The Safety of Inpatient Health Care.

BACKGROUND: Adverse events during hospitalization are a major cause of patient harm, as documented in the 1991 Harvard Medical Practice Study. Patient safety has changed substantially in the decades since that study was conducted, and a more current assessment of harm during hospitalization is warranted. METHODS: We conducted a retrospective cohort study to assess the frequency, preventability, and severity of patient harm in a random sample of admissions from 11 Massachusetts hospitals during the 2018 calendar year. The occurrence of adverse events was assessed with the use of a trigger method (identification of information in a medical record that was previously shown to be associated with adverse events) and from review of medical records. Trained nurses reviewed records and identified admissions with possible adverse events that were then adjudicated by physicians, who confirmed the presence and characteristics of the adverse events. RESULTS: In a random sample of 2809 admissions, we identified at least one adverse event in 23.6%. Among 978 adverse events, 222 (22.7%) were judged to be preventable and 316 (32.3%) had a severity level of serious (i.e., caused harm that resulted in substantial intervention or prolonged recovery) or higher. A preventable adverse event occurred in 191 (6.8%) of all admissions, and a preventable adverse event with a severity level of serious or higher occurred in 29 (1.0%). There were seven deaths, one of which was deemed to be preventable. Adverse drug events were the most common adverse events (accounting for 39.0% of all events), followed by surgical or other procedural events (30.4%), patient-care events (which were defined as events associated with nursing care, including falls and pressure ulcers) (15.0%), and health care-associated infections (11.9%). CONCLUSIONS: Adverse events were identified in nearly one in four admissions, and approximately one fourth of the events were preventable. These findings underscore the importance of patient safety and the need for continuing improvement. (Funded by the Controlled Risk Insurance Company and the Risk Management Foundation of the Harvard Medical Institutions.).

The Safety of Outpatient Health Care : Review of Electronic Health Records.

BACKGROUND: Despite considerable emphasis on delivering safe care, substantial patient harm occurs. Although most care occurs in the outpatient setting, knowledge of outpatient adverse events (AEs) remains limited. OBJECTIVE: To measure AEs in the outpatient setting. DESIGN: Retrospective review of the electronic health record (EHR). SETTING: 11 outpatient sites in Massachusetts in 2018. PATIENTS: 3103 patients who received outpatient care. MEASUREMENTS: Using a trigger method, nurse reviewers identified possible AEs and physicians adjudicated them, ranked severity, and assessed preventability. Generalized estimating equations were used to assess the association of having at least 1 AE with age, sex, race, and primary insurance. Variation in AE rates was analyzed across sites. RESULTS: The 3103 patients (mean age, 52 years) were more often female (59.8%), White (75.1%), English speakers (90.8%), and privately insured (70.4%) and had a mean of 4 outpatient encounters in 2018. Overall, 7.0% (95% CI, 4.6% to 9.3%) of patients had at least 1 AE (8.6 events per 100 patients annually). Adverse drug events were the most common AE (63.8%), followed by health care-associated infections (14.8%) and surgical or procedural events (14.2%). Severity was serious in 17.4% of AEs, life-threatening in 2.1%, and never fatal. Overall, 23.2% of AEs were preventable. Having at least 1 AE was less often associated with ages 18 to 44 years than with ages 65 to 84 years (standardized risk difference, -0.05 [CI, -0.09 to -0.02]) and more often associated with Black race than with Asian race (standardized risk difference, 0.09 [CI, 0.01 to 0.17]). Across study sites, 1.8% to 23.6% of patients had at least 1 AE and clinical category of AEs varied substantially. LIMITATION: Retrospective EHR review may miss AEs. CONCLUSION: Outpatient harm was relatively common and often serious. Adverse drug events were most frequent. Rates were higher among older adults. Interventions to curtail outpatient harm are urgently needed. PRIMARY FUNDING SOURCE: Controlled Risk Insurance Company and the Risk Management Foundation of the Harvard Medical Institutions.

Photoacoustic Calorimetry Studies of O2-Sensing FixL and (R200, I209) Variants from Sinorhizobium meliloti Reveal Conformational Changes Coupled to Ligand Photodissociation from the Heme-PAS Domain.

FixL is an oxygen-sensing heme-PAS protein that regulates nitrogen fixation in the root nodules of plants. In this paper, we present the first photothermal studies of the full-length wild-type FixL protein from Sinorhizobium meliloti and the first thermodynamic profile of a full-length heme-PAS protein. Photoacoustic calorimetry studies reveal a quadriphasic relaxation for SmFixL*WT and the five variant proteins (SmFixL*R200H, SmFixL*R200Q, SmFixL*R200E, SmFixL*R200A, and SmFixL*I209M) with four intermediates from <20 ns to ∼1.5 µs associated with the photodissociation of CO from the heme. The altered thermodynamic profiles of the full-length SmFixL* variant proteins confirm that the conserved heme domain residues R200 and I209 are important for signal transduction. In contrast, the truncated heme domain, SmFixLH128-264, shows only a single, fast monophasic relaxation at <50 ns associated with the fast disruption of a salt bridge and release of CO to the solvent, suggesting that the full-length protein is necessary to observe the conformational changes that propagate the signal from the heme domain to the kinase domain.

Machine learning pipeline for blood culture outcome prediction using Sysmex XN-2000 blood sample results in Western Australia.

BACKGROUND: Bloodstream infections (BSIs) are a significant burden on the global population and represent a key area of focus in the hospital environment. Blood culture (BC) testing is the standard diagnostic test utilised to confirm the presence of a BSI. However, current BC testing practices result in low positive yields and overuse of the diagnostic test. Diagnostic stewardship research regarding BC testing is increasing, and becoming more important to reduce unnecessary resource expenditure and antimicrobial use, especially as antimicrobial resistance continues to rise. This study aims to establish a machine learning (ML) pipeline for BC outcome prediction using data obtained from routinely analysed blood samples, including complete blood count (CBC), white blood cell differential (DIFF), and cell population data (CPD) produced by Sysmex XN-2000 analysers. METHODS: ML models were trained using retrospective data produced between 2018 and 2019, from patients at Sir Charles Gairdner hospital, Nedlands, Western Australia, and processed at Pathwest Laboratory Medicine, Nedlands. Trained ML models were evaluated using stratified 10-fold cross validation. RESULTS: Two ML models, an XGBoost model using CBC/DIFF/CPD features with boruta feature selection (BFS) , and a random forest model trained using CBC/DIFF features with BFS were selected for further validation after obtaining AUC scores of [Formula: see text] and [Formula: see text] respectively using stratified 10-fold cross validation. The XGBoost model obtained an AUC score of 0.76 on a internal validation set. The random forest model obtained AUC scores of 0.82 and 0.76 on internal and external validation datasets respectively. CONCLUSIONS: We have demonstrated the utility of using an ML pipeline combined with CBC/DIFF, and CBC/DIFF/CPD feature spaces for BC outcome prediction. This builds on the growing body of research in the area of BC outcome prediction, and provides opportunity for further research.

Delineating the Drivers and Functionality of Methanogenic Niches within an Arid Landfill.

Microbial communities mediate the transformation of organic matter within landfills into methane (CH4). Yet their ecological role in CH4 production is rarely evaluated. To characterize the microbiome associated with this biotransformation, the overall community and methanogenic Archaea were surveyed in an arid landfill using leachate collected from distinctly aged landfill cells (i.e., younger, intermediate, and older). We hypothesized that distinct methanogenic niches exist within an arid landfill, driven by geochemical gradients that developed under extended and age-dependent waste biodegradation stages. Using 16S rRNA and mcrA gene amplicon sequencing, we identified putative methanogenic niches as follows. The order Methanomicrobiales was the most abundant order in leachate from younger cells, where leachate temperature and propionate concentrations were measured at 41.8°C ± 1.7°C and 57.1 ± 10.7 mg L-1. In intermediate-aged cells, the family Methanocellaceae was identified as a putative specialist family under intermediate-temperature and -total dissolved solid (TDS) conditions, wherein samples had a higher alpha diversity index and near CH4 concentrations. In older-aged cells, accumulating metals and TDS supported Methanocorpusculaceae, "Candidatus Bathyarchaeota," and "Candidatus Verstraetearchaeota" operational taxonomic units (OTUs). Consistent with the mcrA data, we assayed methanogenic activity across the age gradient through stable isotopic measurements of δ13C of CH4 and δ13C of CO2. The majority (80%) of the samples' carbon fractionation was consistent with hydrogenotrophic methanogenesis. Together, we report age-dependent geochemical gradients detected through leachate in an arid landfill seemingly influencing CH4 production, niche partitioning, and methanogenic activity. IMPORTANCE Microbiome analysis is becoming common in select municipal and service ecosystems, including wastewater treatment and anaerobic digestion, but its potential as a microbial-status-informative tool to promote or mitigate CH4 production has not yet been evaluated in landfills. Methanogenesis mediated by Archaea is highly active in solid-waste microbiomes but is commonly neglected in studies employing next-generation sequencing techniques. Identifying methanogenic niches within a landfill offers detail into operations that positively or negatively impact the commercial production of methane known as biomethanation. We provide evidence that the geochemistry of leachate and its microbiome can be a variable accounting for ecosystem-level (coarse) variation of CH4 production, where we demonstrate through independent assessments of leachate and gas collection that the functional variability of an arid landfill is linked to the composition of methanogenic Archaea.

Both real-time and long-term environmental data perform well in predicting shorebird distributions in managed habitat.

Highly mobile species, such as migratory birds, respond to seasonal and interannual variability in resource availability by moving to better habitats. Despite the recognized importance of resource thresholds, species-distribution models typically rely on long-term average habitat conditions, mostly because large-extent, temporally resolved, environmental data are difficult to obtain. Recent advances in remote sensing make it possible to incorporate more frequent measurements of changing landscapes; however, there is often a cost in terms of model building and processing and the added value of such efforts is unknown. Our study tests whether incorporating real-time environmental data increases the predictive ability of distribution models, relative to using long-term average data. We developed and compared distribution models for shorebirds in California's Central Valley based on high temporal resolution (every 16 days), and 17-year long-term average surface water data. Using abundance-weighted boosted regression trees, we modeled monthly shorebird occurrence as a function of surface water availability, crop type, wetland type, road density, temperature, and bird data source. Although modeling with both real-time and long-term average data provided good fit to withheld validation data (the area under the receiver operating characteristic curve, or AUC, averaged between 0.79 and 0.89 for all taxa), there were small differences in model performance. The best models incorporated long-term average conditions and spatial pattern information for real-time flooding (e.g., perimeter-area ratio of real-time water bodies). There was not a substantial difference in the performance of real-time and long-term average data models within time periods when real-time surface water differed substantially from the long-term average (specifically during drought years 2013-2016) and in intermittently flooded months or locations. Spatial predictions resulting from the models differed most in the southern region of the study area where there is lower water availability, fewer birds, and lower sampling density. Prediction uncertainty in the southern region of the study area highlights the need for increased sampling in this area. Because both sets of data performed similarly, the choice of which data to use may depend on the management context. Real-time data may ultimately be best for guiding dynamic, adaptive conservation actions, whereas models based on long-term averages may be more helpful for guiding permanent wetland protection and restoration.

Flows of X-ray gas reveal the disruption of a star by a massive black hole.

Tidal forces close to massive black holes can violently disrupt stars that make a close approach. These extreme events are discovered via bright X-ray and optical/ultraviolet flares in galactic centres. Prior studies based on modelling decaying flux trends have been able to estimate broad properties, such as the mass accretion rate. Here we report the detection of flows of hot, ionized gas in high-resolution X-ray spectra of a nearby tidal disruption event, ASASSN-14li in the galaxy PGC 043234. Variability within the absorption-dominated spectra indicates that the gas is relatively close to the black hole. Narrow linewidths indicate that the gas does not stretch over a large range of radii, giving a low volume filling factor. Modest outflow speeds of a few hundred kilometres per second are observed; these are below the escape speed from the radius set by variability. The gas flow is consistent with a rotating wind from the inner, super-Eddington region of a nascent accretion disk, or with a filament of disrupted stellar gas near to the apocentre of an elliptical orbit. Flows of this sort are predicted by fundamental analytical theory and more recent numerical simulations.

Feasibility of training community health workers to conduct periodontal examinations: a validation study in rural Nepal.

BACKGROUND: In many low- and middle-income countries, insufficient human resources limit access to oral health services. Shifting clinical tasks to less specialized health professionals, such as community health workers, has been used as a strategy to expand the health workforce, especially in remote or underserved locations. The objective of this study was to evaluate the validity of periodontal examinations conducted by auxiliary nurse midwives in a rural home setting in Nepal. METHODS: Twenty-one pregnant women < 26 weeks gestation from Sarlahi District, Nepal, underwent full mouth periodontal examinations measuring probing depth (PD) and bleeding on probing (BOP) on 6 sites per tooth by one of five auxiliary nurse midwives, who were trained for this study but had no previous training in dentistry. After a 15-min break, each participant was examined again by an experienced dentist. Measures of validity for PD and BOP were calculated comparing the pooled and individual auxiliary nurse midwives to the dentist. A multivariable GEE model estimated the effect of periodontal characteristics on agreement between the auxiliary nurse midwives and the dentist. RESULTS: Participant mean age was 22 years (SD: ±3 years), mean PD was 1.4 mm (SD: 03 mm), and 86% of women had BOP (according to the dentist). Percent agreement, weighted kappa scores, and intraclass correlation coefficients for PD, with an allowance of ±1 mm, exceeded 99%, 0.7, and 0.9, respectively, indicating an acceptable level of agreement. Auxiliary nurse midwives tended to report higher PD scores relative to the dentist, although this over-estimation was small and unlikely to impact population-based estimates of important indicators of oral health status. GEE regression modeling indicated similar agreement for mandible vs. maxilla, left vs. right side, and PD (≤2 mm, > 2 mm), and lower agreement for posterior teeth and lingual and proximal sites. CONCLUSION: Auxiliary nurse midwives were able to accurately conduct periodontal examinations in a rural home setting, suggesting the potential to shift tasks away from highly trained dentists and periodontal examiners in low-resource communities. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01177111 (Nepal Oil Massage Study); registered on August 6th, 2010.

Tooth loss is associated with atherosclerosis and a poorer functional outcome among stroke patients.

OBJECTIVES: The purpose of the study was twofold: (1) to test the hypothesis that tooth loss is independently associated with carotid atherosclerotic burden (CAB) among individuals with ischemic stroke (IS) or transient ischemic attack (TIA) and (2) to test the association between tooth loss and disability following the occurrence of cerebral ischemia. MATERIALS AND METHODS: This observational study included 418 patients with IS or TIA. Tooth loss and the CAB were measured through a head and neck multidetector computed tomography angiography. CAB was analyzed in both common, internal, and external carotid arteries and classified in five levels of vascular occlusion. The modified Rankin Scale (mRS) was used to evaluate the functional outcome at patient discharge. Health records provided information on sociodemographic and medical covariates. The association between CAB and tooth loss, as well as between tooth loss and subtypes of cerebral ischemia were estimated through Poisson regression. Cox regression was carried out to evaluate the association between tooth loss and the mRS, with α = 5%. RESULTS: Mean age was 65.6 ± 13.8 years, with 52.4% males. Multivariate analyses revealed that severe tooth loss (> 23 missing teeth) was independently associated with CAB ≥ 50% (PR = 2.86, 95% CI = 1.19-6.89) and mRS scores (> 2) (HR = 1.97, 95% CI = 1.10-3.75). CONCLUSION: Tooth loss was independently associated with CAB and predicted a poorer functional outcome among IS and TIA patients. CLINICAL RELEVANCE: Clinical assessment of tooth loss may provide important information on risk for CAB and poorer functional outcome among stroke patients.

Demonstrating the Use of Optical Fibres in Biomedical Sensing: A Collaborative Approach for Engagement and Education.

This paper demonstrates how research at the intersection of physics, engineering, biology and medicine can be presented in an interactive and educational way to a non-scientific audience. Interdisciplinary research with a focus on prevalent diseases provides a relatable context that can be used to engage with the public. Respiratory diseases are significant contributors to avoidable morbidity and mortality and have a growing social and economic impact. With the aim of improving lung disease understanding, new techniques in fibre-based optical endomicroscopy have been recently developed. Here, we present a novel engagement activity that resembles a bench-to-bedside pathway. The activity comprises an inexpensive educational tool (<$70) adapted from a clinical optical endomicroscopy system and tutorials that cover state-of-the-art research. The activity was co-created by high school science teachers and researchers in a collaborative way that can be implemented into any engagement development process.

Survival of dental implants at sites after implant failure: A systematic review.

STATEMENT OF PROBLEM: Despite an overall high survival rate for dental implants, the effectiveness of implant retreatment remains unclear. PURPOSE: The purpose of this systematic review was to examine the survival rate of implants placed at sites which had an implant failure and to investigate factors that might affect outcomes after retreatment. MATERIAL AND METHODS: A search of electronic databases limited to English language articles was conducted using the following MeSH terms: "dental implants," "dental implantation," or "dental restoration failure," combined with "retreatment," "replacement," or "reoperation." A hand search of selected journals was also performed. Of the retrieved 668 publications, 8 retrospective clinical studies met the inclusion criteria, providing the survival outcome for 673 implants in 557 patients after retreatment. Implant- and patient-related characteristics related to implant failures were assessed. RESULTS: The weighted mean survival rate for implants after retreatment was 86.3%, with follow-up ranging from less than 1 year to over 5 years. The survival rates of smooth-surfaced and rough-surfaced implants were compared in 217 retreated implants, revealing a significantly higher survival rate for rough-surfaced implants than for smooth-surfaced implants (90% versus 68.7%). Insufficient data were available to evaluate the effect of patient- or treatment-related characteristics on the survival of implants after retreatment. CONCLUSIONS: The survival rate of retreated implants is lower than that generally reported after initial implant placement. Higher survival rates were reported with rough-surfaced implants than with smooth-surfaced implants in retreatment. An overall implant survival rate of 86.3% after retreatment suggests that most initial implant failures are likely attributable to modifiable risk factors, such as implant architecture, anatomic site, infection, and occlusal overload.

Activity modification in heat: critical assessment of guidelines across athletic, occupational, and military settings in the USA.

Exertional heat illness (EHI) risk is a serious concern among athletes, laborers, and warfighters. US Governing organizations have established various activity modification guidelines (AMGs) and other risk mitigation plans to help ensure the health and safety of their workers. The extent of metabolic heat production and heat gain that ensue from their work are the core reasons for EHI in the aforementioned population. Therefore, the major focus of AMGs in all settings is to modulate the work intensity and duration with additional modification in adjustable extrinsic risk factors (e.g., clothing, equipment) and intrinsic risk factors (e.g., heat acclimatization, fitness, hydration status). Future studies should continue to integrate more physiological (e.g., valid body fluid balance, internal body temperature) and biometeorological factors (e.g., cumulative heat stress) to the existing heat risk assessment models to reduce the assumptions and limitations in them. Future interagency collaboration to advance heat mitigation plans among physically active population is desired to maximize the existing resources and data to facilitate advancement in AMGs for environmental heat.

Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study.

BACKGROUND: Gene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients. METHODS: This multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion status; had a Karnofsky (≥16 years of age) or Lansky (<16 years of age) performance status score of 50 or more, adequate organ function, and full recovery from the acute toxic effects of all previous anticancer therapy. Following a protocol amendment on Sept 12, 2016, patients with locally advanced infantile fibrosarcoma who would require disfiguring surgery to achieve a complete surgical resection were also eligible. Patients were enrolled to three dose cohorts according to a rolling six design. Larotrectinib was administered orally (capsule or liquid formulation), twice daily, on a continuous 28-day schedule, in increasing doses adjusted for age and bodyweight. The primary endpoint of the phase 1 dose escalation component was the safety of larotrectinib, including dose-limiting toxicity. All patients who received at least one dose of larotrectinib were included in the safety analyses. Reported here are results of the phase 1 dose escalation cohort. Phase 1 follow-up and phase 2 are ongoing. This trial is registered with ClinicalTrials.gov, number NCT02637687. FINDINGS: Between Dec 21, 2015, and April 13, 2017, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) with a median age of 4·5 years (IQR 1·3-13·3) were enrolled to three dose cohorts: cohorts 1 and 2 were assigned doses on the basis of both age and bodyweight predicted by use of SimCyp modelling to achieve an area under the curve equivalent to the adult doses of 100 mg twice daily (cohort 1) and 150 mg twice daily (cohort 2); and cohort 3 was assigned to receive a dose of 100 mg/m2 twice daily (maximum 100 mg per dose), regardless of age, equating to a maximum of 173% of the recommended adult phase 2 dose. Among enrolled patients harbouring TRK fusion-positive cancers, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. Adverse events were predominantly grade 1 or 2 (occurring in 21 [88%] of 24 patients); the most common larotrectinib-related adverse events of all grades were increased alanine and aspartate aminotransferase (ten [42%] of 24 each), leucopenia (five [21%] of 24), decreased neutrophil count (five [21%] of 24), and vomiting (five [21%] of 24). Grade 3 alanine aminotransferase elevation was the only dose-limiting toxicity and occurred in one patient without a TRK fusion and with progressive disease. No grade 4 or 5 treatment-related adverse events were observed. Two larotrectinib-related serious adverse events were observed: grade 3 nausea and grade 3 ejection fraction decrease during the 28-day follow-up after discontinuing larotrectinib and while on anthracyclines. The maximum tolerated dose was not reached, and 100 mg/m2 (maximum of 100 mg per dose) was established as the recommended phase 2 dose. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response as per Response Evaluation Criteria In Solid Tumors version 1.1; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. INTERPRETATION: The TRK inhibitor larotrectinib was well tolerated in paediatric patients and showed encouraging antitumour activity in all patients with TRK fusion-positive tumours. The recommended phase 2 dose was defined as 100mg/m2 (maximum 100 mg per dose) for infants, children, and adolescents, regardless of age. FUNDING: Loxo Oncology Inc.

The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas.

BACKGROUND: The highly selective oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib has demonstrated significant activity in adult and pediatric TRK fusion cancers. In the current study, the authors describe the clinical course of children with locally advanced TRK fusion sarcoma who were treated preoperatively with larotrectinib and underwent subsequent surgical resection. METHODS: A total of 24 children were treated on a pediatric phase 1 trial of larotrectinib (ClinicalTrials.gov identifier NCT02637687). Five children who had a documented TRK fusion sarcoma and underwent surgical resection were included in the current analysis. Tumor response (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1) and surgical outcomes were collected prospectively. RESULTS: A total of 5 patients (median age, 2 years; range, 0.4-12 years) had locally advanced infantile fibrosarcoma (3 patients) or soft-tissue sarcoma (2 patients). Four patients had disease that was refractory to standard therapy. All 5 patients achieved a partial response to larotrectinib by version 1.1 of RECIST and underwent surgical resection after a median of 6 cycles (range, 4-9 cycles) of treatment. Surgical resections were R0 (negative resection margins with no tumor at the inked resection margin) in 3 patients, R1 (microscopic residual tumor at the resection margin) in 1 patient, and R2 (macroscopic residual tumor at the resection margin) in 1 patient. Three patients achieved complete (2 patients) or near-complete (>98% treatment effect; 1 patient) pathologic responses. These patients remained in follow-up and were no longer receiving larotrectinib for a minimum of 7 to 15 months postoperatively. Two patients had viable tumor at the time of surgical resection and positive resection margins and continued to receive adjuvant larotrectinib. No patients experienced postoperative complications or wound healing issues. CONCLUSIONS: Children with locally advanced TRK fusion sarcomas may proceed to surgical resection after treatment with the selective TRK inhibitor larotrectinib, thereby sparing them the potentially significant morbidity noted with current approaches. These results support the evaluation of larotrectinib as presurgical therapy in children with newly diagnosed TRK fusion sarcomas.

Brief Report: Potent clinical and radiological response to larotrectinib in TRK fusion-driven high-grade glioma.

Genes encoding TRK are oncogenic drivers in multiple tumour types including infantile fibrosarcoma, papillary thyroid cancer and high-grade gliomas (HGG). TRK fusions have a critical role in tumourigenesis in 40% of infant HGG. Here we report the first case of a TRK fusion-driven HGG treated with larotrectinib-the first selective pan-TRK inhibitor in clinical development. This 3-year-old girl had failed multiple therapies including chemotherapy and radiotherapy. Tumour profiling confirmed an ETV6-NTRK3 fusion. Treatment with larotrectinib led to rapid clinical improvement with near total resolution of primary and metastatic lesions on MRI imaging. This is the first report of a TRK fusion glioma successfully treated with a TRK inhibitor.

Epidemiology and Costs of Sepsis in the United States-An Analysis Based on Timing of Diagnosis and Severity Level.

OBJECTIVES: To characterize the current burden, outcomes, and costs of managing sepsis patients in U.S. hospitals. DESIGN: A retrospective observational study was conducted using the Premier Healthcare Database, which represents ~20% of U.S. inpatient discharges among private and academic hospitals. Hospital costs were obtained from billing records per the cost accounting method used by each hospital. Descriptive statistics were performed on patient demographics, characteristics, and clinical and economic outcomes for the index hospitalization and 30-day readmissions. SETTING: Sepsis patient hospitalizations, including inpatient, general ward, and ICU (intermediate and/or step-down). PATIENTS: Adults over 18 years old with a hospital discharge diagnosis code of sepsis from January 1, 2010, to September 30, 2016. INTERVENTIONS: None. This was a retrospective observational study of deidentified data. MEASUREMENTS AND MAIN RESULTS: The final study cohort consisted of 2,566,689 sepsis cases, representing patients with a mean age of 65 years (50.8% female). Overall mortality was 12.5% but varied greatly by severity (5.6%, 14.9%, and 34.2%) for sepsis without organ dysfunction, severe sepsis, and septic shock, respectively. Costs followed a similar pattern increasing by severity level: $16,324, $24,638, and $38,298 and varied widely by sepsis present at admission ($18,023) and not present at admission ($51,022). CONCLUSIONS: The highest burden of incidence and total costs occurred in the lowest severity sepsis cohort population. Sepsis cases not diagnosed until after admission, and those with increasing severity had a higher economic burden and mortality on a case-by-case basis. Methods to improve early identification of sepsis may provide opportunities for reducing the severity and economic burden of sepsis in the United States.

Using ricelands to provide temporary shorebird habitat during migration.

To help mitigate large wetland losses in California, The Nature Conservancy launched a dynamic conservation incentive program to create temporary wetland habitats in harvested and fallow rice fields for shorebirds migrating along the Pacific Flyway. Farmers were invited to participate in a reverse auction bidding process and winning bids were selected based on their cost and potential to provide high quality shorebird habitat. This was done in 2014 and 2015, for separate enrollment periods that overlapped with spring and fall migration, both before and after the traditional post-harvest flooding period. To assess the success of the program, we monitored shorebird use of fields that were enrolled (treatments), and others that were subject to typical rice farm management (controls). To put these observations in context, we used satellites to simultaneously monitor the extent of shallow-water habitat across the ~215,000 ha of ricelands in the area. Results showed that providing habitat during migration, when it is typically unavailable in rice fields, yielded the largest average shorebird densities ever reported for agriculture in the region. Treatment fields had significantly greater shorebird density, richness and diversity than control fields in both spring and fall (especially September-early October, and late March-early April), but in fall the difference was greater. Shorebird responses to habitat provisioning, and regional habitat conditions, were variable from year to year, and highly dynamic within a given season. Overall, shorebirds densities were found to be negatively related to the total amount of flooded habitat in the rice landscape. Factors that affected habitat availability included allocation schedules of water deliveries from reservoirs, and rainfall patterns, both of which were influenced by drought. Collectively, these results suggest that appropriately managed agricultural lands have great potential to provide high value habitat for shorebirds during times of habitat deficit, including migration, and that fall may be a particularly impactful time to create additional habitat. Migratory species face great challenges due to the climate change, conversion of historical stopover sites, and other factors, but dynamic conservation programs offer promise that, at least in certain instances, their needs can still be met.

Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma.

Mesoblastic nephroma is the most frequent renal tumor in newborns and young infants, and the cellular type is characterized by an ETV6-NTRK fusion, which constitutively activates the tropomyosin-related kinase (TRK) signaling pathway. Larotrectinib is a highly selective TRK inhibitor with activity in adult and pediatric patients who have TRK fusions. We present a rare case of a patient with mesoblastic nephroma metastatic to bone who had a dramatic response to larotrectinib.

Periodontal manifestations of systemic diseases and developmental and acquired conditions: Consensus report of workgroup 3 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions.

BACKGROUND: A variety of systemic diseases and conditions can affect the course of periodontitis or have a negative impact on the periodontal attachment apparatus. Gingival recessions are highly prevalent and often associated with hypersensitivity, the development of caries and non-carious cervical lesions on the exposed root surface and impaired esthetics. Occlusal forces can result in injury of teeth and periodontal attachment apparatus. Several developmental or acquired conditions associated with teeth or prostheses may predispose to diseases of the periodontium. The aim of this working group was to review and update the 1999 classification with regard to these diseases and conditions, and to develop case definitions and diagnostic considerations. METHODS: Discussions were informed by four reviews on 1) periodontal manifestions of systemic diseases and conditions; 2) mucogingival conditions around natural teeth; 3) traumatic occlusal forces and occlusal trauma; and 4) dental prostheses and tooth related factors. This consensus report is based on the results of these reviews and on expert opinion of the participants. RESULTS: Key findings included the following: 1) there are mainly rare systemic conditions (such as Papillon-Lefevre Syndrome, leucocyte adhesion deficiency, and others) with a major effect on the course of periodontitis and more common conditions (such as diabetes mellitus) with variable effects, as well as conditions affecting the periodontal apparatus independently of dental plaque biofilm-induced inflammation (such as neoplastic diseases); 2) diabetes-associated periodontitis should not be regarded as a distinct diagnosis, but diabetes should be recognized as an important modifying factor and included in a clinical diagnosis of periodontitis as a descriptor; 3) likewise, tobacco smoking - now considered a dependence to nicotine and a chronic relapsing medical disorder with major adverse effects on the periodontal supporting tissues - is an important modifier to be included in a clinical diagnosis of periodontitis as a descriptor; 4) the importance of the gingival phenotype, encompassing gingival thickness and width in the context of mucogingival conditions, is recognized and a novel classification for gingival recessions is introduced; 5) there is no evidence that traumatic occlusal forces lead to periodontal attachment loss, non-carious cervical lesions, or gingival recessions; 6) traumatic occlusal forces lead to adaptive mobility in teeth with normal support, whereas they lead to progressive mobility in teeth with reduced support, usually requiring splinting; 7) the term biologic width is replaced by supracrestal tissue attachment consisting of junctional epithelium and supracrestal connective tissue; 8) infringement of restorative margins within the supracrestal connective tissue attachment is associated with inflammation and/or loss of periodontal supporting tissue. However, it is not evident whether the negative effects on the periodontium are caused by dental plaque biofilm, trauma, toxicity of dental materials or a combination of these factors; 9) tooth anatomical factors are related to dental plaque biofilm-induced gingival inflammation and loss of periodontal supporting tissues. CONCLUSION: An updated classification of the periodontal manifestations and conditions affecting the course of periodontitis and the periodontal attachment apparatus, as well as of developmental and acquired conditions, is introduced. Case definitions and diagnostic considerations are also presented.

Gold nanoparticles in injectable calcium phosphate cement enhance osteogenic differentiation of human dental pulp stem cells.

In this study, a novel calcium phosphate cement containing gold nanoparticles (GNP-CPC) was developed. Its osteogenic induction ability on human dental pulp stem cells (hDPSCs) was investigated for the first time. The incorporation of GNPs improved hDPSCs behavior on CPC, including better cell adhesion (about 2-fold increase in cell spreading) and proliferation, and enhanced osteogenic differentiation (about 2-3-fold increase at 14 days). GNPs endow CPC with micro-nano-structure, thus improving surface properties for cell adhesion and subsequent behaviors. In addition, GNPs released from GNP-CPC were internalized by hDPSCs, as verified by transmission electron microscopy (TEM), thus enhancing cell functions. The culture media containing GNPs enhanced the cellular activities of hDPSCs. This result was consistent with and supported the osteogenic induction results of GNP-CPC. In conclusion, GNP-CPC significantly enhanced the osteogenic functions of hDPSCs. GNPs are promising to modify CPC with nanotopography and work as bioactive additives thus enhance bone regeneration.