Invasive fungal infections secondary to traumatic injury

Invasive fungal infection (IFI) is a rare but serious complication of traumatic injury. The purpose of this article is to review the epidemiology, natural history, mycology, risk factors, diagnosis, treatment, and outcomes associated with post-traumatic IFI in military and civilian populations. The epidemiology of post-traumatic IFI is poorly characterized, but incidence appears to be rising. Patients often suffer from severe injuries and require extensive medical interventions. Fungi belonging to the order Mucorales are responsible for most post-traumatic IFI in both civilian and military populations. Risk factors differ between these cohorts but include specific injury patterns and comorbidities. Diagnosis of post-traumatic IFI typically follows positive laboratory results in the appropriate clinical context. The gold standard of treatment is surgical debridement in addition to systemic antifungal therapy. Patients with post-traumatic IFI may be at greater risk of amputation, delays in wound healing, hospital complications, and death as compared to trauma patients who do not develop IFI. More research is needed to understand the factors surrounding the development and management of post-traumatic IFI to reduce the significant morbidity and mortality associated with this disease

Circumbinary disk evolution in the presence of an outer companion star

We consider a hierarchical triple system consisting of an inner eccentric binary with an outer companion. A highly misaligned circumbinary disk around the inner binary is subject to two competing effects: (i) nodal precession about the inner binary eccentricity vector that leads to an increase in misalignment (polar alignment) and (ii) Kozai-Lidov (KL) oscillations of eccentricity and inclination driven by the outer companion that leads to a reduction in the misalignment. The outcome depends upon the ratio of the timescales of these effects. If the inner binary torque dominates, then the disk aligns to a polar orientation. If the outer companion torque dominates, then the disk undergoes KL oscillations. In that case, the highly eccentric and misaligned disk is disrupted and accreted by the inner binary, while some mass is transferred to the outer companion. However, when the torques are similar, the outer parts of the circumbinary disk can undergo large eccentricity oscillations while the inclination remains close to the polar orientation. The range of initial disk inclinations that evolve to a polar orientation is smaller in the presence of the outer companion. Disk breaking is also more likely, at least temporarily, during the polar alignment process. The stellar orbits in HD 98800 have parameters such that polar alignment of the circumbinary disk is expected. In the absence of the gas, solid particles are unstable at much smaller radii than the gas disk inner tidal truncation radius because KL driven eccentricity leads to close encounters with the binary.Comment: Accepted for publication in ApJ

Haploinsufficiency for BRCA1 is associated with normal levels of DNA nucleotide excision repair in breast tissue and blood lymphocytes

BACKGROUND: Screening mammography has had a positive impact on breast cancer mortality but cannot detect all breast tumors. In a small study, we confirmed that low power magnetic resonance imaging (MRI) could identify mammographically undetectable tumors by applying it to a high risk population. Tumors detected by this new technology could have unique etiologies and/or presentations, and may represent an increasing proportion of clinical practice as new screening methods are validated and applied A very important aspect of this etiology is genomic instability, which is associated with the loss of activity of the breast cancer-predisposing genes BRCA1 and BRCA2. In sporadic breast cancer, however, there is evidence for the involvement of a different pathway of DNA repair, nucleotide excision repair (NER), which remediates lesions that cause a distortion of the DNA helix, including DNA cross-links. CASE PRESENTATION: We describe a breast cancer patient with a mammographically undetectable stage I tumor identified in our MRI screening study. She was originally considered to be at high risk due to the familial occurrence of breast and other types of cancer, and after diagnosis was confirmed as a carrier of a Q1200X mutation in the BRCA1 gene. In vitro analysis of her normal breast tissue showed no differences in growth rate or differentiation potential from disease-free controls. Analysis of cultured blood lymphocyte and breast epithelial cell samples with the unscheduled DNA synthesis assay (UDS) revealed no deficiency in nucleotide excision repair (NER). CONCLUSION: As new breast cancer screening methods become available and cost effective, patients such as this one will constitute an increasing proportion of the incident population, so it is important to determine whether they differ from current patients in any clinically important ways. Despite her status as a BRCA1 mutation carrier, and her mammographically dense breast tissue, we did not find increased cell proliferation or deficient differentiation potential in her breast epithelial cells, which might have contributed to her cancer susceptibility. Although NER deficiency has been demonstrated repeatedly in blood samples from sporadic breast cancer patients, analysis of blood cultured lymphocytes and breast epithelial cells for this patient proves definitively that heterozygosity for inactivation of BRCA1 does not intrinsically confer this type of genetic instability. These data suggest that the mechanism of genomic instability driving the carcinogenic process may be fundamentally different in hereditary and sporadic breast cancer, resulting in different genotoxic susceptibilities, oncogene mutations, and a different molecular pathogenesis

Cost Analysis of Outpatient Anterior Cruciate Ligament Reconstruction: Autograft versus Allograft

Prior studies suggest the cost of allograft anterior cruciate ligament (ACL) reconstruction is less than that for autograft reconstruction. Charges in these studies were influenced by patients requiring inpatient hospitalization. We therefore determined if allograft ACL reconstruction would still be less costly if all procedures were performed in a completely outpatient setting. We retrospectively reviewed 155 patients who underwent ACL reconstruction in an ambulatory surgery center between 2001 and 2004; 105 had an autograft and 50 had an allograft. Charges were extracted from itemized billing records, standardized to eliminate cost increases, and categorized for comparison. Surgeon and anesthesiologist fees were not included in the analysis. Groups were compared for age, gender, mean total cost, mean cost of implants, and several other cost categories. The mean total cost was $5465 for allograft ACL reconstruction and$4872 for autograft ACL reconstruction. There were no differences in complications between the two groups. Allograft ACL reconstruction was more costly than autograft ACL reconstruction in the outpatient setting. The cost of the allograft outweighs the increased surgical time needed for harvesting an autograft. Level II, economic and decision analyses. See Guidelines for Authors for a complete description of levels of evidence

Missed opportunities for tuberculosis prevention among patients accessing a UK HIV service.

United Kingdom guidelines recommend screening for and treatment of latent tuberculosis infection (LTBI) in HIV-positive patients at high risk of active tuberculosis (TB) disease, but implementation is suboptimal. We investigated potential missed opportunities to identify and treat LTBI among HIV-positive patients accessing a large HIV outpatient service in London. Case records of all adult patients attending our service for HIV care diagnosed with active TB between 2011 and 2015 were reviewed to determine whether they met criteria for LTBI screening and whether screening was undertaken. Twenty-five patients were treated for TB. Of 15 (60%) patients who started TB treatment ≥6 months after HIV diagnosis, 14 (93%) met UK guideline-recommended criteria for LTBI screening and treatment; only one (7%) had been screened for LTBI. Eight of these 15 (53%) patients had additional risk factors for TB which are not reflected in current UK guidelines. Of 15 patients treated for TB ≥6 months after diagnosis of HIV, 14 (93%) had not been screened for LTBI, suggesting missed opportunities for TB prevention. People living with HIV may benefit from a broader approach to LTBI screening which takes into account additional recognised TB risk factors and ongoing TB exposure

Influenza Vaccine Effectiveness against Hospitalisation with Confirmed Influenza in the 2010-11 Seasons: A Test-negative Observational Study

Immunisation programs are designed to reduce serious morbidity and mortality from influenza, but most evidence supporting the effectiveness of this intervention has focused on disease in the community or in primary care settings. We aimed to examine the effectiveness of influenza vaccination against hospitalisation with confirmed influenza. We compared influenza vaccination status in patients hospitalised with PCR-confirmed influenza with patients hospitalised with influenza-negative respiratory infections in an Australian sentinel surveillance system. Vaccine effectiveness was estimated from the odds ratio of vaccination in cases and controls. We performed both simple multivariate regression and a stratified analysis based on propensity score of vaccination. Vaccination status was ascertained in 333 of 598 patients with confirmed influenza and 785 of 1384 test-negative patients. Overall estimated crude vaccine effectiveness was 57% (41%, 68%). After adjusting for age, chronic comorbidities and pregnancy status, the estimated vaccine effectiveness was 37% (95% CI: 12%, 55%). In an analysis accounting for a propensity score for vaccination, the estimated vaccine effectiveness was 48.3% (95% CI: 30.0, 61.8%). Influenza vaccination was moderately protective against hospitalisation with influenza in the 2010 and 2011 seasons

Altered Thalamocortical Development in the SAP102 Knockout Model of Intellectual Disability

Genetic mutations known to cause intellectual disabilities (IDs) are concentrated in specific sets of genes including both those encoding synaptic proteins and those expressed during early development. We have characterized the effect of genetic deletion of Dlg3, an ID-related gene encoding the synaptic NMDA-receptor interacting protein synapse-associated protein 102 (SAP102), on development of the mouse somatosensory cortex. SAP102 is the main representative of the PSD-95 family of postsynaptic MAGUK proteins during early development and is proposed to play a role in stabilizing receptors at immature synapses. Genetic deletion of SAP102 caused a reduction in the total number of thalamocortical (TC) axons innervating the somatosensory cortex, but did not affect the segregation of barrels. On a synaptic level SAP102 knockout mice display a transient speeding of NMDA receptor kinetics during the critical period for TC plasticity, despite no reduction in GluN2B-mediated component of synaptic transmission. These data indicated an interesting dissociation between receptor kinetics and NMDA subunit expression. Following the critical period NMDA receptor function was unaffected by loss of SAP102 but there was a reduction in the divergence of TC connectivity. These data suggest that changes in synaptic function early in development caused by mutations in SAP102 result in changes in network connectivity later in life

Impact of Plasmodium falciparum malaria and intermittent preventive treatment of malaria in pregnancy on the risk of malaria in infants: a systematic review.

BACKGROUND: Studies of the association between malaria in pregnancy (MiP) and malaria during infancy have provided mixed results. A systematic review was conducted to evaluate available evidence on the impact of Plasmodium falciparum malaria infection during pregnancy, and intermittent preventive treatment of malaria during pregnancy (IPTp), on the risk of clinical malaria or parasitaemia during infancy. METHODS: MEDLINE, EMBASE, Global Health, and Malaria in Pregnancy Library databases were searched from inception to 22 May 2018 for articles published in English that reported on associations between MiP and malaria risk in infancy. Search terms included malaria, Plasmodium falciparum, pregnancy, placenta, maternal, prenatal, foetal, newborn, infant, child or offspring or preschool. Randomized controlled trials and prospective cohort studies, which followed infants for at least 6 months, were included if any of the following outcomes were reported: incidence of clinical malaria, prevalence of parasitaemia, and time to first episode of parasitaemia or clinical malaria. Substantial heterogeneity between studies precluded meta-analysis. Thus, a narrative synthesis of included studies was conducted. RESULTS: The search yielded 14 published studies, 10 prospective cohort studies and four randomized trials; all were conducted in sub-Saharan Africa. Infants born to mothers with parasitaemia during pregnancy were at higher risk of malaria in three of four studies that assessed this association. Placental malaria detected by microscopy or histology was associated with a higher risk of malaria during infancy in nine of 12 studies, but only one study adjusted for malaria transmission intensity. No statistically significant associations between the use of IPTp or different IPTp regimens and the risk of malaria during infancy were identified. CONCLUSION: Evidence of an association between MiP and IPTp and risk of malaria in infancy is limited and of variable quality. Most studies did not adequately adjust for malaria transmission intensity shared by mothers and their infants. Further research is needed to confirm or exclude an association between MiP and malaria in infancy. Randomized trials evaluating highly effective interventions aimed at preventing MiP, such as IPTp with dihydroartemisinin-piperaquine, may help to establish a causal association between MiP and malaria in infancy