False positive bronchoalveolar lavage galactomannan: Effect of host and cut-off value.

OBJECTIVES: Bronchoalveolar lavage galactomannan (BAL-GM) is a mycological criterion for diagnosis of probable invasive aspergillosis (IA) per European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORT-MSG) consensus criteria, but its real-world positive predictive value (PPV) has not been well-studied. Our aim was to estimate the PPV of BAL-GM in a contemporary cohort of patients with positive BAL-GM. METHODS: We identified consecutive patients with ≥1 positive BAL-GM value (index ≥ 0.5) at Brigham and Women's Hospital from 11/2009 to 3/2016. We classified patients as having no, possible, probable, or proven IA, excluding BAL-GM as mycological criterion. RESULTS: We studied 134 patients: 54% had hematologic malignancy (HM), and 10% were solid organ transplant (SOT) recipients. A total of 42% of positive (≥0.5) BAL-GM results were falsely positive (PPV 58%). The number of probable IA cases was increased by 23% using positive BAL-GM as mycologic criterion alone. PPV was higher in patients with HM or SOT (P < 0.001) and with use of higher thresholds for positivity (BAL-GM ≥ 1 vs 1-0.8 vs 0.8-0.5: P = 0.002). CONCLUSIONS: 42% of positive BAL-GM values were falsely positive. We propose a critical reassessment of BAL-GM cutoff values in different patient populations. Accurate noninvasive tests for diagnosis of IA are urgently needed.

Initial Treatment of Cancer Patients with Fluconazole-Susceptible Dose-Dependent Candida glabrata Fungemia: Better Outcome with an Echinocandin or Polyene Compared to an Azole?

The 28-day crude mortality rate in 68 cancer patients with fluconazole-susceptible dose-dependent Candida glabrata fungemia started on treatment (within 48 h after blood culture collection) with an echinocandin or liposomal amphotericin-B was better (30%) than those treated with azole monotherapy (52%) (P = 0.07). After adjusting for confounders, azole monotherapy also was associated with worse 28-day survival (hazard ratio, 3.8; P = 0.003).

Optimizing Aesthetic Outcomes in Autologous Breast Reconstruction: 20 Pearls for Practice.

Autologous breast reconstruction with a deep inferior epigastric artery perforator (DIEP) flap is an excellent option for many patients proceeding with mastectomy for surgical management of their breast cancer. As microsurgical techniques and results improve and ensure consistent flap survival, optimizing aesthetic outcomes may become a primary focus. This article outlines 20 tips that can improve aesthetic results in DIEP flap breast reconstruction, based on our senior author's 8-year career in microsurgical breast reconstruction, with an emphasis on enhanced cosmesis. We highlight tips on preoperative planning, intraoperative, and revision stages of the reconstruction and provide a schematic for integrating the tips into a reader's microsurgical breast reconstruction practice.

Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures.

The neurotrophin nerve growth factor (NGF) regulates neuronal growth, differentiation, and survival during development. However, the precursor of NGF, proNGF, is a potent apoptotic ligand for the p75 neurotrophin receptor (p75(NTR))-sortilin complex. The mechanisms that regulate cleavage of proNGF, therefore, are critical determinants of whether this factor promotes neuronal survival or death. In this study, we demonstrate that, following kainic acid-induced seizures, the proNGF processing enzyme matrix metalloproteinase 7 (MMP-7) and its inhibitor TIMP-1 (tissue inhibitor of matrix metalloproteinase 1) are regulated in a manner that prevents proneurotrophin cleavage and leads to increased proNGF in the extracellular milieu. Furthermore, we demonstrate both in vitro and in vivo that exogenous MMP-7 enhances proNGF cleavage and provides neuroprotection following kainic acid treatment. These data demonstrate that increased extracellular proNGF levels following seizures are stabilized by altered MMP-7 enzymatic activity, leading to increased neuronal death via activation of p75(NTR).

A human phospholipid phosphatase activated by a transmembrane control module.

In voltage-sensitive phosphatases (VSPs), a transmembrane voltage sensor domain (VSD) controls an intracellular phosphoinositide phosphatase domain, thereby enabling immediate initiation of intracellular signals by membrane depolarization. The existence of such a mechanism in mammals has remained elusive, despite the presence of VSP-homologous proteins in mammalian cells, in particular in sperm precursor cells. Here we demonstrate activation of a human VSP (hVSP1/TPIP) by an intramolecular switch. By engineering a chimeric hVSP1 with enhanced plasma membrane targeting containing the VSD of a prototypic invertebrate VSP, we show that hVSP1 is a phosphoinositide-5-phosphatase whose predominant substrate is PI(4,5)P(2). In the chimera, enzymatic activity is controlled by membrane potential via hVSP1's endogenous phosphoinositide binding motif. These findings suggest that the endogenous VSD of hVSP1 is a control module that initiates signaling through the phosphatase domain and indicate a role for VSP-mediated phosphoinositide signaling in mammals.

CO2 laser resurfacing for burn and traumatic scars of the hand and upper extremity.

BACKGROUND: Scar formation is a normal part of the proliferative phase in wound healing where collagen is remodelled to better approximate normal skin. When collagen is not effectively redistributed, excessive scarring may occur. Recently, CO2 laser has emerged as an adjunct in improving scar quality via remodelling and redistribution of dermal collagen fibres. Due to the paucity of literature related to its use in the hands and upper extremities, we created a study to examine its effects on hypertrophic scars focused on the hands and upper extremities. METHODS: Patients treated with CO2 laser for hypertrophic scars of the hand and upper extremity were included. The Vancouver Scar Scale (VSS) and Patient and Observer Scar Assessment Scale (POSAS) were used to assess the progression of scar quality. Unpaired t-tests were performed to determine statistical difference between pre- and post-treatment scores on each scale. Pearson correlation coefficients were used to understand the relationship between number of treatments and scar quality. RESULTS: Of the 90 patients enrolled, 54 patients completed serial scar assessment forms. All patient and observer-reported POSAS domains showed improvement (P < 0.05) apart from Itching. All VSS domains showed improvement (P < 0.05). There was moderate correlation between overall patient-reported opinion of scar quality and Discoloration, Stiffness and Thickness, and strong correlation between overall patient opinion and Irregularity (r = 0.715). All observer-reported domains were strongly correlated (r = 7.56-8.74) with overall observer opinion of scar quality. CONCLUSION: The results of this study may further substantiate CO2 laser as a treatment modality for excessive scarring in a variety of surgical subspecialties. LAY SUMMARY: Complex trauma and burns that impact the skin sometimes result in abnormal healing of the skin called, "hypertrophic scarring". In our study we assessed how using focused CO2 laser therapy impacts patients and health care provider assessment of wound progression. Our results were based upon patient reported and healthcare provider observations based upon two standardized forms the Vancouver Scar Scale (VSS) and the Patient and Observer Scar Assessment Scale (POSAS). What we found is that after CO2 Laser Therapy, our 64 patients with 77 treated scars received on average almost 3 treatments and these treatments helped them with physical function and improved aesthetic appearance of their scars. The health care providers also found that the treatments improved functional and aesthetic end points. Overall, our study helps substantiate the body of evidence that using CO2 laser therapy improves aesthetics and function of hypertrophic scars in the upper extremity.

Surgical management of advanced hidradenitis suppurativa via a one-stage procedure: A single-center experience.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating skin condition; in severe forms it requires excision and skin grafting for cure. This is commonly performed as a multi-stage procedure; we explored single-stage operation as a more efficient alternative. METHODS: Retrospective review 2007-2018 evaluating outcomes of patients undergoing single-stage surgery. RESULTS: 139 one-stage procedures were performed: 35 excision and primary closure, 104 split-thickness skin grafting (STSG). Success rate was higher for STSG at 75% versus 60% with primary closure. Of failed primary closures, 57% required revision by grafting due to recurrence. Axilla procedures were most successful at 91% compared to 70%, 54%, and 50% for inguinal, gluteal, and perineal areas, respectively. Infection was the most common complication (17%), with 38% requiring readmission. CONCLUSION: Compared to prior literature on multi-stage HS treatment, one-stage operations are a feasible, cost-effective alternative. STSG should remain the procedure of choice, even when primary closure appears feasible.

Bedside sonographic measurement of optic nerve sheath diameter as a predictor of increased intracranial pressure in children.

STUDY OBJECTIVE: We investigate the test performance of emergency physician-performed sonographic measurement of optic nerve sheath diameter for diagnosis of increased intracranial pressure. METHODS: Children between the ages of 0 and 18 years with suspected increased intracranial pressure were prospectively recruited from the emergency department and ICU of an urban, tertiary-level, freestanding pediatric facility. Pediatric emergency physicians with goal-directed training in ophthalmic sonography measured optic nerve sheath diameter. Images were recorded and subsequently reviewed by a pediatric ophthalmologist and an ophthalmic sonographer, both of whom were blind to the patient's clinical condition. Measurements obtained by the ophthalmic sonographer were considered the criterion standard. An optic nerve sheath diameter greater than 4.0 mm in subjects younger than 1 year and greater than 4.5 mm in older children was considered abnormal. The diagnosis of increased intracranial pressure was based on results of cranial imaging or direct measurement of intracranial pressure. RESULTS: Sixty-four patients were recruited, of whom 24 (37%) had a confirmed diagnosis of increased intracranial pressure. The sensitivity of optic nerve sheath diameter as a screening test for increased intracranial pressure was 83% (95% confidence interval [CI] 0.60 to 0.94); specificity was 38% (95% CI 0.23 to 0.54); positive likelihood ratio was 1.32 (95% CI 0.97 to 1.79) and negative likelihood ratio was 0.46 (95% CI 0.18 to 1.23). There was fair to good interobserver agreement between the pediatric emergency physician and ophthalmic sonographer (kappa 0.52) and pediatric ophthalmologist (kappa 0.64). CONCLUSION: The sensitivity and specificity of bedside sonographic measurement of optic nerve sheath diameter is inadequate to aid medical decisionmaking in children with suspected increased intracranial pressure. Pediatric emergency physicians with focused training by a pediatric ophthalmologist familiar with ophthalmic sonography can measure optic nerve sheath diameter accurately.

Pruritic Rash in a Patient with Hodgkin's Lymphoma.

Bleomycin-induced flagellate erythema (FE), a skin finding associated with cutaneous deposition of bleomycin, is so called due to its characteristic pattern of whip-like, linear streaks. As bleomycin use in standard chemotherapeutic regimens has decreased, the clinical diagnosis has become increasingly rare. The authors present a case of a 43-year-old female patient with Hodgkin's lymphoma on her first cycle of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) treatment, who subsequently developed a diffuse rash classic for FE. This benign condition is important to recognize to avoid potentially unnecessary and harmful treatment for other dermatologic diagnoses for which it may be mistaken. In severe cases of FE, discontinuation of bleomycin should be considered.

The crying infant.

Infants with the chief complaint of crying can present a diagnostic dilemma to the health care provider. This article discusses the differential diagnosis and management of the crying infant.

The Effects of Double Gloving on Microsurgical Skills.

Objective To determine whether double gloving would negatively affect participants' ability to perform a simulated microsurgical task. Study Design Randomized single-blinded controlled crossover trial. Setting Temporal bone laboratory of an academic otolaryngology department. Subjects and Methods This study involved the simulated insertion of a stapes prosthesis into a model of the ossicular chain under microscopy. Forty-one participants were recruited from our medical and dental school and randomized into 2 groups. All groups began by performing the task without gloves, acting as their own control arm. The first group (A) then performed the task with a single pair of gloves while the second group (B) next performed the task with 2 pairs of gloves. The groups then switched gloving methods. The total time taken to perform the task was recorded for each participant and the results subjected to a series of statistical measures. Results This study found a statistically significant difference in the average time taken to complete the task between the "no-glove" arm of the study and both experimental groups but no difference between the 2 experimental groups. Likewise, no significant difference was found between the 2 experimental groups when comparing the rate at which they improved at performing the task. Conclusion These data suggest that wearing 2 pairs of surgical gloves does not negatively affect the speed at which a microsurgical procedure may be performed, lending support to the practice of double gloving, even in the setting of microsurgical fine motor tasks.

Retigabine holds KV7 channels open and stabilizes the resting potential.

The anticonvulsant Retigabine is a KV7 channel agonist used to treat hyperexcitability disorders in humans. Retigabine shifts the voltage dependence for activation of the heteromeric KV7.2/KV7.3 channel to more negative potentials, thus facilitating activation. Although the molecular mechanism underlying Retigabine's action remains unknown, previous studies have identified the pore region of KV7 channels as the drug's target. This suggested that the Retigabine-induced shift in voltage dependence likely derives from the stabilization of the pore domain in an open (conducting) conformation. Testing this idea, we show that the heteromeric KV7.2/KV7.3 channel has at least two open states, which we named O1 and O2, with O2 being more stable. The O1 state was reached after short membrane depolarizations, whereas O2 was reached after prolonged depolarization or during steady state at the typical neuronal resting potentials. We also found that activation and deactivation seem to follow distinct pathways, suggesting that the KV7.2/KV7.3 channel activity displays hysteresis. As for the action of Retigabine, we discovered that this agonist discriminates between open states, preferentially acting on the O2 state and further stabilizing it. Based on these findings, we proposed a novel mechanism for the therapeutic effect of Retigabine whereby this drug reduces excitability by enhancing the resting potential open state stability of KV7.2/KV7.3 channels. To address this hypothesis, we used a model for action potential (AP) in Xenopus laevis oocytes and found that the resting membrane potential became more negative as a function of Retigabine concentration, whereas the threshold potential for AP firing remained unaltered.

Plexin-B2 promotes invasive growth of malignant glioma.

Invasive growth is a major determinant of the high lethality of malignant gliomas. Plexin-B2, an axon guidance receptor important for mediating neural progenitor cell migration during development, is upregulated in gliomas, but its function therein remains poorly understood. Combining bioinformatic analyses, immunoblotting and immunohistochemistry of patient samples, we demonstrate that Plexin-B2 is consistently upregulated in all types of human gliomas and that its expression levels correlate with glioma grade and poor survival. Activation of Plexin-B2 by Sema4C ligand in glioblastoma cells induced actin-based cytoskeletal dynamics and invasive migration in vitro. This proinvasive effect was associated with activation of the cell motility mediators RhoA and Rac1. Furthermore, costimulation of Plexin-B2 and the receptor tyrosine kinase Met led to synergistic Met phosphorylation. In intracranial glioblastoma transplants, Plexin-B2 knockdown hindered invasive growth and perivascular spreading, and resulted in decreased tumor vascularity. Our results demonstrate that Plexin-B2 promotes glioma invasion and vascularization, and they identify Plexin-B2 as a potential novel prognostic marker for glioma malignancy. Targeting the Plexin-B2 pathway may represent a novel therapeutic approach to curtail invasive growth of glioblastoma.