Perception of pneumocystis jirovecii pneumonia (PJP) prophylaxis in glioma patients receiving concurrent temozolomide and radiation- a patient and physician survey.

PURPOSE: Pneumocystis jirovecii pneumonia (PJP) prophylaxis is required by provincial and national drug monographs during glioma treatment using temozolomide (TMZ) concurrently with radiation (TMZ-RT). However, real-world data suggest the potential benefits of PJP prophylaxis may not outweigh its potential harms in this population. METHODS: We conducted a single-center patient survey and a national physician survey to explore the role of PJP prophylaxis amongst glioma patients undergoing TMZ-RT. RESULTS: 23% (31/133) of physicians and 60% (44/73) of patients completed a survey. The median patient age was 42 (range 20-77); 85% (34/40) had completed adjuvant TMZ. Although only 2.4% (1/41) of patients received PJP prophylaxis, only one person (without PJP prophylaxis) was hospitalized for pneumonia. When presented with hypothetical PJP risks, 13.2% (5/38) of patients were concerned about PJP infection, while 26% (10/38) were concerned about potential side effects from prophylactic antibiotics. Most physicians (77%, 17/22) perceived the evidence for PJP prophylaxis as weak; 58% (11/19) did not routinely prescribe prophylaxis, and 73% (16/22) felt that PJP prophylaxis should be limited to patients with additional risk factors. Over 95% of physicians estimated that the incidence of PJP was < 1% in their last 5 years of practice regardless of PJP prophylaxis. For 73% (16/22) of physicians, to prescribe PJP prophylaxis, the risk of PJP infection needed to be 3-8%. CONCLUSION: The current recommendation to routinely prescribe PJP prophylaxis in patients receiving TMZ-RT in the absence of other risk factors warrants reconsideration.

Surface-Induced Hydrophobin Assemblies with Versatile Properties and Distinct Underlying Structures.

Hydrophobins are remarkable proteins due to their ability to self-assemble into amphipathic coatings that reverse surface wettability. Here, the versatility of the Class I hydrophobins EASΔ15 and DewY in diverse nanosuspension and coating applications is demonstrated. The hydrophobins are shown to coat or emulsify a range of substrates including oil, hydrophobic drugs, and nanodiamonds and alter their solution and surface behavior. Surprisingly, while the coatings confer new properties, only a subset is found to be resistant to hot detergent treatment, a feature previously thought to be characteristic of the functional amyloid form of Class I hydrophobins. These results demonstrate that substrate surface properties can influence the molecular structures and physiochemical properties of hydrophobin and possibly other functional amyloids. Functional amyloid assembly with different substrates and conditions may be analogous to the propagation of different polymorphs of disease-associated amyloid fibrils with distinct structures, stability, and clinical phenotypes. Given that amyloid formation is not required for Class I hydrophobins to serve diverse applications, our findings open up new opportunities for their use in applications requiring a range of chemical and physical properties. In hydrophobin nanotechnological applications where high stability of assemblies is required, simultaneous structural and functional characterization should be carried out. Finally, while results in this study pertain to synthetic substrates, they raise the possibility that at least some members of the pseudo-Class I and Class III hydrophobins, reported to form assemblies with noncanonical properties, may be Class I hydrophobins adopting alternative structures in response to environmental cues.

Fungal Hydrophobins and Their Self-Assembly into Functional Nanomaterials.

In recent years, much attention has focused on incorporating biological and bio-inspired nanomaterials into various applications that range from functionalising surfaces and enhancing biomolecule binding properties, to coating drugs for improved bioavailability and delivery. Hydrophobin proteins, which can spontaneously assemble into amphipathic layers at hydrophobic:hydrophilic interfaces, are exciting candidates for use as nanomaterials. These unique proteins, which are only expressed by filamentous fungi, have been the focus of increasing interest from the biotechnology industry, as evidenced by the sharply growing number of hydrophobin-associated publications and patents. Here, we explore the contribution of different hydrophobins to supporting fungal growth and development. We describe the key structural elements of hydrophobins and the molecular characteristics that underlie self-assembly of these proteins at interfaces. We outline the multiple roles that hydrophobins can play in supporting aerial growth of filamentous structures, facilitating spore dispersal and preventing an immune response in the infected host. The growing understanding of the hydrophobin protein structure and self-assembly process highlights the potential for hydrophobin proteins to be engineered for use in a variety of novel applications that require biocompatible coatings.

Critical Care Management of Cerebral Edema in Brain Tumors.

Cerebral edema associated with brain tumors is extremely common and can occur in both primary and metastatic tumors. The edema surrounding brain tumors results from leakage of plasma across the vessel wall into the parenchyma secondary to disruption of the blood-brain barrier. The clinical signs of brain tumor edema depend on the location of the tumor as well as the extent of the edema, which often exceeds the mass effect induced by the tumor itself. Uncontrolled cerebral edema may result in increased intracranial pressure and acute herniation syndromes that can result in permanent neurological dysfunction and potentially fatal herniation. Treatment strategies for elevated intracranial pressure consist of general measures, medical interventions, and surgery. Alhough the definitive treatment for the edema may ultimately be surgical resection of the tumor, the impact of the critical care management cannot be underestimated and thus patients must be vigilantly monitored in the intensive care unit. In this review, we discuss the pathology, pathophysiology, and clinical features of patients presenting with cerebral edema. Imaging findings and treatment modalities used in the intensive care unit are also discussed.

Iterative projection algorithms for ab initio phasing in virus crystallography.

Iterative projection algorithms are proposed as a tool for ab initio phasing in virus crystallography. The good global convergence properties of these algorithms, coupled with the spherical shape and high structural redundancy of icosahedral viruses, allows high resolution phases to be determined with no initial phase information. This approach is demonstrated by determining the electron density of a virus crystal with 5-fold non-crystallographic symmetry, starting with only a spherical shell envelope. The electron density obtained is sufficiently accurate for model building. The results indicate that iterative projection algorithms should be routinely applicable in virus crystallography, without the need for ancillary phase information.

Predicting malignant neck lymphadenopathy using color duplex sonography based on multivariate analysis.

PURPOSE: To select the best predictors of cervical lymph node malignancy based on gray-scale and power Doppler sonography using multivariate analysis. METHODS: We evaluated sonographically a total of 97 lymph nodes in the neck that were subjected to fine-needle aspiration biopsy. The gray-scale and power Doppler sonography parameters that we analyzed using multivariate logistic regression included size, shape, echogenicity, echotexture, margins, hilum, presence of microcalcifications or necrosis, vascularization, and resistance index (RI). RESULTS: The three variables with a diagnostic accuracy exceeding 80% were an altered vascularization, heterogeneous echotexture, and abnormal hilum. Malignant nodes exhibited higher RI and larger sizes than benign nodes, and the best cutoff values to distinguish malignant from benign lymph nodes were an RI of 0.77 and a short axis ≥ 0.9 cm. Altered vascularization, a short axis ≥ 0.9 cm, and abnormal hilum were the best predictors of malignancy. CONCLUSIONS: The best sonographic predictors of lymph node malignancy are, in descending order, an altered vascularization, a short axis ≥ 0.9 cm, an abnormal hilum, and a heterogeneous echotexture. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:587-594, 2016.

Recovery of phosphorus from dairy manure: a pilot-scale study.

Phosphorus was recovered from dairy manure via a microwave-enhanced advanced oxidation process (MW/H2O2-AOP) followed by struvite crystallization in a pilot-scale continuous flow operation. Soluble phosphorus in dairy manure increased by over 50% after the MW/H2O2-AOP, and the settleability of suspended solids was greatly improved. More than 50% of clear supernatant was obtained after microwave treatment, and the maximum volume of supernatant was obtained at a hydrogen peroxide dosage of 0.3% and pH 3.5. By adding oxalic acid into the supernatant, about 90% of calcium was removed, while more than 90% of magnesium was retained. As a result, the resulting solution was well suited for struvite crystallization. Nearly 95% of phosphorus in the treated supernatant was removed and recovered as struvite.

Effectiveness, acceptability, and potential of lay student vaccinators to improve vaccine delivery.

SETTING: Task sharing can fill health workforce gaps, improve access to care, and enhance health equity by redistributing health services to providers with less training. We report learnings from a demonstration project designed to assess whether lay student vaccinators can support community immunizations. INTERVENTION: Between July 2022 and February 2023, 27 undergraduate and graduate students were recruited from the University of Toronto Emergency First Responders organization and operated 11 immunization clinics under professional supervision. Medical directives, supported with online and in-person training, enabled lay providers to administer and document vaccinations when supervised by nurses, physicians, or pharmacists. Participants were invited to complete a voluntary online survey to comment on their experience. OUTCOMES: Lay providers administered 293 influenza and COVID-19 vaccines without adverse events. A total of 141 participants (122 patients, 17 lay vaccinators, 1 nurse, and 1 physician) responded to our survey. More than 80% of patients strongly agreed to feeling safe and comfortable with lay providers administering vaccines under supervision, had no concerns with lay vaccinators, and would attend another lay vaccinator clinic. Content and thematic analysis of open-text responses revealed predominantly positive experiences, with themes about excellent vaccinators, organized and efficient clinics, and the importance of training, communication, and access to regulated professionals. The responding providers expressed comfort working in collaborative immunization teams. IMPLICATIONS: Lay student providers can deliver vaccines safely under a medical directive while potentially improving patient experiences. Rather than redeploying scarce professionals, task sharing strategies could position trained lay vaccinators to support immunizations, improve access, and foster community engagement.

RéSUMé: LIEU: Le partage de tâches peut combler les pénuries de personnels de santé et améliorer l'accès aux soins et l'équité en santé en redistribuant les services de santé vers des prestataires ayant moins de formation. Nous rendons compte des enseignements d'un projet de démonstration visant à déterminer si des vaccinateurs étudiants profanes pourraient appuyer l'immunisation communautaire. INTERVENTION: Entre juillet 2022 et février 2023, 27 étudiantes et étudiants de premier cycle et de cycles supérieurs ont été recrutés auprès de l'organisation des secouristes opérationnels de l'Université de Toronto pour gérer 11 cliniques de vaccination sous la supervision de personnel spécialisé. Des directives médicales, appuyées par une formation en ligne et en présentiel, ont permis à ces prestataires profanes d'administrer des vaccins et de les consigner en dossier sous la supervision d'infirmières, de médecins ou de pharmaciens. Les personnes participantes ont été invitées à répondre à un sondage en ligne sur leur expérience. RéSULTATS: Les prestataires profanes ont administré 293 vaccins contre la grippe et la COVID-19 sans manifestations postvaccinales indésirables. En tout, 141 personnes (122 patients, 17 vaccinateurs profanes, 1 infirmière et 1 médecin) ont répondu au sondage. Plus de 80 % des patients ont dit se sentir tout à fait en sécurité et à l'aise de recevoir des vaccins administrés par des prestataires profanes sous supervision, n'avoir aucune inquiétude vis-à-vis des vaccinateurs profanes et être disposés à se présenter à une autre clinique gérée par des vaccinateurs profanes. L'analyse du contenu et des thèmes des réponses aux questions ouvertes a révélé des expériences majoritairement positives, et des thèmes axés sur l'excellence des vaccinateurs, l'organisation et l'efficacité des cliniques, ainsi que l'importance de la formation, des communications et de l'accès à des professionnels réglementés. Les prestataires ayant répondu au sondage se sont dit à l'aise de travailler au sein d'équipes de vaccination collaboratives. CONSéQUENCES: Des prestataires étudiants profanes peuvent administrer des vaccins en toute sécurité en suivant une directive médicale, et cela peut potentiellement améliorer l'expérience des patients. Plutôt que de redéployer des ressources professionnelles limitées, les stratégies de partage de tâches pourraient placer des vaccinateurs profanes formés pour appuyer l'immunisation, améliorer l'accès et favoriser l'engagement communautaire.

Perphenazine-Macrocycle Conjugates Rapidly Sequester the Aß42 Monomer and Prevent Formation of Toxic Oligomers and Amyloid.

Alzheimer's disease is imposing a growing social and economic burden worldwide, and effective therapies are urgently required. One possible approach to modulation of the disease outcome is to use small molecules to limit the conversion of monomeric amyloid (Aß42) to cytotoxic amyloid oligomers and fibrils. We have synthesized modulators of amyloid assembly that are unlike others studied to date: these compounds act primarily by sequestering the Aß42 monomer. We provide kinetic and nuclear magnetic resonance data showing that these perphenazine conjugates divert the Aß42 monomer into amorphous aggregates that are not cytotoxic. Rapid monomer sequestration by the compounds reduces fibril assembly, even in the presence of pre-formed fibrillar seeds. The compounds are therefore also able to disrupt monomer-dependent secondary nucleation, the autocatalytic process that generates the majority of toxic oligomers. The inhibitors have a modular design that is easily varied, aiding future exploration and use of these tools to probe the impact of distinct Aß42 species populated during amyloid assembly.

Beyond radiation therapy: photodynamic therapy maintains structural integrity of irradiated healthy and metastatically involved vertebrae in a pre-clinical in vivo model.

Spinal metastasis commonly occurs in advanced breast cancer. Treatment is often multimodal including radiation therapy (RT), bisphosphonates (BPs), and surgery, yet alternative minimally invasive local treatments are needed. Photodynamic therapy (PDT) has been shown to ablate tumor cells and enhance bone formation secondary to metastatic breast cancer, demonstrating potential as a treatment for spinal metastasis. Combined with previous BP treatment, bone formation was further enhanced by PDT. This study aimed to determine the effects of PDT in combination with previous RT on healthy and metastatically involved vertebrae. Forty-six athymic rats underwent RT (4 Gy on day-7), twenty-three of them were inoculated with MT-1 human breast cancer cells on day 0. Thirteen healthy and ten metastatically involved rats underwent PDT treatment on day 14. All rats were sacrificed on day 21. L2 vertebrae were analyzed using µCT imaging, mechanical testing, and histological methods. In healthy vertebrae, while modest increases in trabecular structure were found in RT + PDT compared to RT only, mechanical stability was negatively affected. The 4 Gy RT dose was found to ablate all tumor cells and prevent further vertebral metastasis. As such, in metastatically involved rats, no differences in stereological or mechanical properties were detected. RT + PDT and RT-only treatment resulted in greatly improved vertebral structural and mechanical properties versus untreated or PDT-only treatment in metastatically involved rats, due to early tumor destruction in RT-treated groups. Increased amounts of woven bone and osteoid volume were found in PDT-treated vertebrae. Further investigation is needed to understand if structural improvements seen in RT + PDT treatment can translate into longer-term improvements in strength to support the potential of PDT as a viable adjuvant treatment for spinal metastasis postradiation.

The impact of Timothy's Law on hospitalization among patients with mental health conditions in New York State.

BACKGROUND: Timothy's law to reduce mental health care disparities was enacted in January 2007 in New York state (NY). According to Timothy's law, "if a patient is suffering from a Biologically Based Mental Illness, or is a Child with Serious Emotional Disturbances, the Inpatient mental health benefit will be the same as for any other illness". An assessment of its impact on inpatient mental health care is lacking. We provide a rigorous study of this policy intervention's effect over the first year of its implementation. METHODS: We used a quasi-experimental design to combine the difference-in-difference method and propensity score weighting. Data are from inpatient records in NY and California (CA) (as a control) between January 2006 to December 2006 (the pre-enactment year in NY) and January to December 2007 (the enactment year) for non-Medicare/Medicaid patients hospitalized in both years with specific illnesses covered by Timothy's Law. Change in length of stay from 2006 to 2007 was measured for each patient, and the differences observed in NY and California were compared to each other (Difference-in-Difference), with differences in the characteristics of patients in NY and California addressed through Propensity Score Weighting (PSW). RESULTS: Before Timothy's Law was enacted (2006), length of stay (LOS) in NY was 16.3 days on average, and length of stay per hospitalization (LOSPH) was 11.72 days on average for the 1237 patients under study in 2006. In 2007, LOS increased by 4.91 days in NY (95% CI (2.89, 7.01)) compared with similar patients in California, and LOSPH by 3.25 days (95% CI (1.96, 4.57)). Among patients with serious mental illness diagnoses, LOS in NY increased by 7.07 days (95% CI (4.15, 10.17)), and LOSPH by 4.04 days (95% CI (1.93, 6.03)) compared to California. CONCLUSIONS: Our study strongly suggests that, within the time frame of just a single year, Timothy's Law significantly increased inpatient mental healthcare utilization in NY. Our study raises the possibility that similar laws in other locations could have similar effects.

Carbon/iron by-product from catalytic methane decomposition as recyclable Fenton catalyst for pollutant degradation.

Direct catalytic decomposition of methane (CDM) has been studied as a possible emission-free hydrogen production route for over 100 years. However, the high cost of catalyst regeneration limits its practical applications. Here, we demonstrate that the solid by-product from CDM using Fe ore catalysts comprising carbon nano onions encapsulated with magnetic Fe cores (Fe@C) can serve as efficient and recyclable Fenton catalysts for pollutant degradation. Fe@C/H2O2 has better performance than FeSO4/H2O2 at similar Fe concentrations and can be used to decompose various pollutants. Mechanistic studies reveal that graphitic carbon layers and encapsulated Fe0 contribute to their high catalytic activity. Further, Fe@C can be easily recovered from an aqueous solution and reused due to the encapsulated magnetic Fe particles. Over three reused cycles, Fe@C/H2O2 only yields 1/8 of Fe sludges compared to FeSO4/H2O2, significantly reducing Fe sludge treatment costs. Overall, Fe@C demonstrates excellent application potentials in water and wastewater treatment, making H2 production via CDM economically more viable.

Investigation into the Effects of Backrest Angle and Stick Location on Female Strength.

OBJECTIVES: The purpose of this study was to investigate the effects of backrest angle and hand maneuver direction on maximum hand strength and to recommend a strength value for the hand-controlled stick of an aircraft. METHODS: Forty-eight female subjects were recruited to perform simulated forward-backward and adduction-abduction maneuvers using control sticks. Each subject was free from musculoskeletal disorders and pain. The independent variables included four control maneuvers (forward, backward, adduction, abduction), two right-hand control stick locations (central, side), and three backrest angles (90°, 103°, 108°). The dependent variable was maximum hand strength. RESULTS: The maximum strength for forward maneuvers with both central and side sticks was strongest at a 90° backrest angle (p < 0.001). The maximum strength for adduction maneuvers with both central and side sticks was also strongest at a 90° backrest angle (p < 0.001). On the other hand, the highest strength was observed at a 108° backrest angle when pulling the stick backward (p < 0.001). The abduction strength was significantly stronger than the adduction strength with a central stick (p < 0.001), but the adduction strength was significantly stronger than the abduction strength with a side stick (p < 0.001-p = 0.017). The forward and abduction strength were significantly different in different locations (p < 0.001). The recommended strength in the Code of Federal Regulations (CFR) by the US FAA is higher than the strength values observed in this study. CONCLUSIONS: The backrest angle, directions, and location affected the muscular strength. The recommended values should be reevaluated and adjusted for Taiwanese pilots.

Can We Use Grip Strength to Predict Other Types of Hand Exertions? An Example of Manufacturing Industry Workers.

BACKGROUND: There are different types of hand motions in people's daily lives and working environments. However, testing duration increases as the types of hand motions increase to build a normative database. Long testing duration decreases the motivation of study participants. The purpose of this study is to propose models to predict pinch and press strength using grip strength. METHODS: One hundred ninety-eight healthy volunteers were recruited from the manufacturing industries in Central Taiwan. The five types of hand motions were grip, lateral pinch, palmar pinch, thumb press, and ball of thumb press. Stepwise multiple linear regression was used to explore the relationship between force type, gender, height, weight, age, and muscle strength. RESULTS: The prediction models developed according to the variable of the strength of the opposite hand are good for explaining variance (76.9-93.1%). Gender is the key demographic variable in the predicting models. Grip strength is not a good predictor of palmar pinch (adjusted-R2: 0.572-0.609), nor of thumb press and ball of thumb (adjusted-R2: 0.279-0.443). CONCLUSIONS: We recommend measuring the palmar pinch and ball of thumb strength and using them to predict the other two hand motions for convenience and time saving.

Body volume estimation equation for male laborers in Taiwan.

The purpose of this study was to develop a body volume (BV) estimation equation for male laborers in Taiwan with body weight (W) and stature height (H) as initial estimators. A three-dimensional (3D) body scanner and a 3D foot scanner were used to measure the 3D range data of 100 male laborers in this study. Subjects' BV was extracted from the 3D body model, and H and W were used as independent variables in regression analysis. The results show that the final BV estimation equation is BV = 1122.927 × W0.972, with R2 = 0.949. Thirty extra male subjects were scanned to compare this BV estimation equation with those in previous studies. The results show that this BV estimation equation had the smallest absolute mean difference at 1.1458 L and the smallest standard error of the estimate at 2.48% in comparison.

Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein.

Recessive mutations in parkin are the most common cause of familial early-onset Parkinson's disease (PD). Recent studies suggest that certain parkin mutants may exert dominant toxic effects to cultured cells and such dominant toxicity can lead to progressive dopaminergic (DA) neuron degeneration in Drosophila. To explore whether mutant parkin could exert similar pathogenic effects to mammalian DA neurons in vivo, we developed a BAC (bacterial artificial chromosome) transgenic mouse model expressing a C-terminal truncated human mutant parkin (Parkin-Q311X) in DA neurons driven by a dopamine transporter promoter. Parkin-Q311X mice exhibit multiple late-onset and progressive hypokinetic motor deficits. Stereological analyses reveal that the mutant mice develop age-dependent DA neuron degeneration in substantia nigra accompanied by a significant loss of DA neuron terminals in the striatum. Neurochemical analyses reveal a significant reduction of the striatal dopamine level in mutant mice, which is significantly correlated with their hypokinetic motor deficits. Finally, mutant Parkin-Q311X mice, but not wild-type controls, exhibit age-dependent accumulation of proteinase K-resistant endogenous alpha-synuclein in substantia nigra and colocalized with 3-nitrotyrosine, a marker for oxidative protein damage. Hence, our study provides the first mammalian genetic evidence that dominant toxicity of a parkin mutant is sufficient to elicit age-dependent hypokinetic motor deficits and DA neuron loss in vivo, and uncovers a causal relationship between dominant parkin toxicity and progressive alpha-synuclein accumulation in DA neurons. Our study underscores the need to further explore the putative link between parkin dominant toxicity and PD.

Normative Hand Strength of Healthcare Industry Workers in Central Taiwan.

Objectives: The purpose of this study is to establish the norms of hand grip strength in the healthcare industry in Taiwan and propose models to predict the strength of hand movement by regression with demographic and anthropometric factors. Methods: This is a cross-sectional study with a stratified convenience sample of workers in healthcare service industries in central Taiwan. Three hundred twenty-nine healthy subjects were recruited. Strength of different hand movement were tested three times in both hands and rests were given between tests. Results: Female strength of these hand movement was 59.1% to 73.0% that in males (p < 0.001). In general, the hand strength of male workers in the healthcare industry was less than that of male workers in the manufacturing industry (p < 0.001). In the prediction model, sex and weight played important roles in predicting hand strength. Conclusions: The norms of different types of hand strength was investigated the first time in workers in the healthcare industry in Taiwan. The tasks performed by healthcare personnel vary widely, and this variable should be considered in a future prediction model.

Formation of Amphipathic Amyloid Monolayers from Fungal Hydrophobin Proteins.

The fungal hydrophobins are small proteins that are able to self-assemble spontaneously into amphipathic monolayers at hydrophobic:hydrophilic interfaces. These protein monolayers can reverse the wettability of a surface, making them suitable for increasing the biocompatibility of many hydrophobic nanomaterials. One subgroup of this family, the class I hydrophobins, forms monolayers that are composed of extremely robust amyloid-like fibrils, called rodlets. Here, we describe the protocols for the production and purification of recombinant hydrophobins and oxidative refolding to a biologically active, soluble, monomeric form. We describe methods to trigger the self-assembly into the fibrillar rodlet state and techniques to characterize the physicochemical properties of the polymeric forms.

Management of Patients With Sepsis in Canadian Community Emergency Departments: A Retrospective Multicenter Observational Study.

BACKGROUND: Sepsis is a life-threatening syndrome and a leading cause of morbidity and mortality representing significant financial burden on the health-care system. Early identification and intervention is crucial to maximizing positive outcomes. We studied a quality improvement initiative with the aim of reviewing the initial management of patients with sepsis in Canadian community emergency departments, to identify areas for improving the delivery of sepsis care. We present a retrospective, multicenter, observational study during 2011 to 2015 in the community setting. METHODS: We collected data on baseline characteristics, clinical management metrics (triage-to-physician-assessment time, triage-to-lactate-drawn time, triage-to-antibiotic time, and volume of fluids administered within the first 6 hours of triage), and outcomes (intensive care unit [ICU] admission, in-hospital mortality) from a regional database. RESULTS: A total of 2056 patients were analyzed. The median triage-to-physician-assessment time was 50 minutes (interquartile range [IQR]: 25-104), triage-to-lactate-drawn time was 50 minutes (IQR: 63-94), and triage-to-antibiotics time was 129 minutes (IQR: 70-221). The median total amount of fluid administered within 6 hours of triage was 2.0 L (IQR: 1.5-3.0). The ICU admission rate was 36% and in-hospital mortality was 25%. We also observed a higher ICU admission rate (51% vs 24%) and in-hospital mortality (44% vs 14%) in those with higher lactate concentration (≥4 vs ≤2 mmol/L), independent of other sepsis-related parameters. CONCLUSION: Time-to-physician-assessment, time-to-lactate-drawn, time-to-antibiotics, and fluid resuscitation in community emergency departments could be improved. Future quality improvement interventions are required to optimize management of patients with sepsis. Elevated lactate concentration was also independently associated with ICU admission rate and in-hospital mortality rate.

Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice.

Expanded polyglutamine (polyQ) proteins in Huntington's disease (HD) as well as other polyQ disorders are known to elicit a variety of intracellular toxicities, but it remains unclear whether polyQ proteins can elicit pathological cell-cell interactions which are critical to disease pathogenesis. To test this possibility, we have created conditional HD mice expressing a neuropathogenic form of mutant huntingtin (mhtt-exon1) in discrete neuronal populations. We show that mhtt aggregation is a cell-autonomous process. However, progressive motor deficits and cortical neuropathology are only observed when mhtt expression is in multiple neuronal types, including cortical interneurons, but not when mhtt expression is restricted to cortical pyramidal neurons. We further demonstrate an early deficit in cortical inhibition, suggesting that pathological interactions between interneurons and pyramidal neurons may contribute to the cortical manifestation of HD. Our study provides genetic evidence that pathological cell-cell interactions elicited by neuropathogenic forms of mhtt can critically contribute to cortical pathogenesis in a HD mouse model.