Using molecular data for epidemiological inference: assessing the prevalence of Trypanosoma brucei rhodesiense in Tsetse in Serengeti, Tanzania

Background: Measuring the prevalence of transmissible Trypanosoma brucei rhodesiense in tsetse populations is essential for understanding transmission dynamics, assessing human disease risk and monitoring spatio-temporal trends and the impact of control interventions. Although an important epidemiological variable, identifying flies which carry transmissible infections is difficult, with challenges including low prevalence, presence of other trypanosome species in the same fly, and concurrent detection of immature non-transmissible infections. Diagnostic tests to measure the prevalence of T. b. rhodesiense in tsetse are applied and interpreted inconsistently, and discrepancies between studies suggest this value is not consistently estimated even to within an order of magnitude. Methodology/Principal Findings: Three approaches were used to estimate the prevalence of transmissible Trypanosoma brucei s.l. and T. b. rhodesiense in Glossina swynnertoni and G. pallidipes in Serengeti National Park, Tanzania: (i) dissection/microscopy; (ii) PCR on infected tsetse midguts; and (iii) inference from a mathematical model. Using dissection/microscopy the prevalence of transmissible T. brucei s.l. was 0% (95% CI 0–0.085) for G. swynnertoni and 0% (0–0.18) G. pallidipes; using PCR the prevalence of transmissible T. b. rhodesiense was 0.010% (0–0.054) and 0.0089% (0–0.059) respectively, and by model inference 0.0064% and 0.00085% respectively. Conclusions/Significance: The zero prevalence result by dissection/microscopy (likely really greater than zero given the results of other approaches) is not unusual by this technique, often ascribed to poor sensitivity. The application of additional techniques confirmed the very low prevalence of T. brucei suggesting the zero prevalence result was attributable to insufficient sample size (despite examination of 6000 tsetse). Given the prohibitively high sample sizes required to obtain meaningful results by dissection/microscopy, PCR-based approaches offer the current best option for assessing trypanosome prevalence in tsetse but inconsistencies in relating PCR results to transmissibility highlight the need for a consensus approach to generate meaningful and comparable data

Short- and long-term cause-specific survival of patients with inflammatory breast cancer

BACKGROUND: Inflammatory breast cancer (IBC) had been perceived to have a poor prognosis. Oncologists were not enthusiastic in the past to give aggressive treatment. Single institution studies tend to have small patient numbers and limited years of follow-up. Most studies do not report 10-, 15- or 20-year results. METHODS: Data was obtained from the population-based database of the Surveillance, Epidemiology, and End Results program of the National Cancer Institute from 1975–1995 using SEER*Stat5.0 software. This period of 21 years was divided into 7 periods of 3 years each. The years were chosen so that there was adequate follow-up information to 2000. ICD-O-2 histology 8530/3 was used to define IBC. The lognormal model was used for statistical analysis. RESULTS: A total of 1684 patients were analyzed, of which 84% were white, 11% were African Americans, and 5% belonged to other races. Age distribution was < 30 years in 1%, 30–40 in 11%, 40–50 in 22%, 50–60 in 24%, 60–70 in 21%, and > 70 in 21%. The lognormal model was validated for 1975–77 and for 1978–80, since the 10-, 15- and 20-year cause-specific survival (CSS) rates, could be calculated using the Kaplan-Meier method with data available in 2000. The data were then used to estimate the 10-, 15- and 20-year CSS rates for the more recent years, and to study the trend of improvement in survival. There were increasing incidences of IBC: 134 patients in the 1975–77 period to 416 patients in the 1993–95 period. The corresponding 20-year CSS increased from 9% to 20% respectively with standard errors of less than 4%. CONCLUSION: The improvement of survival during the study period may be due to introduction of more aggressive treatments. However, there seem to be no further increase of long-term CSS, which should encourage oncologists to find even more effective treatments. Because of small numbers of patients, randomized studies will be difficult to conduct. The SEER population-based database will yield the best possible estimate of the trend in improvement of survival for patients with IBC

Effectiveness of offloading interventions to heal foot ulcers in persons with diabetes: a systematic review

Background Offloading interventions are commonly used in clinical practice to heal foot ulcers. The aim of this updated systematic review is to investigate the effectiveness of offloading interventions to heal diabetic foot ulcers. Methods We updated our previous systematic review search of PubMed, EMBASE, and Cochrane databases to also include original studies published between July 29, 2014 and August 13, 2018 relating to four offloading intervention categories in populations with diabetic foot ulcers: (a) offloading devices, (b) footwear, (c) other offloading techniques, and (d) surgical offloading techniques. Outcomes included ulcer healing, plantar pressure, ambulatory activity, adherence, adverse events, patient‐reported measures, and cost‐effectiveness. Included controlled studies were assessed for methodological quality and had key data extracted into evidence and risk of bias tables. Included non‐controlled studies were summarised on a narrative basis. Results We identified 41 studies from our updated search for a total of 165 included studies. Six included studies were meta‐analyses, 26 randomised controlled trials (RCTs), 13 other controlled studies, and 120 non‐controlled studies. Five meta‐analyses and 12 RCTs provided high‐quality evidence for non‐removable knee‐high offloading devices being more effective than removable offloading devices and therapeutic footwear for healing plantar forefoot and midfoot ulcers. Total contact casts (TCCs) and non‐removable knee‐high walkers were shown to be equally effective. Moderate‐quality evidence exists for removable knee‐high and ankle‐high offloading devices being equally effective in healing, but knee‐high devices have a larger effect on reducing plantar pressure and ambulatory activity. Low‐quality evidence exists for the use of felted foam and surgical offloading to promote healing of plantar forefoot and midfoot ulcers. Very limited evidence exists for the efficacy of any offloading intervention for healing plantar heel ulcers, non‐plantar ulcers, and neuropathic ulcers with infection or ischemia. Conclusion Strong evidence supports the use of non‐removable knee‐high offloading devices (either TCC or non‐removable walker) as the first‐choice offloading intervention for healing plantar neuropathic forefoot and midfoot ulcers. Removable offloading devices, either knee‐high or ankle‐high, are preferred as second choice over other offloading interventions. The evidence bases to support any other offloading intervention is still weak and more high‐quality controlled studies are needed in these areas

A Search for leptophilic Z_(l) boson at future linear colliders

We study the possible dynamics associated with leptonic charge in future linear colliders. Leptophilic massive vector boson, Z_(l), have been investigated through the process e^(+)e^(-) -> mu^(+)mu^(-). We have shown that ILC and CLIC will give opportunity to observe Z_(l) with masses up to the center of mass energy if the corresponding coupling constant g_(l) exceeds 10^(-3).Comment: 12 pages, 10 figure

Russell bodies in a skin biopsy: a case report

<p>Abstract</p> <p>Introduction</p> <p>The presence of eosinophilic bodies in a skin biopsy can be found in a variety of situations and this may present a challenge to the pathologist. The differential diagnosis of these eosinophilic structures include microorganisms such as histoplasmosis or cryptococcosis, fungi, Michaelis-Gutmann bodies, deposits of amyloid or immunoglobulins, colloid bodies or elastic bodies.</p> <p>Case presentation</p> <p>During a routine examination of a skin biopsy with actinic keratosis taken from the cheek of a 61-year-old man, clusters of eosinophilic bodies were seen within an inflammatory infiltrate in the dermis, both intracytoplasmic and extracellular. Using additional immunohistochemical staining, these structures were identified as polyclonal Russell bodies.</p> <p>Conclusion</p> <p>The differential diagnosis of intracytoplasmic eosinophilic structures in a skin biopsy includes Russell bodies, an uncommon finding that may be associated with chronic inflammatory conditions.</p

Breathing adapted radiotherapy: a 4D gating software for lung cancer

<p>Abstract</p> <p>Purpose</p> <p>Physiological respiratory motion of tumors growing in the lung can be corrected with respiratory gating when treated with radiotherapy (RT). The optimal respiratory phase for beam-on may be assessed with a respiratory phase optimizer (RPO), a 4D image processing software developed with this purpose.</p> <p>Methods and Materials</p> <p>Fourteen patients with lung cancer were included in the study. Every patient underwent a 4D-CT providing ten datasets of ten phases of the respiratory cycle (0-100% of the cycle). We defined two morphological parameters for comparison of 4D-CT images in different respiratory phases: tumor-volume to lung-volume ratio and tumor-to-spinal cord distance. The RPO automatized the calculations (200 per patient) of these parameters for each phase of the respiratory cycle allowing to determine the optimal interval for RT.</p> <p>Results</p> <p>Lower lobe lung tumors not attached to the diaphragm presented with the largest motion with breathing. Maximum inspiration was considered the optimal phase for treatment in 4 patients (28.6%). In 7 patients (50%), however, the RPO showed a most favorable volumetric and spatial configuration in phases other than maximum inspiration. In 2 cases (14.4%) the RPO showed no benefit from gating. This tool was not conclusive in only one case.</p> <p>Conclusions</p> <p>The RPO software presented in this study can help to determine the optimal respiratory phase for gated RT based on a few simple morphological parameters. Easy to apply in daily routine, it may be a useful tool for selecting patients who might benefit from breathing adapted RT.</p

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.</p> <p>Methods</p> <p>Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the <it>EVC/EVC2 </it>locus. The results did not exclude linkage, so samples were sequenced for mutations.</p> <p>Results</p> <p>We identified a c.1868T>C mutation in <it>EVC</it>, which predicts p.L623P, and was homozygous in affected individuals.</p> <p>Conclusion</p> <p>We conclude that this <it>EVC </it>mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. <it>EVC </it>mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.</p

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.</p> <p>Methods</p> <p>Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the <it>EVC/EVC2 </it>locus. The results did not exclude linkage, so samples were sequenced for mutations.</p> <p>Results</p> <p>We identified a c.1868T>C mutation in <it>EVC</it>, which predicts p.L623P, and was homozygous in affected individuals.</p> <p>Conclusion</p> <p>We conclude that this <it>EVC </it>mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. <it>EVC </it>mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.</p

Loop Quantum Gravity a la Aharonov-Bohm

The state space of Loop Quantum Gravity admits a decomposition into orthogonal subspaces associated to diffeomorphism equivalence classes of spin-network graphs. In this paper I investigate the possibility of obtaining this state space from the quantization of a topological field theory with many degrees of freedom. The starting point is a 3-manifold with a network of defect-lines. A locally-flat connection on this manifold can have non-trivial holonomy around non-contractible loops. This is in fact the mathematical origin of the Aharonov-Bohm effect. I quantize this theory using standard field theoretical methods. The functional integral defining the scalar product is shown to reduce to a finite dimensional integral over moduli space. A non-trivial measure given by the Faddeev-Popov determinant is derived. I argue that the scalar product obtained coincides with the one used in Loop Quantum Gravity. I provide an explicit derivation in the case of a single defect-line, corresponding to a single loop in Loop Quantum Gravity. Moreover, I discuss the relation with spin-networks as used in the context of spin foam models.Comment: 19 pages, 1 figure; v2: corrected typos, section 4 expanded

Assisted evolution enables HIV-1 to overcome a high trim5α-imposed genetic barrier to rhesus macaque tropism

Diversification of antiretroviral factors during host evolution has erected formidable barriers to cross-species retrovirus transmission. This phenomenon likely protects humans from infection by many modern retroviruses, but it has also impaired the development of primate models of HIV-1 infection. Indeed, rhesus macaques are resistant to HIV-1, in part due to restriction imposed by the TRIM5α protein (rhTRIM5α). Initially, we attempted to derive rhTRIM5α-resistant HIV-1 strains using two strategies. First, HIV-1 was passaged in engineered human cells expressing rhTRIM5α. Second, a library of randomly mutagenized capsid protein (CA) sequences was screened for mutations that reduced rhTRIM5α sensitivity. Both approaches identified several individual mutations in CA that reduced rhTRIM5α sensitivity. However, neither approach yielded mutants that were fully resistant, perhaps because the locations of the mutations suggested that TRIM5α recognizes multiple determinants on the capsid surface. Moreover, even though additive effects of various CA mutations on HIV-1 resistance to rhTRIM5α were observed, combinations that gave full resistance were highly detrimental to fitness. Therefore, we employed an 'assisted evolution' approach in which individual CA mutations that reduced rhTRIM5α sensitivity without fitness penalties were randomly assorted in a library of viral clones containing synthetic CA sequences. Subsequent passage of the viral library in rhTRIM5α-expressing cells resulted in the selection of individual viral species that were fully fit and resistant to rhTRIM5α. These viruses encoded combinations of five mutations in CA that conferred complete or near complete resistance to the disruptive effects of rhTRIM5α on incoming viral cores, by abolishing recognition of the viral capsid. Importantly, HIV-1 variants encoding these CA substitutions and SIVmac239 Vif replicated efficiently in primary rhesus macaque lymphocytes. These findings demonstrate that rhTRIM5α is difficult to but not impossible to evade, and doing so should facilitate the development of primate models of HIV-1 infection