. The nonenhancing mass was T2 hyperintense and T1 hypointense. Surgical removal of the lesion was performed through an endoscopic transsphenoidal approach. Histological analysis revealed areas of BNCT with typical features of chordoma. Follow-up did not demonstrate recurrence at 4 years.These cases document histologically concomitant BNCT and chordoma involving the clivus, suggesting that the BNCT component may be a precursor of chordoma.


Genome-wide analysis of the Hsp20 gene family in soybean: comprehensive sequence, genomic organization and expression profile analysis under abiotic and biotic stresses.
The Hsp20 genes are associated with stress caused by HS and other abiotic factors, but have recently been found to be associated with the response to biotic stresses. These genes represent the most abundant class among the HSPs in plants, but little is known about this gene family in soybean. Because of their apparent multifunctionality, these proteins are promising targets for developing crop varieties that are better adapted to biotic and abiotic stresses. Thus, in the present study an in silico identification of GmHsp20 gene family members was performed, and the genes were characterized and subjected to in vivo expression analysis under biotic and abiotic stresses. A search of the available soybean genome databases revealed 51 gene models as potential GmHsp20 candidates. The 51 GmHsp20 genes were distributed across a total of 15 subfamilies where a specific predicted secondary structure was identified. Based on in vivo analysis, only 47 soybean Hsp20 genes were responsive to heat shock stress. Among the GmHsp20 genes that were potentials HSR, five were also cold-induced, and another five, in addition to one GmAcd gene, were responsive to Meloidogyne javanica infection. Furthermore, one predicted GmHsp20 was shown to be responsive only to nematode infection; no expression change was detected under other stress conditions. Some of the biotic stress-responsive GmHsp20 genes exhibited a divergent expression pattern between resistant and susceptible soybean genotypes under M. javanica infection. The putative regulatory elements presenting some conservation level in the GmHsp20 promoters included HSE, W-box, CAAT box, and TA-rich elements. Some of these putative elements showed a unique occurrence pattern among genes responsive to nematode infection. The evolution of Hsp20 family in soybean genome has most likely involved a total of 23 gene duplications. The obtained expression profiles revealed that the majority of the 51 GmHsp20 candidates are induced under HT, but other members of this family could also be involved in normal cellular functions, unrelated to HT. Some of the GmHsp20 genes might be specialized to respond to nematode stress, and the predicted promoter structure of these genes seems to have a particular conserved pattern related to their biological function.


Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti-MicroRNA-122, RG-101.
MicroRNA-122 is an important host factor for the hepatitis C virus (HCV). Treatment with RG-101, an N-acetylgalactosamine-conjugated anti-microRNA-122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic HCV infection. Here, we analyzed the effects of RG-101 therapy on antiviral immunity. Thirty-two chronic HCV patients infected with HCV genotypes 1, 3, and 4 received a single subcutaneous administration of RG-101 at 2 mg/kg (n = 14) or 4 mg/kg (n = 14) or received a placebo (n = 2/dosing group). Plasma and peripheral blood mononuclear cells were collected at multiple time points, and comprehensive immunological analyses were performed. Following RG-101 administration, HCV RNA declined in all patients (mean decline at week 2, 3.27 log10 IU/mL). At week 8 HCV RNA was undetectable in 15/28 patients. Plasma interferon-γ-induced protein 10 (IP-10) levels declined significantly upon dosing with RG-101. Furthermore, the frequency of natural killer (NK) cells increased, the proportion of NK cells expressing activating receptors normalized, and NK cell interferon-γ production decreased after RG-101 dosing. Functional HCV-specific interferon-γ T-cell responses did not significantly change in patients who had undetectable HCV RNA levels by week 8 post-RG-101 injection. No increase in the magnitude of HCV-specific T-cell responses was observed at later time points, including 3 patients who were HCV RNA-negative 76 weeks postdosing. Dosing with RG-101 is associated with a restoration of NK-cell proportions and a decrease of NK cells expressing activation receptors; however, the magnitude and functionality of ex vivo HCV-specific T-cell responses did not increase following RG-101 injection, suggesting that NK cells, but not HCV adaptive immunity, may contribute to HCV viral control following RG-101 therapy. (Hepatology 2017;66:57-68).


Genetic analysis of type 1 diabetes using whole genome approaches.
Whole genome linkage analysis of type 1 diabetes using affected sib pair families and semi-automated genotyping and data capture procedures has shown how type 1 diabetes is inherited. A major proportion of clustering of the disease in families can be accounted for by sharing of alleles at susceptibility loci in the major histocompatibility complex on chromosome 6 (IDDM1) and at a minimum of 11 other loci on nine chromosomes. Primary etiological components of IDDM1, the HLA-DQB1 and -DRB1 class II immune response genes, and of IDDM2, the minisatellite repeat sequence in the 5' regulatory region of the insulin gene on chromosome 11p15, have been identified. Identification of the other loci will involve linkage disequilibrium mapping and sequencing of candidate genes in regions of linkage.


Preangiographic evaluation of spinal dural arteriovenous fistulas with elliptic centric contrast-enhanced MR Angiography and effect on radiation dose and volume of iodinated contrast material.
The detection and localization of spinal dural arteriovenous fistulas (AVFs) remain diagnostic challenges. This study tested the hypothesis that elliptic centric contrast-enhanced MR angiography (MRA) can be used to detect spinal dural AVFs, predict the level of fistulas, and reduce the radiation dose and volume of iodinated contrast material associated with conventional angiography. We examined 31 patients who presented with suspected spinal dural AVF between December 2000 and March 2004. All patients underwent MRA and conventional angiography. The effect of MRA on subsequent conventional angiography was assessed by analyzing total fluoroscopy time and volume of iodinated contrast material used. At angiography, spinal dural AVFs were diagnosed in 22 of 31 patients, and MRA depicted an AVF in 20 of the 22 patients. MRA findings correctly predicted a negative angiogram in seven of nine cases. Of the 20 true-positive MRA results, the level of the fistula was included in the imaging volume in 14. In 13 of these 14 cases, MRA results correctly predicted the side and the level of the fistula to within one vertebral level. Fluoroscopy time and the volume of contrast agent was reduced by more than 50% in the 13 patients with a spinal dural AVF in whom MRA prospectively indicated the correct level. Contrast-enhanced MRA can be used to detect spinal dural AVFs, predict the level of fistulas, and substantially reduce the radiation dose and volume of contrast agent associated with catheter spinal angiography.


Assessing the impact of a novel house design on the incidence of malaria in children in rural Africa: study protocol for a household-cluster randomized controlled superiority trial.
Traditional rural housing in hot, humid regions of sub-Saharan Africa usually consists of single-level, poorly ventilated dwellings. Houses are mostly poorly screened against malaria mosquitoes and limited airflow discourages the use of bednets resulting in high indoor transmission. This study aims to determine whether living in a novel design house with elevated bedrooms and permeable screened walls reduces malaria, respiratory tract infections, and diarrhoea among children in rural Tanzania. This is a household-randomized, controlled study in 60 villages in Mtwara, Tanzania. A total of 550 households are randomly selected, 110 of which are allocated a novel design house and 440 households continue to reside in traditional houses. A dynamic cohort of about 1650 children under 13 years will be enrolled and followed for 3 years, approximately 330 living in novel design houses and 1320 in traditional rural houses. The primary endpoint is the incidence of malaria; secondary endpoints are incidences of acute respiratory tract infections and diarrhoea diseases detected by passive and active surveillance. Exposure to malaria vectors will be assessed using light traps in all study houses. Structural, economic, and social science studies will assess the durability, cost-effectiveness, and acceptability of the new houses compared with traditional housing. Environmental data will be collected indoors and outdoors in study homes to assess the differences between house typologies. This is the first randomized controlled trial to assess the protective efficacy of a new house design targeting malaria in sub-Saharan Africa. The findings of this study could influence the future construction of homes in hot and humid zones of Africa. ClinicalTrials.gov NCT04529434 . Registered on August 27, 2020.


Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians.
CYP2C9 and VKORC1 are two major genetic factors associated with inter-individual variability in warfarin dose. Additionally, genes in the warfarin metabolism pathway have also been associated with dose variance. We analyzed Single Nucleotide Polymorphisms (SNPs) in these genes to identify genetic factors that might confer warfarin sensitivity in Indonesian patients. Direct sequencing method was used to identify SNPs in CYP2C9, VKORC1, CYP4F2, EPHX1, PROC and GGCX genes in warfarin-treated patients. Multiple linear regressions were performed to model the relationship warfarin daily dose requirement with genetic and non-genetic variables measured and used to develop a novel algorithm for warfarin dosing. From the 40 SNPs analyzed, CYP2C9 rs17847036 and VKORC1 rs9923231 showed significant association with warfarin sensitivity. In our study population, no significant correlation could be detected between CYP2C9*3, CYP2C9C-65 (rs9332127), CYP4F2 rs2108622, GGCX rs12714145, EPHX1 rs4653436 and PROC rs1799809 with warfarin sensitivity. VKORC1 rs9923231 AA and CYP2C9 rs17847036 GG genotypes were associated with low dosage requirements of most patients (2.05 ± 0.77 mg/day and 2.09 ± 0.70 mg/day, respectively). CYP2C9 and VKORC1 genetic variants as well as non-genetic factors such as age, body weight and body height account for 15.4% of variance in warfarin dose among our study population. Additional analysis of this combination could allow for personalized warfarin treatment in ethnic Indonesians.


Current treatment options for hereditary angioedema due to C1 inhibitor deficiency.
Hereditary angioedema (HAE) usually results from C1 inhibitor (C1-INH) deficiency or dysfunction. It is a rare autosomal dominant disorder characterized by localized, non-pitting edema of the skin and submucosal tissues of the upper respiratory and gastrointestinal tracts, without significant wheals or pruritus, due to a temporary increase in vascular permeability. Other forms of HAE have been described, but therapies are approved only for HAE with C1-INH deficiency: hence, this review focuses on C1-INH-HAE. The aim of this review article is to present current available therapies for treatment of acute attacks as well as for short- and long-term prophylaxis of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE). The Authors highlight also critical issues on the management of C1-INH-HAE, which is continuously evolving thanks to evidence from clinical trials, post-marketing experience and ongoing studies. In the last decade, the quality of life of C1-INH-HAE patients has significantly improved due to increased knowledge and awareness of the disease, improved patient support and major progress in pharmacotherapy. Ongoing research will probably provide patients with other new effective therapeutic agents in the near future.


Ethical, legal and social issues of genetic studies with African immigrants as research subjects.
There is growing interest in exploring gene-environment interactions in the etiology of diseases in immigrants from sub-Saharan Africa. Our experience working with the Sudanese immigrant population in Omaha, NE, makes clear the pressing need for geneticists and federal and local funding agencies to address the ethical, legal and social implications of genetic research with such vulnerable populations. Our work raises several questions. How does one design research with African immigrant participants to assure it is ethical? Many immigrants may not understand the purposes, risks and benefits involved in research because of low literacy rates, one of the results of civil wars, or concepts of biologic science foreign to their cultures. Is it possible to obtain truly informed consent? Do African immigrants perceive genetic research using them as subjects as racist? Is genetic research on minorities "biopiracy" or "bio-colonialism?" In our experience, some Sudanese immigrants have challenged the legality and ethics of genetic studies with profit-making as an end. We have concluded that it is essential to educate African immigrant or any other non-English-speaking immigrant participants in research using lay language and graphic illustrations before obtaining consent. Cultural proficiency is important in gaining the trust of African immigrants; profit-sharing may encourage their participation in genetic research to benefit all; involvement of African immigrant community leaders in planning, delivery and evaluation using the community-based participatory research approach will facilitate healthcare promotion, health literacy education, as well as genetic research. It is crucial to address the ethical, legal and social implications of genetic studies with African immigrants as research subjects.


Synchronous Bone Metastasis From Multiple Myeloma and Prostate Adenocarcinoma as Initial Presentation of Coexistent Malignancies.
The radiographic appearance of bone metastases is usually determined by tumor histology and can be osteolytic, osteoblastic, or mixed. We present a patient with coexistent bone metastasis from multiple myeloma and prostate adenocarcinoma who exhibited synchronous bone involvement of both histologies within the same bone lesion, a rare phenomenon that has not been previously reported and led to atypical radiographic findings. The radiograph of a 71-year-old man with thigh swelling and pain demonstrated a lytic femoral lesion. Magnetic resonance imaging (MRI) confirmed a destructive process, but showed coexistent metaphyseal sclerosis. Multiple myeloma was suspected by demonstration of monoclonal gammopathy and confirmed by computed tomography (CT)-guided biopsy. Incidentally, CT demonstrated areas of sclerosis corresponding to T2 hypointensity on MRI. Further studies revealed osteoblastic spinal metastasis, prostate enhancement on CT and prostate-specific antigen (PSA) level of 90 ng/mL, concerning for concomitant prostate neoplasm. After endoprosthetic reconstruction, pathology of the femur identified both plasma cell neoplasm and metastatic prostate adenocarcinoma. An association between prostate cancer and multiple myeloma is hypothesized due to tumor microenvironment similarities and possible common genetic variations, however, coexisting bone metastases have never been reported. This unusual finding explains the discrepant imaging features in our patient and is evidenced that certain clinical situations merit contemplation of atypical presentations of common malignancies even if this leads to additional testing.


Macroscopic and tunable nanoparticle superlattices.
We describe a robust method to assemble nanoparticles into highly ordered superlattices by inducing aqueous phase separation of neutral capping polymers. Here we demonstrate the approach with thiolated polyethylene-glycol-functionalized gold nanoparticles (PEG-AuNPs) in the presence of salts (for example, K2CO3) in solutions that spontaneously migrate to the liquid-vapor interface to form a Gibbs monolayer. We show that by increasing salt concentration, PEG-AuNP monolayers transform from two-dimensional (2D) gas-like to liquid-like phase and eventually, beyond a threshold concentration, to a highly ordered hexagonal structure, as characterized by surface sensitive synchrotron X-ray reflectivity and grazing incidence X-ray diffraction. Furthermore, the method allows control of the inplane packing in the crystalline phase by varying the K2CO3 and PEG-AuNPs concentrations and the length of PEG. Using polymer-brush theory, we argue that the assembly and crystallization is driven by the need to reduce surface tension between PEG and the salt solution. Our approach of taking advantage of the phase separation of PEG in salt solutions is general (i.e., can be used with any nanoparticles) leads to high-quality macroscopic and tunable crystals. Finally, we discuss how the method can also be applied to the design of orderly 3D structures.


Muscle expression of a malonyl-CoA-insensitive carnitine palmitoyltransferase-1 protects mice against high-fat/high-sucrose diet-induced insulin resistance.
Impaired skeletal muscle mitochondrial fatty acid oxidation (mFAO) has been implicated in the etiology of insulin resistance. Carnitine palmitoyltransferase-1 (CPT1) is a key regulatory enzyme of mFAO whose activity is inhibited by malonyl-CoA, a lipogenic intermediate. Whereas increasing CPT1 activity in vitro has been shown to exert a protective effect against lipid-induced insulin resistance in skeletal muscle cells, only a few studies have addressed this issue in vivo. We thus examined whether a direct modulation of muscle CPT1/malonyl-CoA partnership is detrimental or beneficial for insulin sensitivity in the context of diet-induced obesity. By using a Cre-LoxP recombination approach, we generated mice with skeletal muscle-specific and inducible expression of a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA inhibition. When fed control chow, homozygous CPT1mt transgenic (dbTg) mice exhibited decreased CPT1 sensitivity to malonyl-CoA inhibition in isolated muscle mitochondria, which was sufficient to substantially increase ex vivo muscle mFAO capacity and whole body fatty acid utilization in vivo. Moreover, dbTg mice were less prone to high-fat/high-sucrose (HFHS) diet-induced insulin resistance and muscle lipotoxicity despite similar body weight gain, adiposity, and muscle malonyl-CoA content. Interestingly, these CPT1mt-protective effects in dbTg-HFHS mice were associated with preserved muscle insulin signaling, increased muscle glycogen content, and upregulation of key genes involved in muscle glucose metabolism. These beneficial effects of muscle CPT1mt expression suggest that a direct modulation of the malonyl-CoA/CPT1 partnership in skeletal muscle could represent a potential strategy to prevent obesity-induced insulin resistance.


Overproduction of encapsulated insecticidal crystal proteins in a Bacillus thuringiensis spo0A mutant.
The spo0A gene of Bacillus subtilis encodes the key factor involved in the initiation of sporulation. It was previously shown that the B. thuringiensis (Bt) cryIIIA gene, encoding a toxin active against coleopteran larvae, is overexpressed in an spo0A mutant of B. subtilis. In this paper we describe the construction of a Bt spo0A mutant strain and its use to produce insecticidal crystal proteins. The spo0A gene of Bt was cloned and identified by its ability to transform a B. subtilis spo0A mutant to prototrophy. Its nucleotide sequence is homologous to the B. subtilis gene. The spo0A gene was replaced in the Bt genome with a disrupted copy to give an Spo- strain unable to initiate sporulation. When the cryIIIA gene was cloned in the Bt spo0A mutant, large amounts of toxins were produced and accumulated to form a large crystal inclusion which remained encapsulated within the ghost cell. These encapsulated toxins were highly active against coleopteran larvae. We anticipate that the cryIIIA expression system and the Bt spo0A mutant will provide a convenient process to generate novel formulations of stabilized and environmentally safe Bt-based biopesticides.


Biological activity of Stevia rebaudiana Bertoni and their relationship to health.
The leaves of Stevia rebaudiana Bertoni has nutrients and phytochemicals, which make it an adequate source for the extraction and production of functional food ingredients. Preclinical and clinical studies suggest therapeutic and pharmacological applications for stevia and their extracts because they are not toxic and exhibit several biological activities. This review presents the biological activity of Stevia rebaudiana Bertoni and their relationship to antidiabetic, anticariogenic, antioxidant, hypotensive, antihypertensive, antimicrobial, anti-inflammatory and antitumor activities. Consumption and adverse effects were also reviewed.


Methods and algorithms for statistical analysis of protein sequences.
We describe several protein sequence statistics designed to evaluate distinctive attributes of residue content and arrangement in primary structure. Considered are global compositional biases, local clustering of different residue types (e.g., charged residues, hydrophobic residues, Ser/Thr), long runs of charged or uncharged residues, periodic patterns, counts and distribution of homooligopeptides, and unusual spacings between particular residue types. The computer program SAPS (statistical analysis of protein sequences) calculates all the statistics for any individual protein sequence input and is available for the UNIX environment through electronic mail on request to V.B. (email@example.com).


Contribution of alcohol use disorders on the burden of chronic hepatitis C in France, 2008-2013: A nationwide retrospective cohort study.
Hepatitis C virus (HCV) patients are at risk of alcohol use disorders (AUDs). We measured the contribution of AUDs on the burden of chronic HCV infection in French HCV patients. The hospital trajectory of 97,347 French HCV patients aged 18-65 in January 2008 were tracked and followed until in-hospital death or December 2013. Primary outcome was the frequency of liver-related complications. Secondary outcomes were the frequency of liver transplantation and otherwise cause-specific mortality. Adjusted odds ratios (OR), population attributable risks of AUDs and other cofactors of liver disease progression associated with HCV transmission were measured. The 28,101 (28.9%) individuals with AUDs had the highest odds for liver-related complications (OR=7.19; 95% confidence interval [CI], 6.90 to 7.50), liver transplantation (OR=4.28; 95% CI, 3.80 to 4.82), and liver death (OR=6.20; 95% CI, 5.85 to 6.58). Alcohol rehabilitation and abstinence were associated with 60% (95% CI, 57% to 63%) and 78% (95% CI, 76% to 80%) reduction of liver-related complications, respectively. The attributable risk of AUDs was 71.8% (95% CI, 66.0 to 76.8) of 17,669 liver-related complications, 67.4% (95% CI, 61.6 to 72.4) of 1,599 liver transplantations, and 68.8% (95% CI, 63.4 to 73.5) of 6,677 liver deaths. The number of liver transplantations remained stable and the number of liver deaths increased, at a faster rate for individuals with AUDs, over the observational period. In France, AUDs contributed to more than two-thirds of the burden of chronic HCV infection in young and middle-aged adults over 2008-2013. This study tracked liver-related complications and mortality of all 97,347 young and middle-aged patients (18-65years old) discharged with chronic HCV infection from French hospitals over 2008-2013. About 30% patients were recorded with alcohol use disorders (AUDs) and had the highest odds for liver-related complications (i.e. decompensated cirrhosis and liver cancer). AUDs contributed to more than two-thirds of 1,599 liver transplantations and 6,677 liver deaths recorded in patients with chronic HCV infection over 2008-2013 in France. Alcohol rehabilitation and abstinence were associated with above a 50% risk reduction of liver-related complications. Promoting alcohol abstinence should receive high priority to reduce the burden of chronic HCV infection.


Does the morphological fit between flowers and pollinators affect pollen deposition? An experimental test in a buzz-pollinated species with anther dimorphism.
Some pollination systems, such as buzz-pollination, are associated with floral morphologies that require a close physical interaction between floral sexual organs and insect visitors. In these systems, a pollinator's size relative to the flower may be an important feature determining whether the visitor touches both male and female sexual organs and thus transfers pollen between plants efficiently. To date, few studies have addressed whether in fact the "fit" between flower and pollinator influences pollen transfer, particularly among buzz-pollinated species. Here we use Solanum rostratum, a buzz-pollinated plant with dimorphic anthers and mirror-image flowers, to investigate whether the morphological fit between the pollinator's body and floral morphology influences pollen deposition. We hypothesized that when the size of the pollinator matches the separation between the sexual organs in a flower, more pollen should be transferred to the stigma than when the visitor is either too small or too big relative to the flower. To test this hypothesis, we exposed flowers of S. rostratum with varying levels of separation between sexual organs, to bumblebees (Bombus terrestris) of different sizes. We recorded the number of visits received, pollen deposition, and fruit and seed production. We found higher pollen deposition when bees were the same size or bigger than the separation between anther and stigma within a flower. We found a similar, but not statistically significant pattern for fruit set. In contrast, seed set was more likely to occur when the size of the flower exceeded the size of the bee, suggesting that other postpollination processes may be important in translating pollen receipt to seed set. Our results suggest that the fit between flower and pollinator significantly influences pollen deposition in this buzz-pollinated species. We speculate that in buzz-pollinated species where floral morphology and pollinators interact closely, variation in the visitor's size may determine whether it acts mainly as a pollinator or as a pollen thief (i.e., removing pollen rewards but contributing little to pollen deposition and fertilization).


Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain.
Disinhibition of neurons in the superficial spinal dorsal horn, via microglia - neuron signaling leading to disruption of chloride homeostasis, is a potential cellular substrate for neuropathic pain. But, a central unresolved question is whether this disinhibition can transform the activity and responses of spinal nociceptive output neurons to account for the symptoms of neuropathic pain. Here we show that peripheral nerve injury, local spinal administration of ATP-stimulated microglia or pharmacological disruption of chloride transport change the phenotype of spinal lamina I output neurons, causing them to 1) increase the gain of nociceptive responsiveness, 2) relay innocuous mechanical input and 3) generate spontaneous bursts of activity. The changes in the electrophysiological phenotype of lamina I neurons may account for three principal components of neuropathic pain: hyperalgesia, mechanical allodynia and spontaneous pain, respectively. The transformation of discharge activity and sensory specificity provides an aberrant signal in a primarily nociceptive ascending pathway that may serve as a basis for the symptoms of neuropathic pain.


The safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12-17 years old with hepatitis C virus genotype 1 infection.
No all-oral, direct-acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a phase 2, multicenter, open-label study to evaluate the efficacy and safety of ledipasvir-sofosbuvir in adolescents with chronic HCV genotype 1 infection. One hundred patients aged 12-17 years received a combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. On the tenth day following initiation of dosing, 10 patients underwent an intensive pharmacokinetic evaluation of the concentrations of sofosbuvir, ledipasvir, and the sofosbuvir metabolite GS-331007. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at 12 weeks posttreatment. Median age of patients was 15 years (range 12-17). A majority (80%) were HCV treatment-naive, and 84% were infected through perinatal transmission. One patient had cirrhosis, and 42 did not; in 57 patients the degree of fibrosis was unknown. Overall, 98% (98/100; 95% confidence interval 93%-100%) of patients reached sustained virologic response at 12 weeks. No patient had virologic failure. The 2 patients who did not achieve sustained virologic response at 12 weeks were lost to follow-up either during or after treatment. The three most commonly reported adverse events were headache (27% of patients), diarrhea (14%), and fatigue (13%). No serious adverse events were reported. Area under the concentration-time curve (tau) and maximum concentration values for sofosbuvir, ledipasvir, and GS-331007 were within the predefined pharmacokinetic equivalence boundaries of 50%-200% when compared with adults from phase 2 and 3 studies of ledipasvir and sofosbuvir. Ledipasvir-sofosbuvir was highly effective at treating adolescents with chronic HCV genotype 1 infection; the dose of ledipasvir-sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile. (Hepatology 2017;66:371-378).


Vagus Nerve Stimulation as a Gateway to Interoception.
The last two decades have seen a growing interest in the study of interoception. Interoception can be understood as a hierarchical phenomenon, referring to the body-to-brain communication of internal signals, their sensing, encoding, and representation in the brain, influence on other cognitive and affective processes, and their conscious perception. Interoceptive signals have been notoriously challenging to manipulate in experimental settings. Here, we propose that this can be achieved through electrical stimulation of the vagus nerve (either in an invasive or non-invasive fashion). The vagus nerve is the main pathway for conveying information about the internal condition of the body to the brain. Despite its intrinsic involvement in interoception, surprisingly little research in the field has used Vagus Nerve Stimulation to explicitly modulate bodily signals. Here, we review a range of cognitive, affective and clinical research using Vagus Nerve Stimulation, showing that it can be applied to the study of interoception at each level of its hierarchy. This could have considerable implications for our understanding of the interoceptive dimension of cognition and affect in both health and disease, and lead to development of new therapeutic tools.


Seeking safety and empathy: adolescent health seeking behavior during pregnancy and early motherhood in central Uganda.
To explore adolescent health seeking behavior during pregnancy and early motherhood in order to contribute to health policy formulation and improved access to health care. This will in long-term have an impact on the reduction of morbidity and mortality among adolescent mothers and their newborns. This was a qualitative study that employed focus group discussions (FGDs) among adolescent girls (10-19 years) and key informant (KI) interviews with health workers. Age for FGD participants ranged from 16 to 19 years. The FGD participants were recruited while seeking antenatal care for their first pregnancy or immunization service for their first child, not being older than 6 months. Six health facilities were selected. Key informants were purposefully selected on the basis of being in-charge of maternity units. Thirteen FGDs comprising of a total of 92 adolescent girls were conducted. The FGDs were held with homogeneously constituted categories; married pregnant adolescents (5), unmarried pregnant adolescents (3) and married or not married adolescents with children (5). Semi structured interviews were held with six KIs who were in-charge of maternity units of health facilities. Latent content analysis technique was used for data analysis. Two main themes emerged; 'feeling exposed and powerless', and 'seeking safety and empathy'. The categories identified in the first theme were "the dilemma of becoming an adolescent mother" and "lack of decision power". In the second theme the following categories were identified: "cultural practices and beliefs about birth", "expectations and experiences", "transport, a key determinant to health seeking", and "dealing with constraints". Adolescents felt exposed and powerless due to the dilemma of early motherhood and lack of decision making power. The adolescent mothers seemed to be in continuous quest for safety and empathy. In so doing they are part of cultural practices and beliefs about birth. They had expectations about the health care services but their experiences of the services were rather negative. Transport was a key determinant for health seeking and adolescents to some extent had learnt how to cope with constraints they face. Pregnant adolescents seek health care in both modern and traditional health sectors in order to get safety and empathy. However, our findings indicate that they mostly utilize the traditional sector because it is most accessible in terms of distance, cost and cultural context. Adolescent mothers are disempowered in decision making because of their pregnancy state which often puts them in dilemma. We therefore suggest that policy makers need to improve health systems (including the traditional sector) especially maternal health services for adolescent girls. Improved infrastructure and attitudes of health worker as well as training in delivery of adolescent health services is critical.


Adjuvant Chemotherapy After Lobectomy for T1-2N0 Non-Small Cell Lung Cancer: Are the Guidelines Supported?
Evidence guiding adjuvant chemotherapy (AC) use after lobectomy for stage I non-small cell lung cancer (NSCLC) is limited. This study evaluated the impact of AC use and tumor size on outcomes using a large, nationwide cancer database. The effect of AC on long-term survival among patients who underwent lobectomy for margin-negative pathologic T1-2N0M0 NSCLC in the National Cancer Data Base from 2003 to 2006 was estimated using the Kaplan-Meier method. The specific tumor size threshold at which AC began providing benefit was estimated with multivariable Cox proportional hazards modeling. Overall 3,496 of 34,360 patients (10.2%) who met inclusion criteria were treated with AC, although AC use increased over time from 2003, when only 2.7% of patients with tumors less than 4 cm and 6.2% of patients with tumors of 4 cm or larger received AC. In unadjusted survival analysis, AC was associated with a significant 5-year survival benefit for patients with tumors less than 4 cm (74.3% vs 66.9%; P<.0001) and 4 cm or greater (64.8% vs 49.8%; P<.0001). In subanalyses of patients grouped by strata of 0.5-cm increments in tumor size, AC was associated with a survival advantage for tumor sizes ranging from 3.0 to 8.5 cm. Use of AC among patients with stage I NSCLC has increased over time but remains uncommon. The results of this study support current treatment guidelines that recommend AC use after lobectomy for stage I NSCLC tumors larger than 4 cm. These results also suggest that AC use is associated with superior survival for patients with tumors ranging from 3.0 to 8.5 cm in diameter.


Fermentation performance and physiology of two strains of Saccharomyces cerevisiae during growth in high gravity spruce hydrolysate and spent sulphite liquor.
Lignocellulosic materials are a diverse group of substrates that are generally scarce in nutrients, which compromises the tolerance and fermentation performance of the fermenting organism. The problem is exacerbated by harsh pre-treatment, which introduces sugars and substances inhibitory to yeast metabolism. This study compares the fermentation behaviours of two yeast strains using different types of lignocellulosic substrates; high gravity dilute acid spruce hydrolysate (SH) and spent sulphite liquor (SSL), in the absence and presence of yeast extract. To this end, the fermentation performance, energy status and fermentation capacity of the strains were measured under different growth conditions. Nutrient supplementation with yeast extract increased sugar uptake, cell growth and ethanol production in all tested fermentation conditions, but had little or no effect on the energy status, irrespective of media. Nutrient-supplemented medium enhanced the fermentation capacity of harvested cells, indicating that cell viability and reusability was increased by nutrient addition. Although both substrates belong to the lignocellulosic spruce hydrolysates, their differences offer specific challenges and the overall yields and productivities largely depend on choice of fermenting strain.


The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection.
Hepatitis B virus (HBV) is a noncytopathic virus, and the recognition of infected hepatocytes by HBV-specific CD8 cells has been assumed to be the central mechanism causing both liver damage and virus control. To understand the role of cytotoxic T cells in the pathogenesis of HBV infection, we used functional assays that require T cell expansion in vitro and human histocompatibility leukocyte antigen (HLA)-peptide tetramers that allow direct ex vivo quantification of circulating and liver-infiltrating HBV-specific CD8 cells. Two groups of patients with persistent HBV infection were studied: one without liver inflammation and HBV replication, the other with liver inflammation and a high level of HBV replication. Contrary to expectation, a high frequency of intrahepatic HBV-specific CD8 cells was found in the absence of hepatic immunopathology. In contrast, virus-specific T cells were more diluted among liver infiltrates in viremic patients, but their absolute number was similar because of the massive cellular infiltration. Furthermore, inhibition of HBV replication was associated with the presence of a circulating reservoir of CD8(+) cells able to expand after specific virus recognition that was not detectable in highly viremic patients with liver inflammation. These results show that in the presence of an effective HBV-specific CD8 response, inhibition of virus replication can be independent of liver damage. When the HBV-specific CD8 response is unable to control virus replication, it may contribute to liver pathology not only directly but by causing the recruitment of nonvirus-specific T cells.


Clinician views of patient decisional conflict when deciding between dialysis and conservative management: Qualitative findings from the PAlliative Care in chronic Kidney diSease (PACKS) study.
Only a paucity of studies have addressed clinician perspectives on patient decisional conflict, in making complex decisions between dialysis and conservative management (renal supportive and palliative care). To explore clinician views on decisional conflict in patients with end-stage kidney disease. Interpretive, qualitative study. As part of the wider National Institute for Health Research, PAlliative Care in chronic Kidney diSease study, semi-structured interviews were conducted with clinicians (nephrologists n = 12; 7 female and clinical nurse specialists n = 15; 15 female) across 10 renal centres in the United Kingdom. Interviews took place between April 2015 and October 2016 and a thematic analysis of the interview data was undertaken. Three major themes with associated subthemes were identified. The first, 'Frequent changing of mind regarding treatment options', revealed how patients frequently altered their treatment decisions, some refusing to make a decision until deterioration occurred. The second theme, 'Obligatory beneficence', included clinicians helping patients to make informed decisions where outcomes were uncertain. In weighing up risks and benefits, and the impact on patients, clinicians sometimes withheld information they thought might cause concern. Finally, 'Intricacy of the decision' uncovered clinicians' views on the momentous and brave decision to be made. They also acknowledged the risks associated with this complex decision in giving prognostic information which might be inaccurate. Relies on interpretative description which uncovers constructed truths and does not include interviews with patients. Findings identify decisional conflict in patient decision-making and a tension between the prerequisite for shared decision-making and current clinical practice. Clinicians also face conflict when discussing treatment options due to uncertainty in equipoise between treatments and how much information should be shared. The findings are likely to resonate across countries outside the United Kingdom.


Posttraumatic Headache: Basic Mechanisms and Therapeutic Targets.
Frequent or continuous headache, often refractory to medical therapy, is a common occurrence after head trauma. In addition to being the most common acute symptom after traumatic brain injury (TBI), headache is also one of the most persistent and disabling symptoms. Different studies indicate that 18-58% of those suffering a TBI will have significant headache at 1 year following the trauma. In addition to being disabling on its own, posttraumatic headache (PTH) is a predictor of overall outcome after concussion. Despite its remarkable prevalence and associated social and economic costs, many fundamental and important questions about PTH remain unanswered. The purpose of this review is to identify key questions regarding the clinical characteristics of posttraumatic headache, its basic mechanisms, and its optimal management. We discuss phenotypic features of PTH, pathophysiological mechanisms of TBI including potential overlaps with those of migraine and other primary headache disorders, and potential novel targets for treatment. We suggest different strategies to finding answers to the questions regarding PTH in order to advance the understanding of the disorder and develop more effective therapies.


When an object appears unexpectedly: anticipatory movement and object circumvention in individuals with and without Developmental Coordination Disorder.
Obstacles often appear unexpectedly in our pathway and these require us to make adjustments to avoid collision. Previous research has demonstrated that healthy adults will make anticipatory adjustments to gait where they have been told there is the possibility of an obstacle appearing. One population that may find this type of anticipatory movement difficult is individuals with Developmental Coordination Disorder (DCD). The current study considered how individuals with and without DCD adjust to the possibility of an obstacle appearing which would require circumvention. Fortyfour individuals with DCD and 44 age-matched controls (aged from 7 to 34 years of age) walked down an 11 m walkway under three conditions. Initially they were told this was a clear pathway and nothing in the environment would change (1, no possibility of an obstacle, no obstacle). They then performed a series of trials in which a gate may (2, possibility of an obstacle, obstacle) or may not (3, possibility of an obstacle, no obstacle) partially obstruct their pathway. We found that all participants increased medio-lateral trunk acceleration when there was the possibility of an obstacle but before the obstacle appeared, in addition the typical adults and older children also increased step width. When describing circumvention we found that the younger children showed an increase in trunk velocity and acceleration in all three directions compared to older children and adults. We also found that the individuals with DCD adjusted their path sooner and deviated more than their peers. The degree of adjustment to step width in anticipation of an obstacle was related to later medio-lateral velocity and timing of the deviation. Therefore, the lack of 'readying' the system where there is the possibility of an obstacle appearing seen in the individuals with DCD and the younger typical children may explain the increased medio-lateral velocity seen during circumvention.


Ultrahigh-resolution, high-speed spectral domain optical coherence phase microscopy.
We present an ultrahigh-resolution, high-speed spectral domain optical coherence phase microscopy (SD-OCPM) system that combines submicrometer transverse spatial resolution and subnanometer optical path length sensitivity, with an acquisition speed of over 217,000 voxels/s. The proposed SD-OCPM system overcomes two significant drawbacks of traditional common-path interferometers-limited transverse spatial resolution and suboptimal detection sensitivity-while maintaining phase stability that is comparable with common-path interferometer setups. The transverse and axial spatial resolution of the setup is measured to be 0.6 and 1.9 μm, respectively, with a phase sensitivity of 0.0027 rad (corresponds to optical path length sensitivity of 110 pm). High-speed acquisition allows for phase-sensitive 4D imaging of biological samples with subcellular resolution.


Beta2-agonists for acute bronchitis.
There are no clearly effective treatments for the cough of acute bronchitis, and beta2-agonists are often prescribed, perhaps because clinicians suspect many patients also have reversible airflow restriction contributing to the symptoms. To determine whether beta2-agonists improve symptoms of acute bronchitis in patients who do not have underlying pulmonary disease. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2005), MEDLINE (January 1966 to November 2005) and EMBASE (1974 to November 2005). Trials in which patients (adults or children over two years of age) who were diagnosed with acute bronchitis or acute cough (without known pulmonary disease and without other cause) were randomized to beta2-agonist versus placebo, no treatment or alternative treatment. Three authors independently selected outcomes and evaluated trial quality while blinded to study results, they then extracted data. Trials in children and in adults were analyzed separately. Two trials in children (n = 109) with acute cough and no evidence of airway obstruction did not find any benefits from beta2-agonists. Combined data did not show a significant difference in daily cough scores between patients given oral beta2-agonists and those in the control groups. Five trials in adults (n = 418) with acute cough or acute bronchitis had mixed results but overall summary statistics did not reveal any significant benefits from oral (three trials) nor inhaled (two trials) beta2-agonists. There were no significant differences in daily cough scores nor in the number of patients still coughing after seven days (control rate 73%; relative risks (RR) 0.77, 95% CI 0.54 to 1.09). Subgroups of patients with evidence of airflow limitation had lower symptom scores if given beta2-agonists, in one trial. Furthermore, the trials that did note quicker resolution of cough in patients given beta2-agonists were those that had a higher proportion of patients with wheezing at baseline. Patients given beta2-agonists were more likely to report tremor, shakiness or nervousness than patients in the control groups (for trials in children: control rate 0%; RR 6.76, 95% CI 0.86 to 53.12; number needed to harm (NNH) 9, 95% CI 5 to 100; for trials in adults: control rate 11%; RR 7.94, 95% CI 1.17 to 53.94; NNH 2.3, 95% CI 2 to 3). There is no evidence to support the use of beta2-agonists in children with acute cough who do not have evidence of airflow obstruction. There is also little evidence that the routine use of beta2-agonists is helpful for adults with acute cough. These agents may reduce symptoms, including cough, in patients with evidence of airflow obstruction. However, this potential benefit is not well-supported by the available data and must be weighed against the adverse effects associated with beta2-agonists.


Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice.
Worldwide, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. Despite the urgency to develop and implement novel approaches capable of preventing HIV transmission, this process has been hindered by the lack of adequate small animal models for preclinical efficacy and safety testing. Given the importance of this route of transmission, we investigated the susceptibility of humanized mice to intravaginal HIV-1 infection. We show that the female reproductive tract of humanized bone marrow-liver-thymus (BLT) mice is reconstituted with human CD4+ T and other relevant human cells, rendering these humanized mice susceptible to intravaginal infection by HIV-1. Effects of HIV-1 infection include CD4+ T cell depletion in gut-associated lymphoid tissue (GALT) that closely mimics what is observed in HIV-1-infected humans. We also show that pre-exposure prophylaxis with antiretroviral drugs is a highly effective method for preventing vaginal HIV-1 transmission. Whereas 88% (7/8) of BLT mice inoculated vaginally with HIV-1 became infected, none of the animals (0/5) given pre-exposure prophylaxis of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) showed evidence of infection (Chi square = 7.5, df = 1, p = 0.006). The fact that humanized BLT mice are susceptible to intravaginal infection makes this system an excellent candidate for preclinical evaluation of both microbicides and pre-exposure prophylactic regimens. The utility of humanized mice to study intravaginal HIV-1 transmission is particularly highlighted by the demonstration that pre-exposure prophylaxis can prevent intravaginal HIV-1 transmission in the BLT mouse model.


Development of a quantitative assay amenable for high-throughput screening to target the type II secretion system for new treatments against plant-pathogenic bacteria.
Plant-pathogenic bacteria are the causative agents of diseases in important agricultural crops and ornamental plants. The severe economic burden of these diseases requires seeking new approaches for their control, particularly because phytopathogenic bacteria are often resistant to available treatments. The type II secretion (T2S) system is a key virulence factor used by major groups of phytopathogenic bacteria. The T2S machinery transports many hydrolytic enzymes responsible for degradation of the plant cell wall, thus enabling successful colonization and dissemination of the bacteria in the plant host. The genetic inactivation of the T2S system leads to loss of virulence, which strongly suggests that targeting the T2S could enable new treatments against plant-pathogenic bacteria. Accordingly, we have designed and optimized an assay to identify small-molecule inhibitors of the T2S system. This assay uses a double parametric output: measurement of bacterial growth and the enzymatic activity of cellulase, which is secreted via the T2S pathway in our model organism Dickeya dadantii. The assay was evaluated by screening natural extracts, culture filtrates isolated from rhizosphere bacteria, and a collection of pharmaceutically active compounds in LOPAC(1280). The calculated Z' values of 0.63, 0.63, and 0.58, respectively, strongly suggest that the assay is applicable for a high-throughput screening platform.


Psychosocial effects of living with an increased risk of breast cancer: an exploratory study using telephone focus groups.
Research to date has mainly focused on the short-term psychological impact of genetic risk counselling for breast cancer. This study aimed to explore the long-term consequences for women of being informed about an increased risk of breast cancer in terms of: the effect on their everyday lives, their coping strategies and their unmet needs in terms of the current service. The participants were 25 women with a family history of breast cancer who had received genetic risk counselling and had consequently been receiving clinical surveillance for at least 2 years. They took part in one of seven telephone focus groups and subsequently completed a feedback questionnaire. Transcripts of the focus groups were qualitatively analysed by three independent researchers with inter-rater agreement between pairs of raters ranging from Kappa = 0.61-0.79. Six key issues emerged from the data, which provide an important insight into the long-term consequences of living with an increased risk of breast cancer concerning: (1) psychological adaptation, (2) behavioural adaptation, (3) family issues, (4) clinical surveillance, (5) provision of information, and (6) peer support. These findings, together with the quantitative results of the feedback questionnaire, have clinical implications that require further investigation in larger scale quantitative research.


Transmission of Multidrug-Resistant and Drug-Susceptible Tuberculosis within Households: A Prospective Cohort Study.
The "fitness" of an infectious pathogen is defined as the ability of the pathogen to survive, reproduce, be transmitted, and cause disease. The fitness of multidrug-resistant tuberculosis (MDRTB) relative to drug-susceptible tuberculosis is cited as one of the most important determinants of MDRTB spread and epidemic size. To estimate the relative fitness of drug-resistant tuberculosis cases, we compared the incidence of tuberculosis disease among the household contacts of MDRTB index patients to that among the contacts of drug-susceptible index patients. This 3-y (2010-2013) prospective cohort household follow-up study in South Lima and Callao, Peru, measured the incidence of tuberculosis disease among 1,055 household contacts of 213 MDRTB index cases and 2,362 household contacts of 487 drug-susceptible index cases. A total of 35/1,055 (3.3%) household contacts of 213 MDRTB index cases developed tuberculosis disease, while 114/2,362 (4.8%) household contacts of 487 drug-susceptible index patients developed tuberculosis disease. The total follow-up time for drug-susceptible tuberculosis contacts was 2,620 person-years, while the total follow-up time for MDRTB contacts was 1,425 person-years. Using multivariate Cox regression to adjust for confounding variables including contact HIV status, contact age, socio-economic status, and index case sputum smear grade, the hazard ratio for tuberculosis disease among MDRTB household contacts was found to be half that for drug-susceptible contacts (hazard ratio 0.56, 95% CI 0.34-0.90, p = 0.017). The inference of transmission in this study was limited by the lack of genotyping data for household contacts. Capturing incident disease only among household contacts may also limit the extrapolation of these findings to the community setting. The low relative fitness of MDRTB estimated by this study improves the chances of controlling drug-resistant tuberculosis. However, fitter multidrug-resistant strains that emerge over time may make this increasingly difficult.